TREA

MADCAM TARGETED THERAPEUTICS AND USES THEREOF

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Information

  • Patent Application
  • 20240010722
  • Publication Number
    20240010722
  • Date Filed
    November 18, 2021
    3 years ago
  • Date Published
    January 11, 2024
    11 months ago
Information
Abstract
Methods and compounds for conferring site-specific or local immune privilege, such as targeting to a cell expressing MAdCAM.
Description
SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Nov. 18, 2021, is named 145256_001602_SL.txt and is 1,095,063 bytes in size.


FIELD

The embodiments provided herein relate to, for example, methods and compositions for local or targeted immune-privilege.


BACKGROUND

Instances of unwanted immune responses, e.g., as in the rejection of transplanted tissue or in autoimmune disorders, constitute a major health problem for millions of people across the world. Long-term outcomes for organ transplantation are frequently characterized by chronic rejection, and eventual failure of the transplanted organ. More than twenty autoimmune disorders are known, affecting essentially every organ of the body, and affecting over fifty million people in North America alone. The broadly active immunosuppressive medications used to combat the pathogenic immune response in both scenarios have serious side effects.


SUMMARY

In some embodiments, antibodies, or antigen binding fragments thereof, that binds to MAdCAM are provided. In some embodiments, antibodies, or antigen binding fragments thereof, comprising a heavy chain variable region and a light chain variable region, wherein:

    • the heavy chain variable region comprises a variable heavy CDR1 (HCDR1) having at least 90% identity to an amino acid sequence of SEQ ID NO: 1499, a variable heavy CDR2 (HCDR2) having at least 90% identity to an amino acid sequence of SEQ ID NO: 1506, and variable heavy CDR3 (HCDR3) having at least 90% identity to an amino acid sequence of SEQ ID NO: 1507, 1531 or 1532; and
    • the light chain variable region comprises a variable light CDR1 (LCDR1) having at least 90% identity to an amino acid sequence of SEQ ID NO: 1502, a variable light CDR2 (LCDR2) having at least 90% identity to an amino acid sequence of SEQ ID NO: 1497, and a variable light CDR3 (LCDR3) having at least 90% identity to an amino acid sequence of SEQ ID NO: 1498, are provided.


In some embodiments, antibodies, or antigen binding fragments thereof are provided, wherein the antibody comprises: a light chain variable region comprising an amino acid sequence having at least 90% identity to an amino acid sequence selected from SEQ ID NOs: 592, 663, 667, 669, 670, 671, 673, 674, 675, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 689, 690, 692, 694, 696, 698, 700, 702, 704, 706, 708, 710, 713, 715, 717, 719, 721, 723, 725, 727, 729, 731, 733, 735, 737, 739, 741, 743, 745, 747, 749, 751, 753, 755, 757, 759, 761, 763, 765, 768, 770, 772, 774, 776, 778, 780, 782, 784, 786, 788, 790, 792, 794, 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832, 834, 836, 838, 840, 841, 843, 845, 847, 848, 850, 852, 853, 855, 857, 859, 861, 863, 864, 866, 868, 870, 872, 874, 875, 876, 878, 882, 1360, 1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1374, 1375, 1376, 1380, 1381, 1382, 1383, 1384, 1385, 1386, 1464, 1465, 1466, 1467, 1535, 1536, 1537, or 1543; and the variable heavy chain comprising an amino acid sequence having at least 90% identity to an amino acid sequence selected from SEQ ID NOs: 591, 662, 664, 665, 666, 668, 672, 676, 688, 691, 693, 695, 697, 699, 701, 703, 705, 707, 709, 711, 712, 714, 716, 718, 720, 722, 724, 726, 728, 730, 732, 734, 736, 738, 740, 742, 744, 746, 748, 750, 752, 754, 756, 758, 760, 762, 764, 767, 769, 771, 773, 775, 777, 779, 781, 783, 785, 787, 789, 791, 793, 795, 797, 799, 801, 803, 805, 807, 809, 811, 813, 815, 817, 819, 821, 823, 825, 827, 829, 831, 833, 835, 837, 839, 841, 842, 844, 846, 849, 851, 854, 856, 858, 860, 862, 865, 867, 869, 871, 873, 877, 879, 880, 881, 1346, 1347, 1348, 1349, 1350, 1351, 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1377, 1378, 1379, 1387, 1388, 1389, 1390, 1391, 1392, 1393, 1394, 1395, 1396, 1397, 1398, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1450, 1451, 1452, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1469, 1470, 1471, 1472, 1473, 1474, 1475, 1477, 1480, 1533, 1534, 1542, 1544, or 1545.


In some embodiments, pharmaceutical compositions comprising the antibody, or antigen binding fragment thereof, as provided herein, and a pharmaceutically acceptable carrier are provided.


In some embodiments, methods of treating a subject with inflammatory bowel disease are provided. In some embodiments, the method comprises administering a polypeptide or antibody as provided herein, or a pharmaceutical composition comprising the same, to the subject to treat the inflammatory bowel disease.


In some embodiments, methods of treating a subject with an auto-immune hepatitis, a primary sclerosing cholangitis, a Type 1 diabetes, a transplant, a GVHD, an elevated risk, or at risk, for having, an autoimmune disorder are provided. In some embodiments, the method comprises administering a polypeptide or antibody as provided herein, or a pharmaceutical composition comprising the same, to the subject to treat the auto-immune hepatitis, the primary sclerosing cholangitis, the Type 1 diabetes, the transplant, the GVHD, the elevated risk, or at risk, for having, an autoimmune disorder.





BRIEF DESCRIPTION OF THE DRAWINGS


FIG. 1 depicts non-limiting embodiments of the therapeutic compounds provided herein.



FIG. 2 depicts a non-limiting illustration of how a therapeutic compound provided herein could function.



FIG. 3 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 3A depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 4 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 5 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 6 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 7 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 8 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 9 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 10 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 11 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 12 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 13 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 14 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 15 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 16 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 17 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 18 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIG. 19 depicts a non-limiting illustration of the therapeutic compounds provided herein.



FIGS. 20A and 20B depict localization of antibodies in the gut 4 weeks following SC administration.





DETAILED DESCRIPTION

This application incorporates by reference each of the following in its entirety: U.S. Provisional Application No. 63/115,243 filed Nov. 18, 2020, U.S. Provisional Application No. 63/115,235 filed Nov. 18, 2020, PCT Application No. PCT/US2020/046920 filed Aug. 19, 2020, U.S. Non-Provisional application Ser. No. 16/997,238 filed Aug. 19, 2020, PCT Application No. PCT/US2020/033707 filed May 20, 2020, and U.S. Provisional Application No. 62/850,172, filed May 20, 2019, U.S. application Ser. No. 15/922,592 filed Mar. 15, 2018 and PCT Application No. PCT/US2018/022675, filed Mar. 15, 2018. This application also incorporate by reference, each of the following in their entirety: U.S. Provisional Application No. 62/721,644, filed Aug. 23, 2018, U.S. provisional Application No. 62/675,972 filed May 24, 2018, U.S. provisional Application No. 62/595,357 filed Dec. 6, 2017, U.S. Provisional Application No. 62/595,348, filed Dec. 6, 2017, U.S. Non-Provisional application Ser. No. 16/109,875, filed Aug. 23, 2018, U.S. Non-Provisional application Ser. No. 16/109,897, filed Aug. 23, 2018, U.S. Non-Provisional application Ser. No. 15/988,311, filed May 24, 2018, PCT Application No. PCT/US2018/034334, filed May 24, 2018, and, PCT/US2018/062780, filed Nov. 28, 2018.


As used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise.


As used herein, the term “about” means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, “about” means the numerical value can vary by ±5% and remain within the scope of the disclosed embodiments. Thus, about 100 means 95 to 105.


As used herein, the term “animal” includes, but is not limited to, humans and non-human vertebrates such as wild, domestic, and farm animals.


As used herein, the term “contacting” means bringing together of two elements in an in vitro system or an in vivo system. For example, “contacting” a therapeutic compound with an individual or patient or cell includes the administration of the compound to an individual or patient, such as a human, as well as, for example, introducing a compound into a sample containing a cellular or purified preparation containing target.


As used herein, the terms “comprising” (and any form of comprising, such as “comprise”, “comprises”, and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. Any composition or method that recites the term “comprising” should also be understood to also describe such compositions as consisting, consisting of, or consisting essentially of the recited components or elements.


As used herein, the term “fused” or “linked” when used in reference to a protein having different domains or heterologous sequences means that the protein domains are part of the same peptide chain that are connected to one another with either peptide bonds or other covalent bonding. The domains or section can be linked or fused directly to one another or another domain or peptide sequence can be between the two domains or sequences and such sequences would still be considered to be fused or linked to one another. In some embodiments, the various domains or proteins provided for herein are linked or fused directly to one another or via a linker sequence, such as the glycine/serine sequences described herein to link the two domains together. Two peptide sequences are linked directly if they are directly connected to one another or indirectly if there is a linker or other structure that links the two regions. A linker can be directly linked to two different peptide sequences or domains.


As used herein, the term “individual,” “subject,” or “patient,” used interchangeably, means any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, such as humans. Subject, as that term is used herein, refers to a mammalian subject, e.g., a human subject. In some embodiments, the subject is a non-human mammal, e.g., a horse, dog, cat, cow, goat, or pig.


As used herein, the term “inhibit” refers to a result, symptom, or activity being reduced as compared to the activity or result in the absence of the compound that is inhibiting the result, symptom, or activity. In some embodiments, the result, symptom, or activity, is inhibited by about, or, at least, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%. An result, symptom, or activity can also be inhibited if it is completely elimination or extinguished.


As used herein, the phrase “in need thereof” means that the subject has been identified as having a need for the particular method or treatment. In some embodiments, the identification can be by any means of diagnosis. In any of the methods and treatments described herein, the subject can be in need thereof. In some embodiments, the subject is in an environment or will be traveling to an environment in which a particular disease, disorder, or condition is prevalent.


As used herein, the phrase “integer from X to Y” means any integer that includes the endpoints. For example, the phrase “integer from 1 to 5” means 1, 2, 3, 4, or 5.


As used herein, the term “mammal” means a rodent (i.e., a mouse, a rat, or a guinea pig), a monkey, a cat, a dog, a cow, a horse, a pig, or a human. In some embodiments, the mammal is a human.


In some embodiments, therapeutic compounds are provided herein. In some embodiments, the therapeutic compound is a protein or a polypeptide, that has multiple peptide chains that interact with one another. The polypeptides can interact with one another through non-covalent interactions or covalent interactions, such as through disulfide bonds or other covalent bonds. Therefore, if an embodiment refers to a therapeutic compound it can also be said to refer to a protein or polypeptide as provided for herein and vice versa as the context dictates.


As used herein, the phrase “ophthalmically acceptable” means having no persistent detrimental effect on the treated eye or the functioning thereof, or on the general health of the subject being treated. However, it will be recognized that transient effects such as minor irritation or a “stinging” sensation are common with topical ophthalmic administration of drugs and the existence of such transient effects is not inconsistent with the composition, formulation, or ingredient (e.g., excipient) in question being “ophthalmically acceptable” as herein defined. In some embodiments, the pharmaceutical compositions can be ophthalmically acceptable or suitable for ophthalmic administration.


“Specific binding” or “specifically binds to” or is “specific for” a particular antigen, target, or an epitope means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.


Specific binding for a particular antigen, target, or an epitope can be exhibited, for example, by an antibody having a KD for an antigen or epitope of at least about 10−4 M, at least about 10−5 M, at least about 10−6 M, at least about 10−7 M, at least about 10−8 M, at least about 10−9 M, alternatively at least about 10−10 M at least about 10−11 M at least about 10−12 M, or greater, where KD refers to a dissociation rate of a particular antibody-target interaction. Typically, an antibody that specifically binds an antigen or target will have a K D that is, or at least, 2-, 4-, 5-, 10-, 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000-, or more times greater for a control molecule relative to the antigen or epitope.


In some embodiments, specific binding for a particular antigen, target, or an epitope can be exhibited, for example, by an antibody having a KA or Ka for a target, antigen, or epitope of at least 2-, 4-, 5-, 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for the target, antigen, or epitope relative to a control, where KA or Ka refers to an association rate of a particular antibody-antigen interaction.


As provided herein, the therapeutic compounds and compositions can be used in methods of treatment as provided herein. As used herein, the terms “treat,” “treated,” or “treating” mean both therapeutic treatment and prophylactic measures wherein the object is to slow down (lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results. For purposes of these embodiments, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e., not worsening) state of condition, disorder or disease; delay in onset or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Thus, “treatment of an auto-immune disease/disorder” means an activity that alleviates or ameliorates any of the primary phenomena or secondary symptoms associated with the auto-immune disease/disorder or other condition described herein. The various disease or conditions are provided herein. The therapeutic treatment can also be administered prophylactically to preventing or reduce the disease or condition before the onset.


PD-1 Agonists

Provided herein are therapeutic compounds, e.g., therapeutic protein molecules, e.g., fusion proteins, including a targeting moiety and an effector binding/modulating moiety, typically as separate domains. Also provided are methods of using and making the therapeutic compounds. The targeting moiety serves to localize the therapeutic compound, and thus the effector binding/modulating moiety, to a site at which immune-privilege is desired. As used herein, “immune privilege” means lack of, or suppression of an inflammatory response. As a non-limiting example, immune privilege includes situations where a tissue or site in the body is able to tolerate the introduction of antigens without eliciting an inflammatory immune response (Forester J. V., Lambe H. Xu, Cornall R. Immune Privilege or privileged immunity? Mucosal Immunology, 1, 372-381 (2008)).


The effector binding/modulating moiety comprises one or more of: (a) an immune cell inhibitory molecule binding/modulating moiety (an ICIM binding/modulating moiety): (b) an immunosuppressive immune cell binding/modulating moiety (an IIC binding/modulating moiety); (c) a soluble molecule binding/modulating moiety (a SM binding/modulating moiety) or (d) a molecule that blocks or inhibits immune cell stimulatory molecule binding/modulating moiety (referred to herein as an ICSM binding/modulating moiety). In some embodiments, the ICSM inhibits immune activation by, for example, blocking the interaction between a costimulatory molecule and its counter structure. In some embodiments, a therapeutic compound comprises: (a) and (b); (a) and (c); (a) and (d); (b) and (c); (b) and (d); (c) and (d); or (a), (b), (c), and (d).


The present disclosure provides, for example, molecules that can act as PD-1 agonists. Without being bound to any particular theory, agonism of PD-1 inhibits T cell activation/signaling and can be accomplished by different mechanisms. For example crosslinking of bead-bound functional PD-1 agonists can lead to agonism. Functional PD-1 agonists have been described (Akkaya. Ph.D. Thesis: Modulation of the PD-1 pathway by inhibitory antibody superagonists. Christ Church College, Oxford, UK, 2012), which is hereby incorporated by reference. Crosslinking of PD-1 with two mAbs that bind non-overlapping epitopes induces PD-1 signaling (Davis, US 2011/0171220), which is hereby incorporated by reference. Another example is illustrated through the use of a goat anti-PD-1 antiserum (e.g. AF1086, R&D Systems) which is hereby incorporated by reference, which acts as an agonist when soluble (Said et al., 2010, Nat Med) which is hereby incorporated by reference. Non-limiting examples of PD-1 agonists that can be used in the present embodiments include, but are not limited to, UCB clone 19 or clone 10, PD1AB-1, PD1AB-2, PD1AB-3, PD1AB-4 and PD1AB-5, PD1AB-6 (Anaptys/Celgene), PD1-17, PD1-28, PD1-33 and PD1-35 (Collins et al, US 2008/0311117 A1 Antibodies against PD-1 and uses therefor, which is incorporated by reference), or can be a bi-specific, monovalent anti-PD-1/anti-CD3 (Ono), and the like. In some embodiments, the PD-1 agonist antibodies can be antibodies that block binding of PD-L1 to PD-1. In some embodiments, the PD-1 agonist antibodies can be antibodies that do not block binding of PD-L1 to PD-1.


PD-1 agonism can be measured by any method, such as the methods described in the examples. For example, cells can be constructed that express, including stably express, constructs that include a human PD-1 polypeptide fused to a b-galactosidase “Enzyme donor” and 2) a SHP-2 polypeptide fused to a b-galactosidase “Enzyme acceptor.” Without being bound by any theory, when PD-1 is engaged, SHP-2 is recruited to PD-1. The enzyme acceptor and enzyme donor form a fully active b-galactosidase enzyme that can be assayed. Although, the assay does not directly show PD-1 agonism, but shows activation of PD-1 signaling. PD-1 agonism can also be measured by measuring inhibition of T cell activation because, without being bound to any theory, PD-1 agonism inhibits anti-CD3-induced T cell activation. For example, PD-1 agonism can be measured by preactivating T cells with PHA (for human T cells) or ConA (for mouse T cells) so that they express PD-1. The cells can then be reactivated with anti-CD3 in the presence of anti-PD-1 (or PD-L1) for the PD-1 agonism assay. T cells that receive a PD-1 agonist signal in the presence of anti-CD3 will show decreased activation, relative to anti-CD3 stimulation alone. Activation can be readout by proliferation or cytokine production (IL-2, IFNg, IL-17) or other markers, such as CD69 activation marker. Thus, PD-1 agonism can be measured by either cytokine production or cell proliferation. Other methods can also be used to measure PD-1 agonism.


PD-1 is Ig superfamily member expressed on activated T cells and other immune cells. The natural ligands for PD-1 appear to be PD-L1 and PD-L2. Without being bound to any particular theory, when PD-L1 or PD-L2 bind to PD-1 on an activated T cell, an inhibitory signaling cascade is initiated, resulting in attenuation of the activated T effector cell function. Thus, blocking the interaction between PD-1 on a T cell, and PD-L1/2 on another cell (for example, a tumor cell) with a PD-1 antagonist is known as checkpoint inhibition, and releases the T cells from inhibition. In contrast, PD-1 agonist antibodies can bind to PD-1 and send an inhibitory signal and attenuate the function of a T cell. Thus, PD-1 agonist antibodies can be incorporated into various embodiments described herein as an effector molecule binding/modulating moiety (sometimes also referred to herein as an effector molecule), which can accomplish localized tissue-specific immunomodulation when paired with a targeting moiety.


The effector molecule binding/modulating moiety can provide an immunosuppressive signal or environment in a variety of ways. In some embodiments, the effector binding/modulating moiety comprises an ICIM binding/modulating moiety that directly binds and (under the appropriate conditions as described herein) activates an inhibitory receptor expressed by immune cells responsible for driving disease pathology. In another embodiment the effector binding/modulating moiety comprises and IIC binding/modulating moiety and binds and accumulates immunosuppressive immune cells. In some embodiments, the accumulated immune suppressive cells promote immune privilege. In another embodiment the effector binding/modulating moiety comprises an SM binding/modulating moiety which manipulates the surrounding microenvironment to make it less permissible for the function of immune cells, e.g., immune cells driving disease pathology. In some embodiments, the SM binding/modulating moiety depletes an entity that promotes immune attack or activation. In some embodiments the effector binding/modulating moiety comprises an ICSM binding/modulating moiety that binds a member of a pair of stimulatory molecules, e.g., costimulatory molecules, and inhibits the interaction between the costimulatory molecule and the costimulatory molecule counter structure, such as, but not limited to, OX40 or CD30 or CD40 and OX40L, or CD30L or CD40L and inhibits the immune stimulation of a cell, such as, but not limited to, a T cell, B cell, NK cell, or other immune cell comprising a member of the pair.


The targeting moiety and effector binding/modulating moiety are physically tethered, covalently or non-covalently, directly or through a linker entity, to one another, e.g., as a member of the same protein molecule in a therapeutic protein molecule. In some embodiments, the targeting and effector moieties are provided in a therapeutic protein molecule, e.g., a fusion protein, typically as separate domains. In some embodiments, the targeting moiety, the effector binding/modulating moiety, or both each comprises a single domain antibody molecule, e.g., a camelid antibody VHH molecule or human soluble VH domain. It may also contain a single-chain fragment variable (scFv) or a Fab domain. As used herein, the term “Fab” refers to a polypeptide consisting of the VH and CH1 domain of the heavy chain (the “Fab heavy chain”) and the VL and CL domain of the light chain (the “Fab light chain”) of an immunoglobulin. As used herein, the term “scFv” refers to a single-chain polypeptide consisting of the VH domain of the heavy chain (the “scFv heavy chain”) and the VL/VK of the light chain (the “scFv light chain”) of an immunoglobulin. In some embodiments, the therapeutic protein molecule, or a nucleic acid, e.g., an mRNA or DNA, encoding the therapeutic protein molecule, can be administered to a subject. In some embodiments, the targeting and effector molecule binding/modulating moieties are linked to a third entity, e.g., a carrier, e.g., a polymeric carrier, a dendrimer, or a particle, e.g., a nanoparticle. The therapeutic compounds can be used to down regulate an immune response at or in a tissue at a selected target or site while having no or substantially less immunosuppressive function systemically. The target or site can comprise donor tissue or autologous tissue.


Provided herein are methods of providing site-specific immune privilege for a transplanted donor tissue, e.g., an allograft tissue, e.g., a tissue described herein, e.g., an allograft liver, an allograft kidney, an allograft heart, an allograft pancreas, an allograft thymus or thymic tissue, allograft skin, or an allograft lung, with therapeutic compounds disclosed herein. In embodiments the treatment minimizes rejection of, minimizes immune effector cell mediated damage to, prolongs acceptance of, or prolongs the functional life of, donor transplant tissue.


Also provided herein are methods of inhibiting graft versus host disease (GVHD) by minimizing the ability of donor immune cells, e.g., donor T cells, to mediate immune attack of recipient tissue, with therapeutic compounds disclosed herein.


Also provided herein are methods of treating, e.g., therapeutically treating or prophylactically treating (or preventing), an autoimmune disorder or autoimmune response in a subject by administration of a therapeutic compound disclosed herein, e.g., to provide site or tissue specific modulation of the immune system. In some embodiments, the method provides tolerance to, minimization of the rejection of, minimization of immune effector cell mediated damage to, or prolonging a function of, subject tissue. In some embodiments, the therapeutic compound includes a targeting moiety that targets, e.g., specifically targets, the tissue under, or at risk for, autoimmune attack. Non-limiting exemplary tissues include, but are not limited to, the pancreas, myelin, salivary glands, synoviocytes, and myocytes.


In some embodiments, administration of the therapeutic compound begins after the disorder is apparent. In some embodiments, administration of the therapeutic compound begins prior to onset, or full onset, of the disorder. In some embodiments, administration of the therapeutic compound begins prior to onset, or full onset, of the disorder, e.g., in a subject having the disorder, a high-risk subject, a subject having a biomarker for risk or presence of the disorder, a subject having a family history of the disorder, or other indicator of risk of, or asymptomatic presence of, the disorder. For example, in some embodiments, a subject having islet cell damage but which is not yet diabetic, is treated.


While not wishing to be bound by theory, it is believed that the targeting moiety functions to bind and accumulate the therapeutic compound to a target selectively expressed at the anatomical site where immune privilege is desired. In some embodiments, e.g., in the context of donor tissue transplantation, the target moiety binds to a target, e.g., an allelic product, present in the donor tissue but not the recipient. For treatment of autoimmune disorders, the targeting moiety binds a target preferentially expressed at the anatomical site where immune privilege is desired, e.g., in the pancreas. For treatment of GVHD, the targeting moiety targets the host tissue, and protects the host against attack from transplanted immune effector cells derived from transplanted tissue.


Again, while not wishing to be bound by theory it is believed that the effector binding/modulating moiety serves to deliver an immunosuppressive signal or otherwise create an immune privileged environment.


Effector, as that term is used herein, refers to an entity, e.g., a cell or molecule, e.g., a soluble or cell surface molecule, which mediates an immune response.


Effector ligand binding molecule, as used herein, refers to a polypeptide that has sufficient sequence from a naturally occurring counter-ligand of an effector, that it can bind the effector with sufficient specificity that it can serve as an effector binding/modulating molecule. In some embodiments, it binds to effector with at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95% of the affinity of the naturally occurring counter-ligand. In some embodiments, it has at least 60, 80, 90, 95, 99, or 100% sequence identity, or substantial sequence identity, with a naturally occurring counter-ligand for the effector.


Effector specific binding polypeptide, as used herein, refers to a polypeptide that can bind with sufficient specificity that it can serve as an effector binding/modulating moiety. In some embodiments, a specific binding polypeptide comprises a effector ligand binding molecule.


Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which these embodiments belong. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present embodiments, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Headings, sub-headings or numbered or lettered elements, e.g., (a), (b), (i) etc., are presented merely for ease of reading. The use of headings or numbered or lettered elements in this document does not require the steps or elements be performed in alphabetical order or that the steps or elements are necessarily discrete from one another. Other features, objects, and advantages of the embodiments will be apparent from the description and drawings, and from the claims.


Additional Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiments pertains. In describing and claiming the present embodiments, the following terminology and terminology otherwise referenced throughout the present application will be used according to how it is defined, where a definition is provided.


It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.


Antibody molecule, as that term is used herein, refers to a polypeptide, e.g., an immunoglobulin chain or fragment thereof, comprising at least one functional immunoglobulin variable domain sequence. An antibody molecule encompasses antibodies (e.g., full-length antibodies) and antibody fragments. In some embodiments, an antibody molecule comprises an antigen binding or functional fragment of a full length antibody, or a full length immunoglobulin chain. For example, a full-length antibody is an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that is naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes). In embodiments, an antibody molecule refers to an immunologically active, antigen-binding portion of an immunoglobulin molecule, such as an antibody fragment. An antibody fragment, e.g., functional fragment, comprises a portion of an antibody, e.g., Fab, Fab′, F(ab′)2, F(ab)2, variable fragment (Fv), domain antibody (dAb), or single chain variable fragment (scFv). A functional antibody fragment binds to the same antigen as that recognized by the intact (e.g., full-length) antibody. The terms “antibody fragment” or “functional fragment” also include isolated fragments consisting of the variable regions, such as the “Fv” fragments consisting of the variable regions of the heavy and light chains or recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker (“scFv proteins”). In some embodiments, an antibody fragment does not include portions of antibodies without antigen binding activity, such as Fc fragments or single amino acid residues. Exemplary antibody molecules include full length antibodies and antibody fragments, e.g., dAb (domain antibody), single chain, Fab, Fab′, and F(ab′)2 fragments, and single chain variable fragments (scFvs).


Immunoglobulin chains exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. The CDRs from the two chains of each pair are aligned by the framework regions, enabling binding to a specific epitope. From N-terminus to C-terminus, both light and heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The assignment of amino acids to each domain is in accordance with the definitions of Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991)), or Chothia & Lesk J. Mol. Biol. 196:901-917 (1987); Chothia et al. Nature 342:878-883 (1989). In some embodiments, the antibodies provided herein comprise the same FRs and different CDRs. In some embodiments, the antibodies provided herein comprise the same CDRs and different FRs. In some embodiments, mutations in the FR are in the heavy chain. In some embodiments, mutations in the FR are in the FR1 of the heavy chain. In some embodiments, mutations in the FR are in the FR2 of the heavy chain. In some embodiments, mutations in the FR are in the FR3 of the heavy chain. In some embodiments, mutations in the FR are in the FR4 of the heavy chain. In some embodiments, mutations in the FR are in the light chain. In some embodiments, mutations in the FR are in the FR1 of the light chain. In some embodiments, mutations in the FR are in the FR2 of the light chain. In some embodiments, mutations in the FR are in the FR3 of the light chain. In some embodiments, mutations in the FR are in the FR4 of the light chain. In some embodiments, mutations in the FR are in the heavy and light chains. In some embodiments, mutations in the FR are in any one or more of the FRs of the heavy and light chains.


The term “antibody molecule” also encompasses whole or antigen binding fragments of domain, or single domain, antibodies, which can also be referred to as “sdAb” or “VHH.” Domain antibodies comprise either VH or VL that can act as stand-alone, antibody fragments. Additionally, domain antibodies include heavy-chain-only antibodies (HCAbs). Domain antibodies also include a CH2 domain of an IgG as the base scaffold into which CDR loops are grafted. It can also be generally defined as a polypeptide or protein comprising an amino acid sequence that is comprised of four framework regions interrupted by three complementarity determining regions. This is represented as FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. sdAbs can be produced in camelids such as llamas, but can also be synthetically generated using techniques that are well known in the art. The numbering of the amino acid residues of a sdAb or polypeptide is according to the general numbering for VH domains given by Kabat et al. (“Sequence of proteins of immunological interest,” US Public Health Services, NIH Bethesda, MD, Publication No. 91, which is hereby incorporated by reference). According to this numbering, FR1 of a sdAb comprises the amino acid residues at positions 1-30, CDR1 of a sdAb comprises the amino acid residues at positions 31-36, FR2 of a sdAb comprises the amino acids at positions 36-49, CDR2 of a sdAb comprises the amino acid residues at positions 50-65, FR3 of a sdAb comprises the amino acid residues at positions 66-94, CDR3 of a sdAb comprises the amino acid residues at positions 95-102, and FR4 of a sdAb comprises the amino acid residues at positions 103-113. Domain antibodies are also described in WO2004041862 and WO2016065323, each of which is hereby incorporated by reference. The domain antibodies can be a targeting moiety as described herein.


Antibody molecules can be monospecific (e.g., monovalent or bivalent), bispecific (e.g., bivalent, trivalent, tetravalent, pentavalent, or hexavalent), trispecific (e.g., trivalent, tetravalent, pentavalent, hexavalent), or with higher orders of specificity (e.g., tetraspecific) and/or higher orders of valency beyond hexavalency. An antibody molecule can comprise a functional fragment of a light chain variable region and a functional fragment of a heavy chain variable region, or heavy and light chains may be fused together into a single polypeptide.


Examples of formats for multispecific therapeutic compounds, e.g., bispecific antibody molecules are shown in the following non-limiting examples. Although illustrated with antibody molecules, they can be used as platforms for therapeutic molecules that include other non-antibody moieties as specific binding or effector moieties. In some embodiments, these non-limiting examples are based upon either a symmetrical or asymmetrical Fc formats.


For example, the figures illustrate non-limiting and varied symmetric homodimer approach. In some embodiments, the dimerization interface centers around human IgG1 CH2-CH3 domains, which dimerize via a contact interface spanning both CH2/CH2 and CH3/CH3. The resulting bispecific antibodies shown have a total valence comprised of four binding units with two identical binding units at the N-terminus on each side of the dimer and two identical units at the C-terminus on each side of the dimer. In each case the binding units at the N-terminus of the homo-dimer are different from those at the C-terminus of the homo-dimer. Using this type of bivalency for both an inhibitory T cell receptor at either terminus of the molecule and bivalency for a tissue tethering antigen can be achieved at either end of the molecule.


For example, in FIG. 3, a non-limiting embodiment is illustrated. The N-terminus of the homodimer contains two identical Fab domains comprised of two identical light chains, which are separate polypeptides, interfaced with the n-terminal VH—CH1 domains of each heavy chain via the VH/VL interaction and Ckappa or Clambda interaction with CH1. The native disulfide bond between the Ckappa or Clambda with CH1 is present providing a covalent anchor between the light and heavy chains. At the c-terminus of this design are two identical scFv units where by (in this example) the c-terminus of the CH3 domain of the Fc, is followed by a flexible, hydrophilic linker typically comprised of (but not limited to) serine, glycine, alanine, and/or threonine residues, which is followed by the VH domain of each scFv unit, which is followed by a glycine/serine rich linker, followed by a VL domain. These tandem VH and VL domains associate to form a single chain fragment variable (scFv) appended at the c-terminus of the Fc. Two such units exist at the c-terminus of this molecule owing to the homodimeric nature centered at the Fc. The domain order of scFvs may be configured to be from N to C terminus either VH-Linker-VL or VL-Linker-VH.


A non-limiting example of a molecule that has different binding regions on the different ends is where, one end is a PD-1 agonist and the antibody that provides target specificity is an anti-MAdCAM-1 antibody. This can be illustrated as shown, for example, in FIG. 3A, which illustrates the molecules in different orientations.


In some embodiments, the MAdCAM antibody is a blocking or non-blocking antibody as described elsewhere herein. Without being bound to any theory, MAdCAM has been shown to interact with the headpiece of the integrin α4β7 expressed on lymphocytes via multiple residues within its two Ig superfamily I-set domains and the atomic level structural basis for that interaction has been described (Viney J L et al. (1996). J Immunol. 157, 2488-2497; Yu Y et al (2013). J Biol Chem. 288, 6284-6294; Yu Y et al (2012). J Cell Biol. 196, 131-146, each of which is incorporated by reference in its entirety). It has been shown in great structural, mechanistic and functional detail in both the human (Chen J et al (2003). Nat Struct Biol. 10, 995-1001; de Chateau M et al (2001). Biochemistry. 40, 13972-13979) and mouse (Day E S et al (2002). Cell Commun Adhes. 9, 205-219; Hoshino H et al (2011). J Histochem Cytochem. 59, 572-583) molecular systems that any interaction of MAdCAM with α4β7 is dependent on three dication binding sites present in the integrin beta 7 sub unit I-like domain and that these metal binding sites can coordinate with Ca2+, Mn2+, and Mg2+. Using cell adhesion assays, flow cytometry, and/or flow chamber assays in the presence of high levels of Ca2+ with or without Mg2+ or Mn2+, the MAdCAM/α4β7 interaction is shown to be of a lower functional affinity and permits rolling adhesion of lymphocytes, whereas in low Ca2+ but higher Mg2+ or Mn2+ which activates the integrin, the MAdCAM/α4β7 interaction is of a higher functional affinity and mediates firm lymphocyte adhesion (Chen J et al (2003). Nat Struct Biol. 10, 995-1001). A number of groups have shown that various cell:cell, cell:membrane prep, and/or cell:protein based adhesion/interaction assays can be utilized, with FACS, cell flow chamber based counts, or IHC based read-outs to monitor the impact of anti-MAdCAM or anti-α4β7 antibodies upon the interaction of MAdCAM with α4β7, allowing one to identify blocking or non-blocking antibodies (Nakache, M et al (1989). Nature. 337, 179-181; Streeter, P R et al (1988). Nature. 331. 41-46; Yang Y et al (1995). Scand J Immunol. 42. 235-247; Leung E et al (2004). Immunol Cell Biol. 82. 400-409; Pullen N et al (2009). B J Pharmacol. 157. 281-293; Soler D et al (2009). J Pharmacol Exp Ther. 330. 864-875; Qi J et al (2012). J Biol Chem. 287. 15749-15759). This has been exemplified in the mouse system setting with the identification of anti-mouse MAdCAM antibodies such as MECA-89 (non-blocking) and MECA-367 (blocking)) Nakache, M et al (1989). Nature. 337, 179-181; Streeter, P R et al (1988). Nature. 331. 41-46; Yang Y et al (1995). Scand J Immunol. 42. 235-247). In a human system, antibodies have been identified that block the interaction of human MAdCAM with human α4β7 such as anti-human MAdCAM PF-00547659 (Pullen N et al (2009). B J Pharmacol. 157. 281-293) and anti-human α4β7 vedolizumab (Soler D et al (2009). J Pharmacol Exp Ther. 330. 864-875), as well as antibodies that do not block the interaction such as anti-human MAdCAM clone 17F5 (Soler D et al (2009). J Pharmacol Exp Ther. 330. 864-875), and anti-human α4β7 clone J19 (Qi J et al (2012). J Biol Chem. 287. 15749-15759). Thus, the antibody can either be blocking or non-blocking based upon the desired effect. In some embodiments, the antibody is a non-blocking MAdCAM antibody. In some embodiments, the antibody is a blocking MAdCAM antibody. One non-limiting example of demonstrating whether an antibody is blocking or non-blocking can be found throughout the examples, but any method can be used. Each of the references described herein are incorporated by reference in its entirety. In some embodiments, the PD-1 Agonist is replaced with an IL-2 mutein, such as, but not limited to, the ones described herein.


In another example, and as depicted in FIG. 4, the N-terminus of the homodimer contains two identical Fab domains comprised of two identical light chains, which are separate polypeptides, interfaced with the n-terminal VH—CH1 domains of each heavy chain via the VH/VL interaction and Ckappa or Clambda interaction with CH1. The native disulfide bond between the Ckappa or Clambda with CH1 is present providing a covalent anchor between the light and heavy chains. At the c-terminus of this design are two identical VH units (though non-antibody moieties could also be substituted here or at any of the four terminal attachment/fusion points) where by (in this example) the c-terminus of the CH3 domain of the Fc, is followed by a flexible, hydrophilic linker typically comprised of (but not limited to) serine, glycine, alanine, and/or threonine residues, which is followed by a soluble independent VH3 germline family based VH domain. Two such units exist at the c-terminus of this molecule owing to the homodimeric nature centered at the Fc.


In another non-limiting example, as depicted in FIG. 5, the N-terminus of the homodimer contains two identical Fab domains comprised of two identical light chains, which, unlike FIG. 3 and FIG. 4, are physically conjoined with the heavy chain at the N-terminus via a linker between the c-terminus of Ckappa or Clambda and the N-terminus of the VH. The linker may be 36-80 amino acids in length and comprised of serine, glycine, alanine and threonine residues. The physically conjoined n-terminal light chains interface with the n-terminal VH—CH1 domains of each heavy chain via the VH/VL interaction and Ckappa or Clambda interaction with CH1. The native disulfide bond between the Ckappa or Clambda with CH1 is present providing additional stability between the light and heavy chains. At the c-terminus of this design are two identical Fab units where by (in this example) the c-terminus of the CH3 domain of the Fc, is followed by a flexible, hydrophilic linker typically comprised of (but not limited to) serine, glycine, alanine, and/or threonine residues, which is followed by a CH1 domain, followed by a VH domain at the c-terminus. The light chain that is designed to pair with the c-terminal CH1/VH domains is expressed as a separate polypeptide, unlike the N-terminal light chain which is conjoined to the n-terminal VH/CH1 domains as described. The C-terminal light chains form an interface at between VH/VL and Ckappa or Clambda with CH1. The native disulfide anchors this light chain to the heavy chain. Again, any of the antibody moieties at any of the four attachment/fusion points can be substituted with a non-antibody moiety, e.g., a effector binding/modulating moiety that does not comprise an antibody molecule.


The bispecific antibodies can also be asymmetric as shown in the following non-limiting examples. Non-limiting example are also depicted in FIG. 6, FIG. 7, and FIG. 8, which illustrate an asymmetric/heterodimer approach. Again, in any of these formats, any of the antibody moieties at any of the four attachment/fusion points can be substituted with a non-antibody moiety, e.g., a effector binding/modulating moiety that does not comprise an antibody molecule. In some embodiments, the dimerization interface centers around the human IgG1 CH2-CH3 domains, which dimerize via a contact interface spanning both CH2/CH2 and CH3/CH3. However, in order to achieve heterodimerization instead of homodimerization of each heavy chain, mutations are introduced in each CH3 domain. The heterodimerizing mutations include T366W mutation (kabat) in one CH3 domain and T366S, L368A, and Y407V (kabat) mutations in the other CH3 domain. The heterodimerizing interface may be further stabilized with de novo disulfide bonds via mutation of native residues to cysteine residues such as S354 and Y349 on opposite sides of the CH3/CH3 interface. The resulting bispecific antibodies shown have a total valence comprised of four binding units. With this approach, the overall molecule can be designed to have bispecificity at just one terminus and monospecificity at the other terminus (trispecificity overall) or bispecificity at either terminus with an overall molecular specificity of 2 or 4. In the illustrative examples below, the C-terminus comprises two identical binding domains which could, for example, provide bivalent monospecificity for a tissue tethering target. At the N-terminus of all three of the illustrative examples, both binding domains comprise different recognition elements/paratopes and which could achieve recognition of two different epitopes on the same effector moiety target, or could recognize for examples a T cell inhibitory receptor and CD3. In some embodiments, the N-terminal binding moieties may be interchanged with other single polypeptide formats such as scFv, single chain Fab, tandem scFv, VH or VH11 domain antibody configurations for example. Other types of recognition element may be used also, such as linear or cyclic peptides.


An example of an asymmetric molecule is depicted in FIG. 6. Referring to FIG. 6, the N-terminus of the molecule is comprised of a first light chain paired with a first heavy chain via VH/VL and Ckappa or Clambda/CH1 interactions and a covalent tether comprised of the native heavy/light chain disulfide bond. On the opposite side of this heterodimeric molecule at the N-terminus is a second light chain and a second heavy chain which are physically conjoined via a linker between the c-terminus of Ckappa or Clambda and the N-terminus of the VH. The linker may be 36-80 amino acids in length and comprised of serine, glycine, alanine and threonine residues. The physically conjoined n-terminal light chains interface with the n-terminal VH—CH1 domains of each heavy chain via the VH/VL interaction and Ckappa or Clambda interaction with CH1. The native disulfide bond between the Ckappa or Clambda with CH1 is present providing additional stability between the light and heavy chains. At the c-terminus of the molecule are two identical soluble VH3 germline family VH domains joined via an N-terminal glycine/serine/alanine/threonine based linker to the c-terminus of the CH3 domain of both heavy chain 1 and heavy chain 2.


In some embodiments, an asymmetric molecule can be as illustrated as depicted in FIG. 7. For example, the N-terminus of the molecule is comprised of two different VH3 germlined based soluble VH domains linked to the human IgG1 hinge region via a glycine/serine/alanine/threonine based linker. The VH domain connected to the first heavy chain is different to the VH domain connected to the second heavy chain. At the c-terminus of each heavy chain is an additional soluble VH3 germline based VH domain, which is identical on each of the two heavy chains. The heavy chain heterodimerizes via the previously described knobs into holes mutations present at the CH3 interface of the Fc module.


In some embodiments, an asymmetric molecule can be as illustrated in FIG. 8. This example is similar to the molecule shown in FIG. 7, except both N-terminal Fab units are configured in a way that light chain 1 and light chain 2 are physically conjoined with heavy chain 1 and heavy chain 2 via a linker between the c-terminus of Ckappa or Clambda and the N-terminus of each respective VH. The linker in each case may be 36-80 amino acids in length and comprised of serine, glycine, alanine and threonine residues. The physically conjoined n-terminal light chains interface with the n-terminal VH—CH1 domains of each heavy chain via the VH/VL interaction and Ckappa or Clambda interaction with CH1. The native disulfide bond between the Ckappa or Clambda with CH1 is present providing additional stability between the light and heavy chains.


Bi-specific molecules can also have a mixed format. This is illustrated, for example, in FIG. 9, FIG. 10, and FIG. 11. In some embodiments, the bi-specific molecule comprises a Fab moiety and a scFv moiety, for example, as shown in FIG. 3, FIG. 3A, or FIG. 11.


For example, as illustrated in FIG. 9, illustrates a homodimer Fc based approach (see FIGS. 3, 4, and 5), combined with the moiety format selection of FIG. 7, whereby the total molecular valency is four, but specificity is restricted to two specificities. The N-terminus is comprised of two identical soluble VH3 germline based VH domains and the c-terminus is comprised of two identical soluble VH3 germlined based VH domains of different specificity to the N-terminal domains. Therefore, each specificity has a valence of two. Again, in this format, any of the antibody moieties at any of the four attachment/fusion points can be substituted with a non-antibody moiety, e.g., an effector binding/modulating moiety that does not comprise an antibody molecule.



FIG. 10 illustrates another example. In this example, the molecule is comprised of four VH3 germline based soluble VH domains. The first two domains have the same specificity (for example an inhibitory receptor), the 3rd domain from the N-terminus may have specificity for a tissue antigen and the fourth domain from the N-terminus may have specificity for human serum albumin (HSA), thereby granting the molecule extended half-life in the absence of an Ig Fc domain. Three glycine, serine, alanine and/or threonine rich linkers exists between domains 1 and 2, domains 2 and 3, and domains 3 and 4. This format may be configured with up to tetraspecificity, but monovalent in each case, or to have bispecificity with bivalency in each case. The order of domains can be changed. Again, in this format, any of the antibody moieties can be substituted with a non-antibody moiety, e.g., a effector binding/modulating moiety that does not comprise an antibody molecule.



FIG. 11 illustrates yet another approach. This example is similar to FIGS. 3 and 4, in that it is Fc homodimer based with two identical Fab units (bivalent monospecificity) at the N-terminus of the molecule. This example differs in that the C-terminus of each heavy chain is appended with a tandem-scFv. Thus, in each case the c-terminus of the CH3 domain of the Fc is linked via a glycine/serine/alanine/threonine based linker to the N-terminus of a first VH domain, which is linked via the C-terminus by a 12-15 amino acid glycine/serine rich linker to the N-terminus of a first VL domain, which linked via a 25-35 amino acid glycine/serine/alanine/threonine based linker at the c-terminus to the N-terminus of a second VH domain, which is linked via the c-terminus with a 12-15 amino acid glycine/serine based linker to the N-terminus of a 2nd VL domain. In this Fc homodimer based molecule there are therefore two identical tandem scFvs at the c-terminus of the molecule offering either tetravalency for a single tissue antigen for example or bivalency to two different molecules. This format could also be adapted with a heterodimer Fc core allowing two different tandem-scFvs at the c-terminus of the Fc allowing for monovalent tetraspecificity at the c-terminus while retaining either bivalent monospecificity at the N-terminus or monovalent bispecificity at the N-terminal via usage of single chain Fab configurations as in FIGS. 5, 6, and 7. This molecule can therefore be configured to have 2, 3, 4, 5, or 6 specificities. The domain order of scFvs within the tandem—scFv units may be configured to be from N to C terminus either VH-Linker-VL or VL-Linker-VH. Again, in this format, any of the antibody moieties at any of the four attachment/fusion points can be substituted with a non-antibody moiety, e.g., a effector binding/modulating moiety that does not comprise an antibody molecule.


Bi-specific antibodies can also be constructed to have, for example, shorter systemic PK while having increased tissue penetration. These types of antibodies can be based upon, for example, a human VH3 based domain antibody format. These are illustrated, for example, in FIGS. 12, 13, and 14. FIGS. 12, 13, and 14 each comprised a soluble VH3 germline family based VH domain modules. Each domain is approximately 12.5 kDa allowing for a small overall MW, which, without being bound to any particular theory, should be beneficial for enhanced tissue penetration. In these examples, none of the VH domains recognize any half-life extending targets such as FcRn or HSA. As illustrated in FIG. 12, the molecule is comprised of two VH domains joined with a flexible hydrophilic glycine/serine based linker between the C-terminus of the first domain and N-terminus of the second domain. In this example one domain may recognize a T cell co-stimulatory receptor and the second may recognize a tissue tethering antigen. As illustrated in FIG. 13, the molecule is comprised of three VH domains with N—C terminal linkages of hydrophilic glycine/serine based linkers. The molecule may be configured to be trispecific but monovalent for each target. It may be bispecific with bivalency for one target and monovalency for another. As illustrated in FIG. 14, the molecule is comprised of four VH domains with N—C terminal Glycine/Serine rich linkers between each domain. This molecule may be configured to be tetraspecific, trispecific, or bispecific with varying antigenic valencies in each case. Again, in this format, any of the antibody moieties at can be substituted with a non-antibody moiety, e.g., a effector binding/modulating moiety that does not comprise an antibody molecule.


Other embodiments of bi-specific antibodies are illustrated in FIGS. 15 and 16. FIGS. 15 and 16 are comprised of the naturally heterodimerizing core of the human IgG CH1/Ckappa interface, including the c-terminal heavy/light disulfide bond which covalently anchors the interaction. This format does not contain an Fc or any moieties for half-life extension. As illustrated in FIG. 15, the molecule, at the N-terminus of the constant kappa domain is appended with an scFv fragment consisting of an N-terminal VH domain, linked at its C-terminus to the N-terminus of a VL domain via a 12-15 amino acid gly/ser based linker, which is linked by its C-terminus to the N-terminus of the constant kappa domain via the native VL-Ckappa elbow sequence. The CH1 domain is appended at the N-terminus with an scFv fragment consisting of an N-terminal VL domain linked at its c-terminus via a 12-15 amino acid gly/ser linker to the N-terminus of a VH domain, which is linked at its c-terminus to the N-terminus of the CH1 domains via the natural VH—CH1 elbow sequence. As illustrated in FIG. 16, the molecule has the same N-terminal configuration to Example 13. However the C-terminus of the constant kappa and CH1 domains are appended with scFv modules which may be in either the VH-VL or VL-VH configuration and may be either specific for the same antigen or specific for two different antigens. The VH/VL inter-domain linkers may be 12-15 amino acids in length and consisting of gly/ser residues. The scFv binding sub-units may be swapped for soluble VH domains, or peptide recognition elements, or even tandem-scFv elements. This approach can also be configured to use variable lambda and/or constant lambda domains. Again, in this format, any of the antibody moieties at any of the attachment/fusion points can be substituted with a non-antibody moiety, e.g., a effector binding/modulating moiety that does not comprise an antibody molecule.



FIG. 17 illustrates another embodiment. FIG. 17 represents a tandem scFv format consisting of a first N-terminal VL domain linked at its C-terminus to the N-terminus of a first VH domain with a 12-15 amino acid gly/ser rich linker, followed at the first VH c-terminus by a amino acid gly/ser/ala/thr based linker to the N-terminus of a second VL domain. The second VL domain is linked at the C-terminus to the N-terminus of a 2nd VH domain by a 12-15 amino acid gly/ser linker. Each scFv recognizes a different target antigen such as a co-stimulatory T cell molecule and a tissue tethering target. Again, in this format, any of the antibody moieties can be substituted with a non-antibody moiety, e.g., a effector binding/modulating moiety that does not comprise an antibody molecule.



FIG. 18 illustrates another embodiment. FIG. 18 is a F(ab′)2 scFv fusion. This consists of two identical Fab components joined via two disulfide bonds in the native human IgG1 hinge region c-terminal of the human IgG CH1 domain. The human IgG1 CH2 and CH3 domains are absent. At the c-terminus of heavy chains 1 and 2 are two identical scFv fragments linked via a gly/ser/ala/thr rich linker to the c-terminus of the huIgG1 hinge region. In the configuration shown, the VH is N-terminal in each scFv unit and linked via a 12-15 amino acid gly/ser rich linker to the N-terminus of a VL domain. An alternative configuration would be N-term-VL-Linker-VH—C-term. In this design, the construct is bispecific with bivalency for reach target. Again, in this format, any of the antibody moieties at any of the four attachment/fusion points can be substituted with a non-antibody moiety, e.g., a effector binding/modulating moiety that does not comprise an antibody molecule.


CD39 molecule, as that term as used herein, refers to a polypeptide having sufficient CD39 sequence that, as part of a therapeutic compound, it phosphohydrolyzes ATP to AMP. In some embodiments, a CD39 molecule phosphohydrolizes ATP to AMP equivalent to, or at least, 20, 30, 40, 50, 60, 70, 80, 90, or 95% of the rate of a naturally occurring CD39, e.g., the CD39 from which the CD39 molecule was derived. In some embodiments, a CD39 molecule has at least 60, 70, 80, 90, 95, 99, or 100% sequence identity, or substantial sequence identity, with a naturally occurring CD39.


Any functional isoform can be used (with CD39 or other proteins discussed herein). Exemplary CD39 sequence include GenBank accession #NP 001767.3 or a mature form from the following sequence:









(SEQ ID NO: 1)


MEDTKESNVKTFCSKNILAILGESSIIAVIALLAVGLTONKALPENVKYG





IVLDAGSSHTSLYIYKWPAEKENDTGVVHQVEECRVKGPGISKFVQKVNE





IGIYLTDCMERAREVIPRSQHQETPVYLGATAGMRLLRMESEELADRVLD





VVERSLSNYPFDFQGARIITGQEEGAYGWITINYLLGKFSQKTRWFSIVP





YETNNQETFGALDLGGASTQVTFVPQNQTIESPDNALQFRLYGKDYNVYT





HSFLCYGKDQALWQKLAKDIQVASNEILRDPCFHPGYKKVVNVSDLYKTP





CTKRFEMTLPFQQFEIQGIGNYQQCHQSILELFNTSYCPYSQCAFNGIFL





PPLQGDFGAFSAFYFVMKFLNLTSEKVSQEKVTEMMKKFCAQPWEEIKTS





YAGVKEKYLSEYCFSGTYILSLLLQGYHFTADSWEHIHFIGKIQGSDAGW





TLGYMLNLTNMIPAEQPLSTPLSHSTYVFLMVLESLVLFTVAIIGLLIFH





KPSYFWKDMV.






In some embodiments, a CD39 molecule comprises a soluble catalytically active form of CD39 found to circulate in human or murine serum, see, e.g., Metabolism of circulating ADP in the bloodstream is mediated via integrated actions of soluble adenylate kinase-1 and NTPDase1/CD39 activities, Yegutkin et al. FASEB J. 2012 September; 26(9):3875-83. A soluble recombinant CD39 fragment is also described in Inhibition of platelet function by recombinant soluble ecto-ADPase/CD39, Gayle, et al., J Clin Invest. 1998 May 1; 101(9): 1851-1859.


CD73 molecule, as that term as used herein, refers to a polypeptide having sufficient CD73 sequence that, as part of a therapeutic compound, it dephosphorylates extracellular AMP to adenosine. In some embodiments, a CD73 molecule dephosphorylates extracellular AMP to adenosine equivalent to, or at least, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95% of the rate of a naturally occurring CD73, e.g., the CD73 from which the CD73 molecule was derived. In some embodiments, a CD73 molecule has at least 60, 70, 80, 90, 95, 99, or 100% sequence identity, or substantial sequence identity, with a naturally occurring CD73. Exemplary CD73 sequences include GenBank AAH65937.1 5′-nucleotidase, ecto (CD73) [Homo sapiens] or a mature form from the following sequence,









(SEQ ID NO: 2)


MCPRAARAPATLLLALGAVLWPAAGAWELTILHTNDVHSRLEQTSEDSS





KCVNASRCMGGVARLFTKVQQIRRAEPNVLLLDAGDQYQGTIWFTVYKG





AEVAHFMNALRYDAMALGNHEFDNGVEGLIEPLLKEAKFPILSANIKAK





GPLASQISGLYLPYKVLPVGDEVVGIVGYTSKETPFLSNPGTNLVFEDE





ITALQPEVDKLKTLNVNKIIALGHSGFEMDKLIAQKVRGVDVVVGGHSN





TFLYTGNPPSKEVPAGKYPFIVTSDDGRKVPVVQAYAFGKYLGYLKIEF





DERGNVISSHGNPILLNSSIPEDPSIKADINKWRIKLDNYSTQELGKTI





VYLDGSSQSCRFRECNMGNLICDAMINNNLRHADETFWNHVSMCILNGG





GIRSPIDERNNGTITWENLAAVLPFGGTFDLVQLKGSTLKKAFEHSVHR





YGQSTGEFLQVGGIHVVYDLSRKPGDRVVKLDVLCTKCRVPSYDPLKMD





EVYKVILPNFLANGGDGFQMIKDELLRHDSGDQDINVVSTYISKMKVIY





PAVEGRIKFSTGSHCHGSFSLIFLSLWAVIFVLYQ.






In some embodiments, a CD73 molecule comprises a soluble form of CD73 which can be shed from the membrane of endothelial cells by proteolytic cleavage or hydrolysis of the GPI anchor by shear stress see, e.g., Reference: Yegutkin G, Bodin P, Burnstock G. Effect of shear stress on the release of soluble ecto-enzymes ATPase and 5′-nucleotidase along with endogenous ATP from vascular endothelial cells. Br J Pharmacol 2000; 129: 921-6. For CD73 function see Colgan et al., Physiological roles for ecto-5′-nucleotidase (CD73), Purinergic Signalling, June 2006, 2:351.


Cell surface molecule binder, as that term is used herein, refers to a molecule, typically a polypeptide, that binds, e.g., specifically, to a cell surface molecule on a cell, e.g., an immunosuppressive immune cell, e.g., a Treg. In some embodiments, the cell surface binder has sufficient sequence from a naturally occurring ligand of the cell surface molecule, that it can specifically bind the cell surface molecule (a cell surface molecule ligand). In some embodiments, the cell surface binding is an antibody molecule that binds, e.g., specifically binds, the cell surface molecule.


Donor specific targeting moiety, as that term is used herein, refers to a moiety, e.g., an antibody molecule, that as a component of a therapeutic compound, localizes the therapeutic compound preferentially to an implanted donor tissue, as opposed to tissue of a recipient. As a component of a therapeutic compound, the donor specific targeting moiety provides site-specific immune privilege for a transplant tissue, e.g., an organ, from a donor.


In some embodiments, a donor specific targeting moiety it binds to the product, e.g., a polypeptide product, of an allele present at a locus, which allele is not present at the locus in the (recipient) subject. In some embodiments, a donor specific targeting moiety binds to an epitope on product, which epitope is not present in the (recipient) subject.


In some embodiments, a donor specific targeting moiety, as a component of a therapeutic compound, preferentially binds to a donor target or antigen, e.g., has a binding affinity for the donor target that is greater for donor antigen or tissue, e.g., at least 2, 4, 5, 10, 50, 100, 500, 1,000, 5,000, or 10,000 fold greater, than its affinity for than for subject antigen or tissue. In some embodiments, a donor specific targeting moiety, has a binding affinity for a product of an allele of a locus present in donor tissue (but not present in the subject) at least 2, 4, 5, 10, 50, 100, 500, 1,000, 5,000, or 10,000 fold greater, than its affinity for the product of the allele of the locus present in the subject (which allele is not present in donor tissue). Affinity of a therapeutic compound of which the donor specific moiety is a component, can be measured in a cell suspension, e.g., the affinity for suspended cells having the allele is compared with its affinity for suspended cells not having the allele. In some embodiments, the binding affinity for the donor allele cells is below 10 nM. In some embodiments, the binding affinity for the donor allele cells is below 100 pM, 50 pM, or 10 pM.


In some embodiments, the specificity for a product of a donor allele is sufficient that when the donor specific targeting moiety is coupled to an immune-down regulating effector: i) immune attack of the implanted tissue, e.g., as measured by histological inflammatory response, infiltrating T effector cells, or organ function, in the clinical setting—e.g. creatinine for the kidney, is substantially reduced, e.g., as compared to what would be seen in an otherwise similar implant but lacking the donor specific targeting moiety is coupled to an immune-down regulating effector; and/or ii) immune function in the recipient, outside or away from the implanted tissue, is substantially maintained. In some embodiments, one or more of the following is seen: at therapeutic levels of therapeutic compound, peripheral blood lymphocyte counts are not substantially impacted, e.g., the level of T cells is within 25, 50, 75, 85, 90, or 95% of normal, the level of B cells is within 25, 50, 75, 85, 90, or 95% of normal, and/or the level of granulocytes (PMNs) cells is within 25, 50, 75, 85, 90, or 95% of normal, or the level of monocytes is within 25, 50, 75, 85, 90, or 95% of normal; at therapeutic levels of therapeutic compound, the ex vivo proliferative function of PBMCs (peripheral blood mononuclear cells) against non-disease relevant antigens is substantially normal or is within 70, 80, or 90% of normal; at therapeutic levels of therapeutic compound, the incidence or risk of risk of opportunistic infections and cancers associated with immunosuppression is not substantially increased over normal; or at therapeutic levels of therapeutic compound, the incidence or risk of risk of opportunistic infections and cancers associated with immunosuppression is substantially less than would be seen with standard of care, or non-targeted, immunosuppression. In some embodiments, the donor specific targeting moiety comprises an antibody molecule, a target specific binding polypeptide, or a target ligand binding molecule.


Elevated risk, as used herein, refers to the risk of a disorder in a subject, wherein the subject has one or more of a medical history of the disorder or a symptom of the disorder, a biomarker associated with the disorder or a symptom of the disorder, or a family history of the disorder or a symptom of the disorder.


Functional antibody molecule to an effector or inhibitory immune checkpoint molecule, as that term is used herein, refers to an antibody molecule that when present as the ICIM binding/modulating moiety of a multimerized therapeutic compound, can bind and agonize the effector or inhibitory immune checkpoint molecule. In some embodiments, the anti-effector or inhibitory immune checkpoint molecule antibody molecule, when binding as a monomer (or binding when the therapeutic compound is not multimerized), to the effector or inhibitory immune checkpoint molecule, does not antagonize, substantially antagonize, prevent binding, or prevent substantial binding, of an endogenous counter ligand of the inhibitory immune checkpoint molecule to inhibitory immune checkpoint molecule. In some embodiments, the anti-effector or inhibitory immune checkpoint molecule antibody molecule when binding as a monomer (or binding when the therapeutic compound is not multimerized), to the inhibitory immune checkpoint molecule, does not agonize or substantially agonize, the effector or inhibitory molecule.


ICIM binding/modulating moiety, as that term is used herein, refers to an effector binding/modulating moiety that, as part of a therapeutic compound, binds and agonizes a cell surface inhibitory molecule, e.g., an inhibitory immune checkpoint molecule, e.g., PD-1, or binds or modulates cell signaling, e.g., binds a FCRL, e.g., FCRL1-6, or binds and antagonizes a molecule that promotes immune function.


IIC binding/modulating moiety, as that term is used herein, refers to an effector binding/modulating moiety that, as part of a therapeutic compound, binds an immunosuppressive immune cell. In some embodiments, the IIC binding/modulating moiety increases the number or concentration of an immunosuppressive immune cell at the binding site.


ICSM binding/modulating moiety, as that term is used herein, refers to an effector binding/modulating moiety that antagonizes an immune stimulatory effect of a stimulatory, e.g., co-stimulatory, binding pair. A stimulatory or co-stimulatory binding pair, as that term is used herein, comprises two members, 1) a molecule on the surface of an immune cell; and 2) the binding partner for that cell molecule, which may be an additional immune cell, or a non-immune cell. Ordinarily, upon binding of one member to the other, assuming other requirements are met, the member on the immune cell surfaces stimulates the immune cell, e.g., a costimulatory molecule, and an immune response is promoted. In situations where the costimulatory molecule and the costimulatory molecule counter structure are both expressed on immune cells, bi-directional activation of both cells may occur. In an embodiment an ICSM binding/modulating moiety binds and antagonizes the immune cell expressed member of a binding pair. For example, it binds and antagonizes OX40. In another embodiment, an ICSM binding/modulating moiety binds and antagonizes the member of the binding pair that itself binds the immune cell expressed member, e.g., it binds and antagonizes OX40L. In either case, inhibition of stimulation or co-stimulation of an immune cell is achieved. In an embodiment the ICSM binding/modulating moiety decreases the number or the activity of an immunostimulating immune cell at the binding site.


Inhibitory Immune Checkpoint Molecules

An “inhibitory immune checkpoint molecule ligand molecule,” as that term is used herein, refers to a polypeptide having sufficient inhibitory immune checkpoint molecule ligand sequence, e.g., in the case of a PD-L1 molecule, sufficient PD-L1 sequence, that when present as an ICIM binding/modulating moiety of a multimerized therapeutic compound, can bind and agonize its cognate inhibitory immune checkpoint molecule, e.g., again in the case of a PD-L1 molecule, PD-1.


In some embodiments, the inhibitory immune checkpoint molecule ligand molecule, e.g., a PD-L1 molecule, when binding as a monomer (or binding when the therapeutic compound is not multimerized), to its cognate ligand, e.g., PD-1, does not antagonize or substantially antagonize, or prevent binding, or prevent substantial binding, of an endogenous inhibitory immune checkpoint molecule ligand to the inhibitory immune checkpoint molecule. E.g., in the case of a PD-L1 molecule, the PD-L1 molecule does not antagonize binding of endogenous PD-L1 to PD-1.


In some embodiments, the inhibitory immune checkpoint molecule ligand when binding as a monomer, to its cognate inhibitory immune checkpoint molecule does not agonize or substantially agonize the inhibitory immune checkpoint molecule. By way of example, e.g., a PD-L1 molecule when binding to PD-1, does not agonize or substantially agonize PD-1.


In some embodiments, an inhibitory immune checkpoint molecule ligand molecule has at least 60, 70, 80, 90, 95, 99, or 100% sequence identity, or substantial sequence identity, with a naturally occurring inhibitory immune checkpoint molecule ligand.


Exemplary inhibitory immune checkpoint molecule ligand molecules include: a PD-L1 molecule, which binds to inhibitory immune checkpoint molecule PD-1, and in embodiments has at least 60, 70, 80, 90, 95, 99, or 100% sequence identity, or substantial sequence identity, with a naturally occurring PD-L1, e.g., the PD-L1 molecule comprising the sequence of MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWE MEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMI SYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVL SGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNE RTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET (SEQ ID NO: 3), or an active fragment thereof; in some embodiments, the active fragment comprises residues 19 to 290 of the PD-L1 sequence; a HLA-G molecule, which binds to any of inhibitory immune checkpoint molecules KIR2DL4, LILRB1, and LILRB2, and in embodiments has at least 60, 70, 80, 90, 95, 99, or 100% sequence identity, or substantial sequence identity, with a naturally occurring HLA-G. Exemplary HLA-G sequences include, e.g., a mature form found in the sequence at GenBank P17693.1 RecName: Full=HLA class I histocompatibility antigen, alpha chain G; AltName: Full=HLA G antigen; AltName: Full=MHC class I antigen G; Flags: Precursor, or in the sequence









(SEQ ID NO: 4)


MVVMAPRTLFLLLSGALTLTETWAGSHSMRYFSAAVSRPGRGEPRFIAM





GYVDDTQFVRFDSDSACPRMEPRAPWVEQEGPEYWEEETRNTKAHAQTD





RMNLQTLRGYYNQSEASSHTLQWMIGCDLGSDGRLLRGYEQYAYDGKDY





LALNEDLRSWTAADTAAQISKRKCEAANVAEQRRAYLEGTCVEWLHRYL





ENGKEMLQRADPPKTHVTHHPVFDYEATLRCWALGFYPAEIILTWQRDG





EDQTQDVELVETRPAGDGTFQKWAAVVVPSGEEQRYTCHVQHEGLPEPL





MLRWKQSSLPTIPIMGIVA.






Inhibitory molecule counter ligand molecule, as that term is used herein, refers to a polypeptide having sufficient inhibitory molecule counter ligand sequence such that when present as the ICIM binding/modulating moiety of a multimerized therapeutic compound, can bind and agonize a cognate inhibitory molecule. In some embodiments, the inhibitory molecule counter ligand molecule, when binding as a monomer (or binding when the therapeutic compound is not multimerized), to the inhibitory molecule, does not antagonize, substantially antagonize, prevent binding, or prevent substantial binding, of an endogenous counter ligand of the inhibitory molecule to the inhibitory molecule. In some embodiments, the inhibitory molecule counter ligand molecule when binding as a monomer (or binding when the therapeutic compound is not multimerized), to the inhibitory molecule, does not agonize or substantially agonize, the inhibitory molecule.


Exemplary inhibitory molecules (e.g., an inhibitory immune checkpoint molecule) (together with their counter ligands) can be found in Table 1. This table lists molecules to which exemplary ICIM binding moieties can bind.









TABLE 1







Cell surface inhibitory molecules, e.g., inhibitory


immune checkpoint molecules (column A), counter ligands


(column B) and cell types affected (column C).









A
B
C





PD-1
PD-L1, PD-L2
T cells, B cells


Alkaline


phosphatase


B7-H3
Unknown
T cells


B7-H4
Neuropilin 1,
T cells



neuropilin 2,



Plexin4A


BTLA
HVEM
T cells, B cells


CTLA-4
CD80, CD86
T cells


IDO1
Tryptophan
Lymphocytes


TDO2
Tryptophan
Lymphocytes


KIR2DL1,
HLA MHC class I
NK cells


KIR2DL2/3,


KIR3DL1,


KIR3DL2


LAG3
HLA MHC class II
T cells


TIM-3
Galectin-9
T cells


VISTA
Unknown
T cells, myeloid cells


TIGIT
CD155
T cells


KIR2DL4
HLA-G
NK cells


LILRB1
HLA-G
T cells, NK cells, B cells,




monocytes, dendritic cells


LILRB2
HLA-G
Monocytes, dendritic cells,




neutrophils, some tumor cells


NKG2A
nonclassical MHC
T cells, NK cells



glycoproteins class I


FCRL1-6
FCRL1 - 2 not
B cells



known



FCRL4 = IgA



FCRL5 = IgG



FCRL6 = MHC Class



II



BUTYROPHILINS,
Modulation of immune cells



for example



BTN1A1, BTN2A2,



BTNL2, BTNL1,



BTNL8









Sequence identity, percentage identity, and related terms, as those terms are used herein, refer to the relatedness of two sequences, e.g., two nucleic acid sequences or two amino acid or polypeptide sequences. In the context of an amino acid sequence, the term “substantially identical” is used herein to refer to a first amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical to, or ii) conservative substitutions of aligned amino acid residues in a second amino acid sequence such that the first and second amino acid sequences can have a common structural domain and/or common functional activity. For example, amino acid sequences that contain a common structural domain having at least about 85%, 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g., a sequence provided herein.


In the context of nucleotide sequence, the term “substantially identical” is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having common functional activity, or encode a common structural polypeptide domain or a common functional polypeptide activity. For example, nucleotide sequences having at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g., a sequence provided herein.


The term “functional variant” refers to polypeptides that have a substantially identical amino acid sequence to the naturally-occurring sequence, or are encoded by a substantially identical nucleotide sequence, and are capable of having one or more activities of the naturally-occurring sequence.


Calculations of homology or sequence identity between sequences (the terms are used interchangeably herein) are performed as follows.


To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”).


The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.


The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http://www.gcg.com), using a NWSgapdna. CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the one that should be used unless otherwise specified) are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.


The percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.


The nucleic acid and protein sequences described herein can be used as a “query sequence” to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and) (BLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to for example any a nucleic acid sequence provided herein. BLAST protein searches can be performed with the)(BLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to protein molecules provided herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g.,)(BLAST and NBLAST) can be used. See http://www.ncbi.nlm.nih.gov.


As used herein, the term “hybridizes under low stringency, medium stringency, high stringency, or very high stringency conditions” describes conditions for hybridization and washing. Guidance for performing hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6, which is incorporated by reference. Aqueous and nonaqueous methods are described in that reference and either can be used. Specific hybridization conditions referred to herein are as follows: 1) low stringency hybridization conditions in 6× sodium chloride/sodium citrate (SSC) at about 45° C., followed by two washes in 0.2×SSC, 0.1% SDS at least at 50° C. (the temperature of the washes can be increased to 55° C. for low stringency conditions); 2) medium stringency hybridization conditions in 6×SSC at about 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 60° C.; 3) high stringency hybridization conditions in 6×SSC at about 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 65° C.; and preferably 4) very high stringency hybridization conditions are 0.5 M sodium phosphate, 7% SDS at 65° C., followed by one or more washes at SSC, 1% SDS at 65° C. Very high stringency conditions (4) are the preferred conditions and the ones that should be used unless otherwise specified.


It is understood that the molecules and compounds of the present embodiments may have additional conservative or non-essential amino acid substitutions, which do not have a substantial effect on their functions.


The term “amino acid” is intended to embrace all molecules, whether natural or synthetic, which include both an amino functionality and an acid functionality and capable of being included in a polymer of naturally-occurring amino acids. Exemplary amino acids include naturally-occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs having variant side chains; and all stereoisomers of any of any of the foregoing. As used herein the term “amino acid” includes both the D- or L-optical isomers and peptidomimetics. A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). CD39 molecule, a CD73 molecule, a Cell surface molecule binder, Donor specific targeting moiety Effector ligand binding molecule, ICIM binding/modulating moiety IIC binding/modulating moiety, an inhibitory immune checkpoint molecule ligand molecule, Inhibitory molecule counter ligand molecule, SM binding/modulating moiety, or ICSM binding/modulating moiety.


SM binding/modulating moiety, as that term is used herein, refers to an effector binding/modulating moiety that, as part of a therapeutic compound, promotes an immuno-suppressive local microenvironment, e.g., by providing in the proximity of the target, a substance that inhibits or minimizes attack by the immune system of the target. In some embodiments, the SM binding/modulating moiety comprises, or binds, a molecule that inhibits or minimizes attack by the immune system of the target. In some embodiments, a therapeutic compound comprises an SM binding/modulating moiety that binds and accumulates a soluble substance, e.g., an endogenous or exogenous substance, having immunosuppressive function. In some embodiments, a therapeutic compound comprises an SM binding/modulating moiety that binds and inhibits, sequesters, degrades or otherwise neutralizes a substance, e.g., a soluble substance, typically and endogenous soluble substance, that promotes immune attack. In some embodiments, a therapeutic compound comprises an SM binding/modulating moiety that comprises an immune-suppressive substance, e.g. a fragment of protein known to be immunosuppressive. By way of example, an effector molecule binding moiety that binds, or comprises, a substance e.g., a CD39 molecule or a CD73 molecule, that depletes a component, that promotes immune effector cell function, e.g., ATP or AMP.


Specific targeting moiety, as that term is used herein, refers to donor specific targeting moiety or a tissue specific targeting moiety.


Target ligand binding molecule, as used herein, refers to a polypeptide that has sufficient sequence from a naturally occurring counter-ligand of a target ligand that it can bind the target ligand on a target tissue (e.g., donor tissue or subject target tissue) with sufficient specificity that it can serve as a specific targeting moiety. In some embodiments, it binds to target tissue or cells with at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95% of the affinity of the naturally occurring counter-ligand. In some embodiments, it has at least 60, 70, 80, 90, 95, 99, or 100% sequence identity, or substantial sequence identity, with a naturally occurring counter-ligand for the target ligand.


Target site, as that term is used herein, refers to a site which contains the entity, e.g., epitope, bound by a targeting moiety. In some embodiments, the target site is the site at which immune privilege is established.


Tissue specific targeting moiety, as that term is used herein, refers to a moiety, e.g., an antibody molecule, that as a component of a therapeutic molecule, localizes the therapeutic molecule preferentially to a target tissue, as opposed to other tissue of a subject. As a component of a therapeutic compound, the tissue specific targeting moiety provides site-specific immune privilege for a target tissue, e.g., an organ or tissue undergoing or at risk for autoimmune attack. In some embodiments, a tissue specific targeting moiety binds to a product, e.g., a polypeptide product, which is not present outside the target tissue, or is present at sufficiently low levels that, at therapeutic concentrations of therapeutic molecule, unacceptable levels of immune suppression are absent or substantially absent. In some embodiments, a tissue specific targeting moiety binds to an epitope, which epitope is not present outside, or not substantially present outside, the target site.


In some embodiments, a tissue specific targeting moiety, as a component of a therapeutic compound, preferentially binds to a target tissue or target tissue antigen, e.g., has a binding affinity for the target tissue or antigen that is greater for target antigen or tissue, e.g., at least 2, 4, 10, 50, 100, 500, 1,000, 5,000, or 10,000 fold greater, than its affinity for than for non-target tissue or antigen present outside the target tissue. Affinity of a therapeutic compound of which the tissue specific moiety is a component, can be measured in a cell suspension, e.g., the affinity for suspended cells having the target antigen is compared with its affinity for suspended cells not having the target antigen. In some embodiments, the binding affinity for the target antigen bearing cells is below 10 nM.


In some embodiments, the binding affinity for the target antigen bearing cells is below 100 pM, 50 pM, or 10 pM. In some embodiments, the specificity for a target antigen is sufficient, that when the tissue specific targeting moiety is coupled to an immune-down regulating effector: i) immune attack of the target tissue, e.g., as measured by histological inflammatory response, infiltrating T effector cells, or organ function, in the clinical setting—e.g. creatinine for kidney, is substantially reduced, e.g., as compared to what would be seen in an otherwise similar implant but lacking the tissue specific targeting moiety is coupled to an immune-down regulating effector; and/or ii) immune function in the recipient, outside or away from the target tissue, is substantially maintained.


In some embodiments, one or more of the following is seen: at therapeutic levels of therapeutic compound, peripheral blood lymphocyte counts are not substantially impacted, e.g., the level of T cells is within 25, 50, 75, 85, 90, or 95% of normal, the level of B cells is within 50, 75, 85, 90, or 95% of normal, and/or the level of granulocytes (PMNs) cells is within 25, 75, 85, 90, or 95% of normal, or the level of monocytes is within 25, 50, 75, 85, 90, or 95% of normal 1; at therapeutic levels of therapeutic compound, the ex vivo proliferative function of PBMCs (peripheral blood mononuclear cells) against non-disease relevant antigens is substantially normal or is within 70, 80, or 90% of normal; at therapeutic levels of therapeutic compound, the incidence or risk of risk of opportunistic infections and cancers associated with immunosuppression is not substantially increased over normal; or at therapeutic levels of therapeutic compound, the incidence or risk of risk of opportunistic infections and cancers associated with immunosuppression is substantially less than would be seen with standard of care, or non-targeted, immunosuppression. In some embodiments, the tissue specific targeting moiety comprises an antibody molecule. In some embodiments, the donor specific targeting moiety comprises an antibody molecule, a target specific binding polypeptide, or a target ligand binding molecule. In some embodiments, the tissue specific targeting moiety binds a product, or a site on a product, that is present or expressed exclusively, or substantially exclusively, on target tissue.


ICIM Binding/Modulating Moieties: Effector Binding/Modulating Moieties that Bind Inhibitory Receptors


Methods and compounds described herein provide for a therapeutic compound having an effector binding/modulating moiety comprising an ICIM binding/modulating moiety, that directly binds and activates an inhibitory receptor on the surface of an immune cell, e.g., to reduce or eliminate, or substantially eliminate, the ability of the immune cell to mediate immune attack. Coupling of the ICIM binding/modulating moiety to a targeting entity, promotes site-specific or local down regulation of the immune cell response, e.g., confined substantially to the locations having binding sites for the targeting moiety. Thus, normal systemic immune function is substantially retained. In some embodiments, an ICIM binding/modulating moiety comprises an inhibitory immune checkpoint molecule counter ligand molecule, e.g., a natural ligand, or fragment of a natural ligand (e.g., PD-L1 or HLA-G) of the inhibitory immune checkpoint molecule. In some embodiments, an ICIM binding/modulating moiety comprises a functional antibody molecule, e.g., a functional antibody molecule comprising an scFv binding domain, that engages inhibitory immune checkpoint molecule.


In some embodiments, the ICIM binding/modulating moiety, comprising, e.g., a functional antibody molecule, or inhibitory immune checkpoint molecule ligand molecule, binds the inhibitory receptor but does not prevent binding of a natural ligand of the inhibitory receptor to the inhibitory receptor. In embodiments a format is used wherein a targeting moiety is coupled, e.g., fused, to an ICIM binding/modulating moiety, comprising, e.g., an scFv domain, and configured so that upon binding of an inhibitory receptor while in solution (e.g., in blood or lymph) (and presumably in a monomeric format), the therapeutic molecule: i) fails to agonize, or fails to substantially agonize (e.g., agonizes at less than 30, 20, 15, 10, or 5% of the level seen with a full agonizing molecule) the inhibitory receptor on the immune cell; and/or ii) fails to antagonize, or fails to substantially antagonize (e.g., antagonizes at less than 30, 20, 15, 10, or 5% of the level seen with a full antagonizing molecule) the inhibitory receptor on the immune cell. A candidate molecule can be evaluated for its ability to agonize or not agonize by its ability to either increase or decrease the immune response in an in vitro cell based assay wherein the target is not expressed, e.g., using an MLR-based assay (mixed lymphocyte reaction).


In some embodiments, candidate ICIM binding/modulating moieties can reduce, completely or substantially eliminate systemic immunosuppression and systemic immune activation. In some embodiments, the targeting domain of the therapeutic compound, when bound to target, will serve to cluster or multimerize the therapeutic compound on the surface of the tissue desiring immune protection. In some embodiments, the ICIM binding/modulating moiety, e.g., an ICIM binding/modulating moiety comprising a scFv domain, requires a clustered or multimeric state to be able to deliver an agonistic and immunosuppressive signal, or substantial levels of such signal, to local immune cells. This type of therapeutic can, for example, provide to a local immune suppression whilst leaving the systemic immune system unperturbed or substantially unperturbed. That is, the immune suppression is localized to where the suppression is needed as opposed to being systemic and not localized to a particular area or tissue type.


In some embodiments, upon binding to the target e.g., a target organ, tissue or cell type, the therapeutic compound coats the target, e.g., target organ, tissue or cell type. When circulating lymphocytes attempt to engage and destroy the target, this therapeutic will provide an ‘off’ signal only at, or to a greater extent at, the site of therapeutic compound accumulation.


A candidate therapeutic compound can be evaluated for the ability to bind, e.g., specifically bind, its target, e.g., by ELISA, a cell based assay, or surface plasmon resonance. This property should generally be maximized, as it mediates the site-specificity and local nature of the immune privilege. A candidate therapeutic compound can be evaluated for the ability to down regulate an immune cell when bound to target, e.g., by a cell based activity assay. This property should generally be maximized, as it mediates the site-specificity and local nature of the immune privilege. The level of down regulation effected by a candidate therapeutic compound in monomeric (or non-bound) form can be evaluated, e.g., by a cell based activity assay. This property should generally be minimized, as could mediate systemic down regulation of the immune system. The level of antagonism of a cell surface inhibitory molecule, e.g., an inhibitory immune checkpoint molecule, effected by a candidate therapeutic compound in monomeric (or non-bound) form can be evaluated, e.g., by, e.g., by a cell based activity assay. This property should generally be minimized, as could mediate systemic unwanted activation of the immune system. Generally, the properties should be selected and balanced to produce a sufficiently robust site specific immune privilege without unacceptable levels of non-site specific agonism or antagonism of the inhibitory immune checkpoint molecule.


The PD-L1/PD-1 Pathway

Programmed cell death protein 1, (often referred to as PD-1) is a cell surface receptor that belongs to the immunoglobulin superfamily. PD-1 is expressed on T cells and other cell types including, but not limited to, B cells, myeloid cells, dendritic cells, monocytes, T regulatory cells, iNK T cells. PD-1 binds two ligands, PD-L1 and PD-L2, and is an inhibitory immune checkpoint molecule. Engagement with a cognate ligand, PD-L1 or PD-L2, in the context of engagement of antigen loaded MCH with the T Cell Receptor on a T cell minimizes or prevents the activation and function of T cells. The inhibitory effect of PD-1 can include both promoting apoptosis (programmed cell death) in antigen specific T-cells in lymph nodes and reducing apoptosis in regulatory T cells (suppressor T cells).


In some embodiments, a therapeutic compound comprises an ICIM binding/modulating moiety which agonizes PD-1 inhibition. An ICIM binding/modulating moiety can include an inhibitory molecule counter ligand molecule, e.g., comprising a fragment of a ligand of PD-1 (e.g., a fragment of PD-L1 or PD-L2) or another moiety, e.g., a functional antibody molecule, comprising, e.g., an scFv domain that binds PD-1.


In some embodiments, a therapeutic compound comprises a targeting moiety that is preferentially binds a donor antigen not present in, present in substantially lower levels in the subject, e.g., a donor antigen from Table 2, and is localized to donor graft tissue in a subject. In some embodiments, it does not bind, or does not substantially bind, other tissues. In some embodiments, a therapeutic compound can include a targeting moiety that is specific for HLA-A2 and specifically binds donor allograft tissue but does not bind, or does not substantially bind, host tissues. In some embodiments, the therapeutic compound comprises an ICIM binding/modulating moiety, e.g., an inhibitory molecule counter ligand molecule, e.g., comprising a fragment of a ligand of PD-1 (e.g., a fragment of PD-L1 or PD-L2) or another moiety, e.g., a functional antibody molecule, comprising, e.g., an scFv domain that binds PD-1, such that the therapeutic compound, e.g., when bound to target, activates PD-1. The therapeutic compound targets an allograft and provides local immune privilege to the allograft.


In some embodiments, a therapeutic compound comprises a targeting moiety that is preferentially binds to an antigen of Table 2, and is localized to the target in a subject, e.g., a subject having an autoimmune disorder, e.g., an autoimmune disorder of Table 2. In some embodiments, it does not bind, or does not substantially bind, other tissues. In some embodiments, the therapeutic compound comprises an ICIM binding/modulating moiety, e.g., an inhibitory molecule counter ligand molecule, e.g., comprising a fragment of a ligand of PD-1 (e.g., a fragment of PD-L1 or PD-L2) or another moiety, e.g., a functional antibody molecule, comprising, e.g., an scFv domain that binds PD-1, such that the therapeutic compound, e.g., when bound to target, activates PD-1. The therapeutic compound targets a tissue subject to autoimmune attack and provides local immune privilege to the tissue.


PD-L1 and PDL2, or polypeptides derived therefrom, can provide candidate ICIM binding moieties. However, in monomer form, e.g., when the therapeutic compound is circulating in blood or lymph, this molecule could have an undesired effect of antagonizing the PD-L1/PD-1 pathway, and may only agonize the PD-1 pathway when clustered or multimerized on the surface of a target, e.g., a target organ. In some embodiments, a therapeutic compound comprises an ICIM binding/modulating moiety comprising a functional antibody molecule, e.g., a scFv domain, that is inert, or substantially inert, to the PD-1 pathway in a soluble form but which agonizes and drives an inhibitory signal when multimerized (by the targeting moiety) on the surface of a tissue.


The HLA-G: KIR2DL4/LILRB1/LILRB2 Pathway

KIR2DL4, LILRB1, and LILRB2 are inhibitory molecules found on T cells, NK cells, and myeloid cells. HLA-G is a counter ligand for each.


KIR2DL4 is also known as CD158D, G9P, KIR-103AS, KIR103, KIR103AS, KIR, KIR-2DL4, killer cell immunoglobulin like receptor, and two Ig domains and long cytoplasmic tail 4. LILRB1 is also known as LILRB1, CD85J, ILT-2, ILT2, LIR-1, LIR1, MIR-7, MIR7, PIR-B, PIRB, leukocyte immunoglobulin like receptor B1. LILRB2 is also known as CD85D, ILT-4, LIR-2, LIR2, MIR-10, MIR10, and ILT4.


A therapeutic compound comprising an HLA-G molecule can be used to provide inhibitory signals to an immune cell comprising any of KIR2DL4, LILRB1, and LILRB2, e.g., with multimerized therapeutic compound molecules comprising an HLA-G molecule and thus provide site-specific immune privilege.


A therapeutic compound comprising an agonistic anti-KIR2DL4, anti-LILRB1, or anti-LILRB2 antibody molecule can be used to provide inhibitory signals to an immune cell comprising any of KIR2DL4, LILRB1, and LILRB2.


HLA-G only delivers an inhibitory signal when multimerized, for example, when expressed on the surface of a cell or when conjugated to the surface of a bead. In embodiments, a therapeutic compound comprising an HLA-G molecule which therapeutic compound does not multimerize in solution (or does not multimerize sufficiently to result in significant levels of inhibitory molecule agonization), is provided. The use of HLA-G molecules that minimize multimerization in solution will minimize systemic agonization of immune cells and unwanted immune suppression.


While not wishing to be bound by theory it is believed that HLA-G is not effective in down regulation unless multimerized, that binding of the therapeutic compound to target, through the targeting moiety, multimerizes the ICIM binding entity, and that the multimerized ICIM binding entity, binds and clusters inhibitory molecules on the surface of an immune cell, thus mediating a negative signal that down regulates the immune cell. Thus, infiltrating immune cells attempting to damage the target tissue, including antigen presenting cells and other myeloid cells, NK cells and T cells, are down regulated.


While HLA-G molecules minimize antagonism when in monomeric form are desirable, the redundancy of LILRB1 and LILRB2 will minimize, the impact on systemic even with some monomeric antagonism.


In some embodiments, the therapeutic compound comprises an ICIM binding/modulating moiety that comprises a HLA-G molecule, e.g., an B2 M-free isoform (e.g., HLA-G5), see Carosella et al., Advances in Immunology, 2015, 127:33. In a B2 M-free format, HLA-G preferentially binds LILRB2.


Suitable sequences for the construction of HLA-G molecules include GenBank P17693.1 RecName: Full=HLA class I histocompatibility antigen, alpha chain G; AltName: Full=HLA G antigen; AltName: Full=MHC class I antigen G; Flags: Precursor, or MVVMAPRTLFLLLSGALTLTETWAGSHSMRYFSAAVSRPGRGEPRFIAMGYVDDTQFV RFDSDSACPRMEPRAPWVEQEGPEYWEEETRNTKAHAQTDRMNLQTLRGYYNQSEAS SHTLQWMIGCDLGSDGRLLRGYEQYAYDGKDYLALNEDLRSWTAADTAAQISKRKCE AANVAEQRRAYLEGTCVEWLHRYLENGKEMLQRADPPKTHVTHHPVEDYEATLRCW ALGFYPAEIILTWQRDGEDQTQDVELVETRPAGDGTFQKWAAVVVPSGEEQRYTCHVQ HEGLPEPLMLRWKQSSLPTIPIIVIGIVAGLVVLAAVVTGAAVAAVLWRKKSSD (SEQ ID NO: 5). A candidate HLA-G molecule can be tested for suitability for use in methods and compounds, e.g., by methods analogous to those described in “Synthetic HLA-G proteins for therapeutic use in transplantation,” LeMaoult et al., 2013 The FASEB Journal 27:3643.


In some embodiments, a therapeutic compound comprises a targeting moiety that is preferentially binds a donor antigen not present in, present in substantially lower levels in the subject, e.g., a donor antigen from Table 2, and is localized to donor graft tissue in a subject. In some embodiments, it does not bind, or does not substantially bind, other tissues. In some embodiments, a therapeutic compound can include a targeting moiety that is specific for HLA-A2 and specifically binds a donor allograft but does not bind host tissues and is combined with an ICIM binding/modulating moiety that comprises a HLA-G molecule that binds KIR2DL4, LILRB1, or LILRB2, such that the therapeutic compound, e.g., when bound to target, activates KIR2DL4, LILRB1, or LILRB2. The therapeutic compound targets an allograft and provides local immune privilege to the allograft.


In some embodiments, a therapeutic compound comprises a targeting moiety that is preferentially binds a tissue specific antigen, e.g., an antigen from Table 2, and is localized to the target site in a subject, e.g., a subject having an autoimmune disorder, e.g., an autoimmune disorder from Table 2. In some embodiments, it does not bind, or does not substantially bind, other tissues. In embodiments the therapeutic compound comprises an ICIM binding/modulating moiety that comprises a HLA-G molecule binds KIR2DL4, LILRB1, or LILRB2, such that the therapeutic compound, e.g., when bound to target, activates KIR2DL4, LILRB1, or LILRB2. The therapeutic compound targets an tissue subject to autoimmune attack and provides local immune privilege to the tissue.


It is likely possible to engineer a stable and soluble HLA-G-B2 M fusion protein that can also bind LILRB1. For example, the crystal structure of HLA-G was determined using HLA-G/B2 M monomers (Clements et al. 2005 PNAS 102:3360).


FCRL Family

FCRL1-6 generally inhibit B cell activation or function. These type 1 transmembrane glycoproteins are composed of different combinations of 5 types of immunoglobulin-like domains, with each protein consisting of 3 to 9 domains, and no individual domain type conserved throughout all of the FCRL proteins. In general, FCRL expression is restricted to lymphocytes, with the primary expression in B-lymphocytes. Generally, FCRLs function to repress B-cell activation.


An ICIM binding/modulating moiety can comprise an agonistic anti-BCMA antibody molecule. In some embodiments, the therapeutic compound comprises an anti-FCRL antibody molecule and an anti-B cell receptor (BCR) antibody molecule. While not wishing to be bound be theory is believed that a therapeutic compound comprising anti-body molecules of both specificities will bring the FCRL into close proximity with the BCR and inhibit BCR signaling.


Butyrophilins and Butyrophilin-Like Molecules

Effector binding/modulating moiety can comprise an agonist or antagonist of a butyrophilin. In some embodiments, an effector binding/modulating moiety an agonistic or functional BTN1A1 molecule, BTN2A2 molecule, BTNL2 molecule, or BTNL1 molecule.


A functional BTNXi molecule (where Xi=1A1, 2A2, L2 or L1), as that term as used herein, refers to a polypeptide having sufficient BTNXi sequence that, as part of a therapeutic compound, it inhibits T cells. In some embodiments, a BTNXi molecule has at least 60, 70, 80, 95, 99, or 100% sequence identity, or substantial sequence identity, with a naturally occurring butyrophilin or butyrophilin-like molecule.


In some embodiments, an effector binding/modulating moiety an antagonistic BTNL8 molecule.


An antagonistic BTNL8 molecule, as that term as used herein, refers to a polypeptide having sufficient BTNL8 sequence that, as part of a therapeutic compound, it inhibits the activation, proliferation, or secretion of cytokine by a resting T cell. In some embodiments, a BTNL8 molecule has at least 60, 70, 80, 90, 95, 99, or 100% sequence identity, or substantial sequence identity, with a naturally occurring butyrophilin.


Effector binding/modulating moiety can comprise an agonistic BTNL2 molecule. While not wishing to be bound by theory it is believed that agonistic BTNL2 molecules induce Treg cells.


An agonistic BTNL2 molecule as that term as used herein, refers to a polypeptide having sufficient BTNL2 sequence that, as part of a therapeutic compound, it induces Treg cells. In some embodiments, a BTNL2 molecule has at least 60, 70, 80, 90, 95, 99, or 100% sequence identity, or substantial sequence identity, with a naturally occurring butyrophilin.


In some embodiments, an effector binding/modulating moiety an antagonistic BTNL8 molecule.


IIC Binding/Modulating Moieties: Effector Binding/Modulating Moieties that Recruit Immunosuppressive T Cells


In some embodiments, a therapeutic compound comprises an effector binding/modulating moiety, e.g., an IIC binding/modulating moiety, that binds, activates, or retains immunosuppressive cells, e.g., immunosuppressive T cells, at the site mediated by the targeting moiety, providing site-specific immune privilege. The IIC binding/modulating moiety, e.g., an IIC binding/modulating moiety comprising an antibody molecule, comprising, e.g., an scFv binding domain, binds immunosuppressive cell types, e.g., Tregs, e.g., Foxp3+CD25+ Tregs. Organ, tissue or specific cell type tolerance is associated with an overwhelming increase of Tregs proximal and infiltrating the target organ; in embodiments, the methods and compounds described herein synthetically re-create and mimic this physiological state. Upon accumulation of Tregs, an immunosuppressive microenvironment is created that serves to protect the organ of interest from the immune system.


GARP-Binders as a TREG and TGFB Targeting Molecule

GARP is a membrane protein receptor for latent TGF-beta expressed on the surface of activated Tregs (Tran et al. 2009 PNAS 106:13445 and Wang et al. 2009 PNAS 106:13439). In some embodiments, a therapeutic compound comprises an IIC binding entity that binds one or both of soluble GARP and GARP-expressing cells, such as activated human Tregs, and a targeting moiety that targets the therapeutic compound to the target tissue of interest. IIC binding/modulating moieties that comprises a GARP-Binder include, e.g., an IIC binding/modulating moiety that comprises an anti-GARP antibody molecule, e.g., an anti-GARP scFv domain. While not wishing to be bound by theory, it is believed that the therapeutic compound that comprises a GARP binder effects accumulation of GARP-expressing Tregs at the site targeted by the targeting moiety of the therapeutic compound, e.g., a transplant or site of organ injury. Again, while not wishing to be bound by theory, it is believed that a therapeutic compound that comprises a GARP binder effects can also effect accumulation of soluble GARP at site of organ injury, which will serve to bind and activate TGFB1, an immuno-suppressive cytokine, in a local manner (Fridrich et al. 2016 PLoS One 11:e0153290; doi: 10.1371/journal.pone.0153290 and Hahn et al. 2013 Blood 15:1182). Thus, an effector binding/modulating moiety that comprises a GARP binder can act as either a IIC binding/modulating moiety or an SM binding/modulating moiety.


CTLA4 as a TREG Targeting and T Effector Cell Silencing Molecule

In some embodiments, an effector binding/modulating moiety, e.g., comprises an antibody molecule, e.g., an scFv domain, that binds CTLA4 expressed on the surface of Tregs. The therapeutic molecule accumulates or retains CTLA4+ Tregs at the target site, with local immunosuppression the consequence.


Though expressed more highly on Tregs, CTLA4 is also expressed on activated T cells. A therapeutic compound comprising an effector binding/modulating moiety, e.g., an anti-CTLA4 antibody, or a functional anti-CTLA4 antibody, can down regulate the CTLA4 expressing T cell. Thus, in a therapeutic compound comprising an effector binding/modulating moiety that binds CTLA4, the effector moiety can also act as an ICIM binding/modulating moiety.


In some embodiments, the anti-CTLA4 binder is neither antagonizing or agonizing when in monomeric format, and is only agonizing when clustered or multimerized upon binding to the target.


While not wishing to be bound by theory it is believed that the binding of the therapeutic compound, via the targeting moiety, to the target, effects multimerization of therapeutic compound. In the case of memory and activated T cells, CTLA4 bound by the effector binding/modulating moiety of the therapeutic compound, is clustered, and an inhibitory signal by engagement of CTLA4 expressed by memory and activated T cells.


In some embodiments, the anti-CTLA4 binder is neither antagonizing or agonizing when in monomeric format, and is only agonizing when clustered or multimerized upon binding to the target.


IL-2 Mutein Molecules: IL2 Receptor Binders that Activate Tregs


IL-2 mutein molecule, as that term is used herein, refers to an IL2 variant that binds with high affinity to the CD25 (IL-2R alpha chain) and with low affinity to the other IL-2R signaling components CD122 (IL-2R beta) and CD132 (IL-2R gamma). Such an IL-2 mutein molecule preferentially activates Treg cells. In embodiments, either alone, or as a component of a therapeutic compound, an IL-2 mutein activates Tregs at least 2, 5, 10, or 100 fold more than cytotoxic or effector T cells. Exemplary IL-2 mutein molecules are described in WO2010085495, WO2016/164937, US2014/0286898A1, WO2014153111A2, WO2010/085495, cytotoxic WO2016014428A2, WO2016025385A1, and US20060269515. Muteins disclosed in these references that include additional domains, e.g., an Fc domain, or other domain for extension of half-life can be used in the therapeutic compounds and methods described herein without such additional domains. In another embodiment an IIC binding/modulating moiety comprises an IL-2 mutein, or active fragment thereof, coupled, e.g., fused, to another polypeptide, e.g., a polypeptide that extends in vivo half-life, e.g., an immunoglobulin constant region, or a multimer or dimer thereof, e.g., AMG 592. In an embodiment the therapeutic compound comprises the IL-2 portion of AMG 592. In an embodiment the therapeutic compound comprises the IL-2 portion but not the immunoglobulin portion of AMG 592. In some embodiments, the mutein does not comprise a Fc region. For some IL-2 muteins, the muteins are engineered to contain a Fc region because such region has been shown to increase the half-life of the mutein. In some embodiments, the extended half-life is not necessary for the methods described and embodied herein. In some embodiments, the Fc region that is fused with the IL-2 mutein comprises a N297 mutations, such as, but not limited to, N297A. In some embodiments, the Fc region that is fused with the IL-2 mutein does not comprise a N297 mutation, such as, but not limited to, N297A.


IL-2 mutein molecules that preferentially expand or stimulate Treg cells (over cytotoxic T cells) can be used as an IIC binding/modulating moiety.


In some embodiments, IIC binding/modulating moiety comprises a IL-2 mutein molecule. As used herein, the term “IL-2 mutein molecule” or “IL-2 mutein” refers to an IL-2 variant that preferentially activates Treg cells. In some embodiments, either alone, or as a component of a therapeutic compound, an IL-2 mutein molecule activates Tregs at least 2, 5, 10, or 100 fold more than cytotoxic T cells. A suitable assay for evaluating preferential activation of Treg cells can be found in U.S. Pat. No. 9,580,486 at, for example, Examples 2 and 3, or in WO2016014428 at, for example, Examples 3, 4, and 5, each of which is incorporated by reference in its entirety. The sequence of mature IL-2 is











(SEQ ID NO: 6)



APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLT







FKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRP







RDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFC







QSIISTLT (mature IL-2 sequence)







The immature sequence of IL-2 can be represented by











(SEQ ID NO: 15)



MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDL







QMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE







ELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTF







MCEYADETATIVEFLNRWITFCQSIISTLT.






In some embodiments, an IIC binding/modulating moiety comprises an IL-2 mutein, or active fragment thereof, coupled, e.g., fused, to another polypeptide, e.g., a polypeptide that extends in vivo half-life, e.g., an immunoglobulin constant region, or a multimer or dimer thereof.


An IL-2 mutein molecule can be prepared by mutating one or more of the residues of IL-2. Non-limiting examples of IL-2-muteins can be found in WO2016/164937, U.S. Pat. Nos. 9,580,486, 7,105,653, 9,616,105, 9,428,567, US2017/0051029, US2014/0286898A1, WO2014153111A2, WO2010/085495, WO2016014428A2, WO2016025385A1, and US20060269515, each of which are incorporated by reference in its entirety.


In some embodiments, the alanine at position 1 of the sequence above is deleted. In some embodiments, the IL-2 mutein molecule comprises a serine substituted for cysteine at position 125 of the mature IL-2 sequence. Other combinations of mutations and substitutions that are IL-2 mutein molecules are described in US20060269515, which is incorporated by reference in its entirety. In some embodiments, the cysteine at position 125 is also substituted with a valine or alanine. In some embodiments, the IL-2 mutein molecule comprises a V91K substitution. In some embodiments, the IL-2 mutein molecule comprises a N88D substitution. In some embodiments, the IL-2 mutein molecule comprises a N88R substitution. In some embodiments, the IL-2 mutein molecule comprises a substitution of H16 E, D84K, V91N, N88D, V91K, or V91R, any combinations thereof. In some embodiments, these IL-2 mutein molecules also comprise a substitution at position 125 as described herein. In some embodiments, the IL-2 mutein molecule comprises one or more substitutions selected from the group consisting of: T3N, T3A, L12G, L12K, L12Q, L12S, Q13G, EISA, E15G, E15S, H16A, H16D, H16G, H16K, H16 M, H16N, H16R, H16S, H16T, H16V, H16Y, L19A, L19D, L19 E, L19G, L19N, L19R, L19S, L19T, L19V, D20A, D20 E, D20H, D20I, D20Y, D20F, D20G, D20T, D20W, M23R, R81A, R81G, R81S, R81T, D84A, D84 E, D84G, D84I, D84 M, D84Q D84R, D84S, D84T, 587R, N88A, N88D, N88 E, N88I, N88F, N88G, N88 M, N88R, N88S, N88V, N88W, V91D, V91 E, V91G, V91S, I92K, I92R, E95G, and Q126. In some embodiments, the amino acid sequence of the IL-2 mutein molecule differs from the amino acid sequence set forth in mature IL-2 sequence with a C125A or C125S substitution and with one substitution selected from T3N, T3A, L12G, L12K, L12Q L125, Q13G, EISA, E15G, E15S, H16A, H16D, H16G, H16K, H16 M, H16N, H16R, H16S, H16T, H16V, H16Y, L19A, L19D, L19 E, L19G, L19N, L19R, L19S, L19T, L19V, D20A, D20 E, D20F, D20G, D20T, D20W, M23R, R81A, R81G, R81S, R81T, D84A, D84 E, D84G, D84I, D84 M, D84Q, D84R, D84S, D84T, 587R, N88A, N88D, N88 E, N88F, N88I, N88G, N88 M, N88R, N88S, N88V, N88W, V91D, V91 E, V91G, V91S, I92K, I92R, E95G, Q126I, Q126L, and Q126F. In some embodiments, the IL-2 mutein molecule differs from the amino acid sequence set forth in mature IL-2 sequence with a C125A or C125S substitution and with one substitution selected from D20H, D20I, D20Y, D20 E, D20G, D20W, D84A, D84S, H16D, H16G, H16K, H16R, H16T, H16V, I92K, I92R, L12K, L19D, L19N, L19T, N88D, N88R, N88S, V91D, V91G, V91K, and V91S. In some embodiments, the IL-2 mutein comprises N88R and/or D20H mutations.


In some embodiments, the IL-2 mutein molecule comprises a mutation in the polypeptide sequence at a position selected from the group consisting of amino acid 30, amino acid 31, amino acid 35, amino acid 69, and amino acid 74. In some embodiments, the mutation at position 30 is N30S. In some embodiments, the mutation at position 31 is Y31H. In some embodiments, the mutation at position 35 is K35R. In some embodiments, the mutation at position 69 is V69A. In some embodiments, the mutation at position 74 is Q74P. In some embodiments, the mutein comprises a V69A mutation, a Q74P mutation, a N88D or N88R mutation, and one or more of L53I, L56I, L80I, or L118I mutations. In some embodiments, the mutein comprises a V69A mutation, a Q74P mutation, a N88D or N88R mutation, and a L to I mutation selected from the group consisting of: L53I, L56I, L80I, and L118I mutation. In some embodiments, the IL-2 mutein comprises a V69A, a Q74P, a N88D or N88R mutation, and a L53I mutation. In some embodiments, the IL-2 mutein comprises a V69A, a Q74P, a N88D or N88R mutation, and a L56I mutation. In some embodiments, the IL-2 mutein comprises a V69A, a Q74P, a N88D or N88R mutation, and a L80I mutation. In some embodiments, the IL-2 mutein comprises a V69A, a Q74P, a N88D or N88R mutation, and a L118I mutation. As provided for herein, the muteins can also comprise a C125A or C125S mutation.


In some embodiments, the mutein comprises a T3A mutation. The full length IL-2 muteins provided herein may not be illustrated with a T3A or other mutations provided for herein, but such mutations can be added into the muteins provided herein as is the case for any of the other mutations illustrated herein. Accordingly, In some embodiments, the mutein comprises a T3N mutation. In some embodiments, the mutein comprises a T3A mutation. In some embodiments, the mutein comprises a L12G mutation. In some embodiments, the mutein comprises a L12K mutation. In some embodiments, the mutein comprises a L12Q mutation. In some embodiments, the mutein comprises a L12S mutation. In some embodiments, the mutein comprises a Q13G mutation. In some embodiments, the mutein comprises a E15A mutation. In some embodiments, the mutein comprises a E15G mutation. In some embodiments, the mutein comprises a E15S mutation. In some embodiments, the mutein comprises a H16A mutation. In some embodiments, the mutein comprises a H16D mutation. In some embodiments, the mutein comprises a H16G mutation. In some embodiments, the mutein comprises a H16K mutation. In some embodiments, the mutein comprises a H16 M mutation. In some embodiments, the mutein comprises a H16N mutation. In some embodiments, the mutein comprises a H16R mutation. In some embodiments, the mutein comprises a H16S mutation. In some embodiments, the mutein comprises a H16T mutation. In some embodiments, the mutein comprises a H16V mutation. In some embodiments, the mutein comprises a H16Y mutation. In some embodiments, the mutein comprises a L19A mutation. In some embodiments, the mutein comprises a L19D mutation. In some embodiments, the mutein comprises a L19 E mutation. In some embodiments, the mutein comprises a L19G mutation. In some embodiments, the mutein comprises a L19N mutation. In some embodiments, the mutein comprises a L19R mutation. In some embodiments, the mutein comprises a L19S mutation. In some embodiments, the mutein comprises a L19T mutation. In some embodiments, the mutein comprises a L19V mutation. In some embodiments, the mutein comprises a D20A mutation. In some embodiments, the mutein comprises a D20 E mutation. In some embodiments, the mutein comprises a D20H mutation. In some embodiments, the mutein comprises a D20I mutation. In some embodiments, the mutein comprises a D20Y mutation. In some embodiments, the mutein comprises a D20F mutation. In some embodiments, the mutein comprises a D20G mutation. In some embodiments, the mutein comprises a D20T mutation. In some embodiments, the mutein comprises a D20W mutation. In some embodiments, the mutein comprises a M23R mutation. In some embodiments, the mutein comprises a R81A mutation. In some embodiments, the mutein comprises a R81G mutation. In some embodiments, the mutein comprises a R81S mutation. In some embodiments, the mutein comprises a R81T mutation. In some embodiments, the mutein comprises a D84A mutation. In some embodiments, the mutein comprises a D84 E mutation. In some embodiments, the mutein comprises a D84G mutation. In some embodiments, the mutein comprises a D84I mutation. In some embodiments, the mutein comprises a D84 M mutation. In some embodiments, the mutein comprises a D84Q mutation. In some embodiments, the mutein comprises a D84R mutation. In some embodiments, the mutein comprises a D84S mutation. In some embodiments, the mutein comprises a D84T mutation. In some embodiments, the mutein comprises a S87R mutation. In some embodiments, the mutein comprises a N88A mutation. In some embodiments, the mutein comprises a N88D mutation. In some embodiments, the mutein comprises a N88 E mutation. In some embodiments, the mutein comprises a N88I mutation. In some embodiments, the mutein comprises a N88F mutation. In some embodiments, the mutein comprises a N88G mutation. In some embodiments, the mutein comprises a N88 M mutation. In some embodiments, the mutein comprises a N88R mutation. In some embodiments, the mutein comprises a N88S mutation. In some embodiments, the mutein comprises a N88V mutation. In some embodiments, the mutein comprises a N88W mutation. In some embodiments, the mutein comprises a V91D mutation. In some embodiments, the mutein comprises a V91 E mutation. In some embodiments, the mutein comprises a V91G mutation. In some embodiments, the mutein comprises a V91S mutation. In some embodiments, the mutein comprises a I92K mutation. In some embodiments, the mutein comprises a I92R mutation. In some embodiments, the mutein comprises a E95G mutation. In some embodiments, the mutein comprises a Q126 mutation.


Although the mutations are illustrated in list form, this is simply for convenience and the muteins may have one or more of the substitutions provided herein.


In some embodiments, the IL-2 mutein molecule comprises a substitution selected from the group consisting of: N88R, N88I, N88G, D20H, D109C, Q126L, Q126F, D84G, or D84I relative to mature human IL-2 sequence provided above. In some embodiments, the IL-2 mutein molecule comprises a substitution of D109C and one or both of a N88R substitution and a C125S substitution. In some embodiments, the cysteine that is in the IL-2 mutein molecule at position 109 is linked to a polyethylene glycol moiety, wherein the polyethylene glycol moiety has a molecular weight of between 5 and 40 kDa.


In some embodiments, any of the substitutions described herein are combined with a substitution at position 125. The substitution can be a C125S, C125A, or C125V substitution.


In addition to the substitutions or mutations described herein, in some embodiments, the IL-2 mutein has a substitution/mutation at one or more of positions 73, 76, 100, or 138 that correspond to SEQ ID NO: 15 or positions at one or more of positions 53, 56, 80, or 118 that correspond to SEQ ID NO: 6. In some embodiments, the IL-2 mutein comprises a mutation at positions 73 and 76; 73 and 100; 73 and 138; 76 and 100; 76 and 138; 100 and 138; 73, 76, and 100; 73, 76, and 138; 73, 100, and 138; 76, 100 and 138; or at each of 73, 76, 100, and 138 that correspond to SEQ ID NO: 15. In some embodiments, the IL-2 mutein comprises a mutation at positions 53 and 56; 53 and 80; 53 and 118; 56 and 80; 56 and 118; 80 and 118; 53, 56, and 80; 53, 56, and 118; 53, 80, and 118; 56, 80 and 118; or at each of 53, 56, 80, and 118 that correspond to SEQ ID NO: 6. As the IL-2 can be fused or tethered to other proteins, as used herein, the term corresponds to as reference to a SEQ ID NOs: 6 or 15 refer to how the sequences would align with default settings for alignment software, such as can be used with the NCBI website. In some embodiments, the mutation is leucine to isoleucine. Thus, the IL-2 mutein can comprise one more isoleucines at positions 73, 76, 100, or 138 that correspond to SEQ ID NO: or positions at one or more of positions 53, 56, 80, or 118 that correspond to SEQ ID NO: 6. In some embodiments, the mutein comprises a mutation at L53 that correspond to SEQ ID NO: 6. In some embodiments, the mutein comprises a mutation at L56 that correspond to SEQ ID NO: 6. In some embodiments, the mutein comprises a mutation at L80 that correspond to SEQ ID NO: 6. In some embodiments, the mutein comprises a mutation at L118 that correspond to SEQ ID NO: 6. In some embodiments, the mutation is leucine to isoleucine. In some embodiments, the mutein also comprises a mutation as position 69, 74, 88, 125, or any combination thereof in these muteins that correspond to SEQ ID NO: 6. In some embodiments, the mutation is a V69A mutation. In some embodiments, the mutation is a Q74P mutation. In some embodiments, the mutation is a N88D or N88R mutation. In some embodiments, the mutation is a C125A or C125S mutation.


In some embodiments, the IL-2 mutein comprises a mutation at one or more of positions 49, 51, 55, 57, 68, 89, 91, 94, 108, and 145 that correspond to SEQ ID NO: 15 or one or more positions 29, 31, 35, 37, 48, 69, 71, 74, 88, and 125 that correspond to SEQ ID NO: 6. The substitutions can be used alone or in combination with one another. In some embodiments, the IL-2 mutein comprises substitutions at 2, 3, 4, 5, 6, 7, 8, 9, or each of positions 49, 51, 55, 57, 68, 89, 91, 94, 108, and 145. Non-limiting examples such combinations include, but are not limited to, a mutation at positions 49, 51, 55, 57, 68, 89, 91, 94, 108, and 145; 49, 51, 55, 57, 68, 89, 91, 94, and 108; 49, 51, 55, 57, 68, 89, 91, and 94; 49, 51, 55, 57, 68, 89, and 91; 49, 51, 55, 57, 68, and 89; 49, 51, 55, 57, and 68; 49, 51, 55, and 57; 49, 51, and 55; 49 and 51; 51, 55, 57, 68, 89, 91, 94, 108, and 145; 51, 55, 57, 68, 89, 91, 94, and 108; 51, 55, 57, 68, 89, 91, and 94; 51, 55, 57, 68, 89, and 91; 51, 55, 57, 68, and 89; 55, 57, and 68; 55 and 57; 55, 57, 68, 89, 91, 94, 108, and 145; 55, 57, 68, 89, 91, 94, and 108; 55, 57, 68, 89, 91, and 94; 55, 57, 68, 89, 91, and 94; 57, 68, 89, and 91; 55, 57, 68, and 89; 55, 57, and 68; 55 and 57; 57, 68, 89, 91, 94, 108, and 145; 57, 68, 89, 91, 94, and 108; 57, 68, 89, 91, and 94; 57, 68, 89, and 91; 57, 68, and 89; 57 and 68; 68, 89, 91, 94, 108, and 145; 68, 89, 91, 94, and 108; 68, 89, 91, and 94; 68, 89, and 91; 68 and 89; 89, 91, 94, 108, and 145; 89, 91, 94, and 108; 89, 91, and 94; 89 and 91; 91, 94, 108, and 145; 91, 94, and 108; 91, and 94; or 94 and 108. Each mutation can be combined with one another. The same substitutions can be made in SEQ ID NO: 6, but the numbering would adjusted appropriately as is clear from the present disclosure (20 less than the numbering for SEQ ID NO: 15 corresponds to the positions in SEQ ID NO: 6).


In some embodiments, the IL-2 mutein comprises a mutation at one or more positions of 35, 36, 42, 104, 115, or 146 that correspond to SEQ ID NO: 15 or the equivalent positions at SEQ ID NO: 6 (e.g. positions 15, 16, 22, 84, 95, or 126). These mutations can be combined with the other leucine to isoleucine mutations described herein or the mutation at positions 73, 76, 100, or 138 that correspond to SEQ ID NO: 15 or at one or more of positions 53, 56, 80, or 118 that correspond to SEQ ID NO: 6. In some embodiments, the mutation is a E35Q, H36N, Q42 E, D104N, E115Q, or Q146 E, or any combination thereof. In some embodiments, one or more of these substitutions is wild type. In some embodiments, the mutein comprises a wild-type residue at one or more of positions 35, 36, 42, 104, 115, or 146 that correspond to SEQ ID NO: 15 or the equivalent positions at SEQ ID NO: 6 (e.g. positions 15, 16, 22, 84, 95, and 126).


The mutations at these positions can be combined with any of the other mutations described herein, including, but not limited to substitutions at positions 73, 76, 100, or 138 that correspond to SEQ ID NO: 15 or positions at one or more of positions 53, 56, 80, or 118 that correspond to SEQ ID NO: 6 described herein and above. In some embodiments, the IL-2 mutein comprises a N49S mutation that corresponds to SEQ ID NO: 15. In some embodiments, the IL-2 mutein comprises a Y51S or a Y51H mutation that corresponds to SEQ ID NO: 15. In some embodiments, the IL-2 mutein comprises a K55R mutation that corresponds to SEQ ID NO: 15. In some embodiments, the IL-2 mutein comprises a T57A mutation that corresponds to SEQ ID NO: 15. In some embodiments, the IL-2 mutein comprises a K68 E mutation that corresponds to SEQ ID NO: 15. In some embodiments, the IL-2 mutein comprises a V89A mutation that corresponds to SEQ ID NO: 15. In some embodiments, the IL-2 mutein comprises a N91R mutation that corresponds to SEQ ID NO: 15. In some embodiments, the IL-2 mutein comprises a Q94P mutation that corresponds to SEQ ID NO: 15. In some embodiments, the IL-2 mutein comprises a N108D or a N108R mutation that corresponds to SEQ ID NO: 15. In some embodiments, the IL-2 mutein comprises a C145A or C145S mutation that corresponds to SEQ ID NO: 15. These substitutions can be used alone or in combination with one another. In some embodiments, the mutein comprises each of these substitutions. In some embodiments, the mutein comprises 1, 2, 3, 4, 5, 6, 7, or 8 of these mutations. In some embodiments, the mutein comprises a wild-type residue at one or more of positions 35, 36, 42, 104, 115, or 146 that correspond to SEQ ID NO: 15 or the equivalent positions at SEQ ID NO: 6 (e.g. positions 15, 16, 22, 84, 95, and 126).


In some embodiments, the IL-2 mutein comprises a N29S mutation that corresponds to SEQ ID NO: 6. In some embodiments, the IL-2 mutein comprises a Y31S or a Y31H mutation that corresponds to SEQ ID NO: 6. In some embodiments, the IL-2 mutein comprises a K35R mutation that corresponds to SEQ ID NO: 6. In some embodiments, the IL-2 mutein comprises a T37A mutation that corresponds to SEQ ID NO: 6. In some embodiments, the IL-2 mutein comprises a K48 E mutation that corresponds to SEQ ID NO: 6. In some embodiments, the IL-2 mutein comprises a V69A mutation that corresponds to SEQ ID NO: 6. In some embodiments, the IL-2 mutein comprises a N71R mutation that corresponds to SEQ ID NO: 6. In some embodiments, the IL-2 mutein comprises a Q74P mutation that corresponds to SEQ ID NO: 6. In some embodiments, the IL-2 mutein comprises a N88D or a N88R mutation that corresponds to SEQ ID NO: 6. In some embodiments, the IL-2 mutein comprises a C125A or C125S mutation that corresponds to SEQ ID NO: 6. These substitutions can be used alone or in combination with one another. In some embodiments, the mutein comprises 1, 2, 3, 4, 5, 6, 7, or 8 of these mutations. In some embodiments, the mutein comprises each of these substitutions. In some embodiments, the mutein comprises a wild-type residue at one or more of positions 35, 36, 42, 104, 115, or 146 that correspond to SEQ ID NO: 15 or the equivalent positions at SEQ ID NO: 6 (e.g. positions 15, 16, 22, 84, 95, and 126).


For any of the IL-2 muteins described herein, in some embodiments, one or more of positions 35, 36, 42, 104, 115, or 146 that correspond to SEQ ID NO: 15 or the equivalent positions at SEQ ID NO: 6 (e.g. positions 15, 16, 22, 84, 95, or 126) are wild-type (e.g., are as shown in SEQ ID NOs: 6 or 15). In some embodiments, 2, 3, 4, 5, 6, or each of positions 35, 36, 42, 104, 115, or 146 that correspond to SEQ ID NO: 15 or the equivalent positions at SEQ ID NO: 6 (e.g. positions 15, 16, 22, 84, 95, and 126) are wild-type.


In some embodiments, the IL-2 mutein comprises a sequence of:











(SEQ ID NO: 16)



MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDL







QMILNGISNHKNPRLARMLTFKFYMPEKATEIKHLQCLEEE







LKPLEEALRLAPSKNFHLRPRDLISDINVIVLELKGSETTFMC







EYADETATIVEFLNRWITFSQSIISTLT






In some embodiments, the IL-2 mutein comprises a sequence of:











(SEQ ID NO: 17)



MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDL







QMILNGISNHKNPRLARMLTFKFYMPEKATELKHIQCLEEE







LKPLEEALRLAPSKNFHLRPRDLISDINVIVLELKGSETTFMC







EYADETATIVEFLNRWITFSQSIISTLT






In some embodiments, the IL-2 mutein comprises a sequence of:











(SEQ ID NO: 18)



MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDL







QMILNGISNHKNPRLARMLTFKFYMPEKATELKHLQCLEEE







LKPLEEALRLAPSKNFHIRPRDLISDINVIVLELKGSETTFMC







EYADETATIVEFLNRWITFSQSIISTLT






In some embodiments, the IL-2 mutein comprises a sequence of:











(SEQ ID NO: 19)



MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDL







QMILNGISNHKNPRLARMLTFKFYMPEKATELKHLQCLEEE







LKPLEEALRLAPSKNFHLRPRDLISDINVIVLELKGSETTFMC







EYADETATIVEFINRWITFSQSIISTLT






In some embodiments, the IL-2 mutein sequences described herein do not comprise the IL-2 leader sequence. The IL-2 leader sequence can be represented by the sequence of MYRMQLLSCIALSLALVTNS (SEQ ID NO: 20). Therefore, in some embodiments, the sequences illustrated above can also encompass peptides without the leader sequence. Although SEQ ID NOs; 16-20 are illustrated with only mutation at one of positions 73, 76, 100, or 138 that correspond to SEQ ID NO: 15 or positions at one or more of positions 53, 56, 80, or 118 that correspond to SEQ ID NO: 6, the peptides can comprises one, two, three or 4 of the mutations at these positions. In some embodiments, the substitution at each position is isoleucine or other type of conservative amino acid substitution. In some embodiments, the leucine at the recited positions are substituted with, independently, isoleucine, valine, methionine, or phenylalanine.


In some embodiments, the IL-2 mutein molecule is fused to a Fc Region or other linker region as described herein. Examples of such fusion proteins can be found in U.S. Pat. Nos. 9,580,486, 7,105,653, 9,616,105, 9,428,567, US2017/0051029, WO2016/164937, US2014/0286898A1, WO2014153111A2, WO2010/085495, WO2016014428A2, WO2016025385A1, US2017/0037102, and US2006/0269515, each of which are incorporated by reference in its entirety.


In some embodiments, the Fc Region comprises what is known as the LALA mutation. Using the Kabat numbering of the Fc region, this would correspond to L247A, L248A, and G250A. In some embodiments, using the EU numbering of the Fc region, the Fc region comprises a L234A mutation, a L235A mutation, and/or a G237A mutation. Regardless of the numbering system used, in some embodiments, the Fc portion can comprise mutations that correspond to these residues. In some embodiments, the Fc Region comprises N297G or N297A (kabat numbering) mutations. The Kabat numbering is based upon a full-length sequence, but would be used in a fragment based upon a traditional alignment used by one of skill in the art for the Fc region.


In some embodiments, the Fc Region comprises a sequence of:











(SEQ ID NO: 21)



DKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCV







VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR







VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG







QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE







SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV







FSCSVMHEALHNHYTQKSLSLSPG.



or







(SEQ ID NO: 28)



DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV







VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR







VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG







QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE







SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV







FSCSVMHEALHNHYTQKSLSLSPG.






In some embodiments, the IL-2 mutein is linked to the Fc Region. Non-limiting examples of linkers are glycine/serine linkers. For example, a glycine/serine linkers can be a sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22) or GGGGSGGGGSGGGGS (SEQ ID NO: 30). This is simply a non-limiting example and the linker can have varying number of GGGGS (SEQ ID NO: 23) or GGGGA repeats (SEQ ID NO: 29). In some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the GGGGS (SEQ ID NO: 23) or GGGGA repeats (SEQ ID NO: 29) (repeats disclosed as SEQ ID NOS 1550-1551, respectively). In some embodiments, the linker is 10 amino acids in length. In some embodiments, the linker is 5 amino acids in length. In some embodiments, the linker is 15 amino acids in length. In some embodiments, the linker is 20 amino acids in length. In some embodiments, the linker is 25 amino acids in length. In some embodiments, the linker is 30 amino acids in length. In some embodiments, the linker is 35 amino acids in length. In some embodiments, the linker is from 5-50 amino acids in length.


Thus, the IL-2/Fc Fusion can be represented by the formula of ZIL-2M-Lgs-ZFc, wherein ZIL-2M is a IL-2 mutein as described herein, Lgs is a linker sequence as described herein (e.g. glycine/serine linker) and ZFc is a Fc region described herein or known to one of skill in the art. In some embodiments, the formula can be in the reverse orientation ZFc-Lgs-ZIL-2M.


In some embodiments, the IL-2/Fc fusion comprises a sequence of:









(SEQ ID NO: 24)


MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDL





QMILNGISNHKNPRLARMLTFKFYMPEKATEIKHLQCLEEE





LKPLEEALRLAPSKNFHLRPRDLISDINVIVLELKGSETTFMC





EYADETATIVEFLNRWITFSQSIISTLTGGGGSGGGGSGGGG





SGGGGSDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRT





PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ





YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT





ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI





AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW





QQGNVFSCSVMHEALHNHYTQKSLSLSPG;





(SEQ ID NO: 25)


MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDL





QMILNGISNHKNPRLARMLTFKFYMPEKATELKHIQCLEEE





LKPLEEALRLAPSKNFHLRPRDLISDINVIVLELKGSETTFMC





EYADETATIVEFLNRWITFSQSIISTLTGGGGSGGGGSGGGG





SGGGGSDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRT





PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ





YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT





ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI





AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW





QQGNVFSCSVMHEALHNHYTQKSLSLSPG;





(SEQ ID NO: 26)


MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDL





QMILNGISNHKNPRLARMLTFKFYMPEKATELKHLQCLEEE





LKPLEEALRLAPSKNFHIRPRDLISDINVIVLELKGSETTFMC





EYADETATIVEFLNRWITFSQSIISTLTGGGGSGGGGSGGGG





SGGGGSDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRT





PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ





YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT





ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI





AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW





QQGNVFSCSVMHEALHNHYTQKSLSLSPG;


or





(SEQ ID NO: 27)


MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDL





QMILNGISNHKNPRLARMLTFKFYMPEKATELKHLQCLEEE





LKPLEEALRLAPSKNFHLRPRDLISDINVIVLELKGSETTFMC





EYADETATIVEFINRWITFSQSIISTLTGGGGSGGGGSGGGGS





GGGGSDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTP





EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY





NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS





KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA





VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ





QGNVFSCSVMHEALHNHYTQKSLSLSPG.






In some embodiments, the IL-2/Fc Fusion comprises a sequence selected from the following table, Table 3:









TABLE 3







IL-2/Fc Fusion Protein Amino Acid Sequences








Sequence



Identification
Sequence





SEQ ID NO: 7
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE



ELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWI



TFSQSIISTLTGGGGAGGGGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC



VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCK



VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES



NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS



PGK





SEQ ID NO: 8
APTSSSTKKTQLQLEHLLLHLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE



ELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI



TFSQSIISTLTVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQ



FNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKT



ISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP



MLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK





SEQ ID NO: 9
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE



ELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWI



TFSQSIISTLTDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED



PEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP



IEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK



TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG





SEQ ID NO: 10
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE



ELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWI



TFSQSIISTLTGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD



VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNK



ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQP



ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG





SEQ ID NO: 11
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE



ELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWI



TFSQSIISTLTGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT



CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKC



KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE



SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL



SPG





SEQ ID NO: 12
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE



ELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWI



TFSQSIISTLTGGGGSGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR



TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWING



KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI



AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNYHTQ



KSLSLSPG





SEQ ID NO: 13
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE



ELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWI



TFSQSIISTLTGGGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDT



LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQ



DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF



YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH



NHYTQKSLSLSPG





SEQ ID NO: 14
APTSSSTKKTQLQLEHLLLHLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE



ELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI



TFSQSIISTLTGGGGSGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR



TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYPVVSVLTVLHQDWING



KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI



AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ



KSLSLSPG









In some embodiments, the IL-2 muteins comprises one or more of the sequences provided in the following table, which, in some embodiments, shows the IL-2 mutein fused with other proteins or linkers. The table also provides sequences for a variety of Fc domains or variants that the IL-2 can be fused with:














SEQ ID
Brief



NO:
Description
Amino Acid Sequence







31
Human IL-2
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



with C125S
TELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSE



mutation
TTFMCEYADETATIVEFLNRWITFSQSIISTLT





32
Human IL-2
APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



with C125S
TELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSE



and T3A
TTFMCEYADETATIVEFLNRWITFSQSIISTLT



mutations






33
Human IL-2
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



with N88R and
TELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSE



C125S
TTFMCEYADETATIVEFLNRWITFSQSIISTLT





34
Human IL-2
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



with V69A,
TELKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISNINVIVLELKGSE



Q74P and
TTFMCEYADETATIVEFLNRWITFSQSIISTLT



C125S




mutations






35
Human IL-2
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



with V69A,
TELKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISDINVIVLELKGSE



Q74P, N88D
TTFMCEYADETATIVEFLNRWITFSQSIISTLT



and C125S




mutations






36
Human IL-2
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



with V69A,
TELKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISRINVIVLELKGSE



Q74P, N88R
TTFMCEYADETATIVEFLNRWITFSQSIISTLT



and C125S




mutations






37
Human IL-2
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



with N88D and
TELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISDINVIVLELKGSE



C125S
TTFMCEYADETATIVEFLNRWITFSQSIISTLT





38
Human IL-2
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



with L53I,
TEIKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISDINVIVLELKGSE



V69A, Q74P,
TTFMCEYADETATIVEFLNRWITFSQSIISTLT



N88D and




C125S




mutations






39
Human IL-2
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



with L56I,
TELKHIQCLEEELKPLEEALNLAPSKNFHLRPRDLISDINVIVLELKGSE



V69A, Q74P,
TTFMCEYADETATIVEFLNRWITFSQSIISTLT



N88D and




C125S




mutations






40
Human IL-2
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



with V69A,
TELKHLQCLEEELKPLEEALNLAPSKNFHIRPRDLISDINVIVLELKGSE



Q74P, L80I,
TTFMCEYADETATIVEFLNRWITFSQSIISTLT



N88D and




C125S




mutations






41
Human IL-2
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



with V69A,
TELKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISDINVIVLELKGSE



Q74P, N88D,
TTFMCEYADETATIVEFINRWITFSQSIISTLT



L118I, and




C125S




mutations






21
Human IgG1 Fc
DKTHTCPPCPAPEAAGAPSVELFPPKPKDTLMISRTPEVTCVVVDVSHED



(N-terminal
PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK



fusions) with
CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK



L234A, L235A,
GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG



and G237A
NVFSCSVMHEALHNHYTQKSLSLSPG



mutations






30
GGGGSGGGGSGGG
GGGGSGGGGSGGGGS



GS linker (15




amino acids)






22
GGGGSGGGGSGGG
GGGGSGGGGSGGGGSGGGGS



GSGGGGS




linker (20




amino acids)






23
GGGGS linker
GGGGS



(5 amino




acids )






43
Human IgG1 Fc
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED



(truncated)
PEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYK



with N297G
CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK



mutation
GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG




NVFSCSVMHEALHNHYTQKSLSLSPG





44
Antibody
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV



Heavy Chain
HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP



CH1-CH2-CH3
KSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVS



domains
HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK



(human IgG1
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC



with L234A,
LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW



L235A, and
QQGNVFSCSVMHEALHNHYTQKSLSLSPG



G237A)






45
Antibody
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG



Kappa
NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK



Constant
SFNRGEC



Domain




(human)






46
IL-2-G4Sx3-Fc
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA




TELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSE




TTFMCEYADETATIVEFLNRWITFSQSIISTLTGGGGSGGGGSGGGGSDK




THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE




VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK




VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF




YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV




FSCSVMHEALHNHYTQKSLSLSPG





47
IL-2 T3A-
APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



G4Sx3-Fc
TELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSE




TTFMCEYADETATIVEFLNRWITFSQSIISTLTGGGGSGGGGSGGGGSDK




THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE




VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK




VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF




YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV




FSCSVMHEALHNHYTQKSLSLSPG





48
IL-2 N88R-
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



G4Sx3-Fc
TELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISRINVIVLELKGSE




TTFMCEYADETATIVEFLNRWITFSQSIISTLTGGGGSGGGGSGGGGSDK




THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE




VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK




VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF




YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV




FSCSVMHEALHNHYTQKSLSLSPG





49
IL-2 V69A,
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



Q74P, -G4Sx3-
TELKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISNINVIVLELKGSE



Fc
TTFMCEYADETATIVEFLNRWITFSQSIISTLTGGGGSGGGGSGGGGSDK




THTCPPCPAPEAAGAPSVELFPPKPKDTLMISRTPEVTCVVVDVSHEDPE




VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK




VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF




YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV




FSCSVMHEALHNHYTQKSLSLSPG





50
IL-2 N88D
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



V69A, Q74P-
TELKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISDINVIVLELKGSE



G4Sx3-Fc
TTFMCEYADETATIVEFLNRWITFSQSIISTLTGGGGSGGGGSGGGGSDK




THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE




VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK




VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF




YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV




FSCSVMHEALHNHYTQKSLSLSPG





51
IL-2 N88R
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



V69A, Q74P-
TELKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISRINVIVLELKGSE



G4Sx3-Fc
TTFMCEYADETATIVEFLNRWITFSQSIISTLTGGGGSGGGGSGGGGSDK




THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE




VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK




VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF




YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV




FSCSVMHEALHNHYTQKSLSLSPG





52
IL-2 N88D-
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



G4Sx3-Fc
TELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISDINVIVLELKGSE




TTFMCEYADETATIVEFLNRWITFSQSIISTLTGGGGSGGGGSGGGGSDK




THTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE




VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK




VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF




YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV




FSCSVMHEALHNHYTQKSLSLSPG





53
IL-2 L53I
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



N88D V69A,
TEIKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISDINVIVLELKGSE



Q74P, C125S-
TTFMCEYADETATIVEFLNRWITFSQSIISTLTGGGGSGGGGSGGGGSGG



G4Sx4-Fc
GGSDKTHTCPPCPAPEAAGAPSVELFPPKPKDTLMISRTPEVTCVVVDVS




HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK




EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW




QQGNVFSCSVMHEALHNHYTQKSLSLSPG





54
IL-2 L56I
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



N88D V69A,
TELKHIQCLEEELKPLEEALNLAPSKNFHLRPRDLISDINVIVLELKGSE



Q74P, C125S-
TTFMCEYADETATIVEFLNRWITFSQSIISTLTGGGGSGGGGSGGGGSGG



G4Sx4-Fc
GGSDKTHTCPPCPAPEAAGAPSVELFPPKPKDTLMISRTPEVTCVVVDVS




HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK




EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW




QQGNVFSCSVMHEALHNHYTQKSLSLSPG





55
IL-2 L80I
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



N88D V69A,
TELKHLQCLEEELKPLEEALNLAPSKNFHIRPRDLISDINVIVLELKGSE



C125S Q74P-
TTFMCEYADETATIVEFLNRWITFSQSIISTLTGGGGSGGGGSGGGGSGG



G4Sx4-Fc
GGSDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVS




HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK




EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW




QQGNVFSCSVMHEALHNHYTQKSLSLSPG





56
IL-2 L118I
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



N88D V69A,
TELKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISDINVIVLELKGSE



Q74P, C125S-
TTFMCEYADETATIVEFINRWITFSQSIISTLTGGGGSGGGGSGGGGSGG



G4Sx4-Fc
GGSDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVS




HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK




EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW




QQGNVFSCSVMHEALHNHYTQKSLSLSPG





57
IL-2 N88D
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



V69A, Q74P-
TELKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISDINVIVLELKGSE



G4Sx4-Fc
TTFMCEYADETATIVEFLNRWITFSQSIISTLTGGGGGGGGSGGGGSGG




GGSDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVS




HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK




EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC




LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW




QQGNVFSCSVMHEALHNHYTQKSLSLSPG





58
Fc-G4S-IL-2
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED



N88D V69A,
PEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYK



Q74P
CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK




GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG




NVFSCSVMHEALHNHYTQKSLSLSPGGGGGSAPTSSSTKKTQLQLEHLLL




DLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEA




LNLAPSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVEFLN




RWITFAQSIISTLT





59
IL-2 N88D
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



V69A, Q74P,
TEX1KHX2QCLEEELKPLEEALNLAPSKNFHX3RPRDLISDINVIVLELKG



C125S-G4Sx4-
SETTFMCEYADETATIVEFX4NRWITFSQSIISTLTGGGGSGGGGSGGGGS



Fc, wherein
GGGGSDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVD



at least one
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN



of X1, X2, X3,
GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL



and X4 is I
TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS



and the
RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG



remainder are




L or I.






60
IL-2 N88D
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA



V69A, Q74P,
TEX1KHX2QCLEEELKPLEEALNLAPSKNFHX3RPRDLISDINVIVLELKG



C125S,
SETTFMCEYADETATIVEFX4NRWITFSQSIISTLT



wherein at




least one of




X1, X2, X3,




and X4 is I




and the




remainder are




L or I.









In some embodiments, the sequences shown in the table or throughout comprise or don't comprise one or more mutations that correspond to positions L53, L56, L80, and L118. In some embodiments, the sequences shown in the table or throughout the present application comprise or don't comprise one or more mutations that correspond to positions L59I, L63I, I24L, L94I, L96I or L132I or other substitutions at the same positions. In some embodiments, the mutation is leucine to isoleucine. In some embodiments, the mutein does not comprise another mutation other than as shown or described herein. In some embodiments, the peptide comprises a sequence of SEQ ID NO: 21, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, or SEQ ID NO: 60.


In some embodiments, the protein comprises a IL-2 mutein as provided for herein. In some embodiments, a polypeptide is provided comprising SEQ ID NO: 59 or SEQ ID NO: 60, wherein at least one of X1, X2, X3, and X4 is I and the remainder are L or I. In some embodiments, X1, X2, and X3 are L and X4 is I. In some embodiments, X1, X2, and X4 are L and X3 is I. In some embodiments, X2, X3, and X4 are L and X1 is I. In some embodiments, X1, X3, and X4 are L and X2 is I. In some embodiments, X1 and X2 are L and X3 and X4 are I. In some embodiments, X1 and X3 are L and X2 and X4 are I. In some embodiments, X1 and X4 are L and X2 and X3 are I. In some embodiments, X2 and X3 are L and X1 and X4 are I. In some embodiments, X2 and X4 are L and X1 and X3 are I. In some embodiments, X3 and X4 are L and X1 and X2 are I. In some embodiments, X1, X2, and X3 are L and X4 is I. In some embodiments, X2, X3, and X4 are L and X1 is I. In some embodiments, X1, X3, and X4 are L and X2 is I. In some embodiments, X1, X2, and X4 are L and X3 is I.


In some embodiments, the Fc portion of the fusion is not included. In some embodiments, the peptide consists essentially of a IL-2 mutein provided for herein. In some embodiments, the protein is free of a Fc portion.


For illustrative purposes only, embodiments of IL-2 mutein fused with a Fc and with a targeting moiety are illustrated in FIG. 19.


The sequences are for illustrative purposes only and are not intended to be limiting. In some embodiments, the compound comprises an amino acid sequence of SEQ ID NO: 53, 54, 55, or 56. In some embodiments, the compound comprises an amino acid sequence of SEQ ID NO: 53, 54, 55, or 56 with or without a C125A or C125S mutation. In some embodiments, the residue at position 125 is C, S, or A. In some embodiments, the compound comprises an amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 60, wherein at least one of X1, X2, X3, and X4 is I and the remainder are L or I. In some embodiments, the protein comprises a IL-2 mutein as provided for herein. In some embodiments, a polypeptide is provided comprising SEQ ID NO: 59 or SEQ ID NO: 60, wherein at least one of X1, X2, X3, and X4 is I and the remainder are L or I. In some embodiments, X1, X2, and X3 are L and X4 is I. In some embodiments, X1, X2, and X4 are L and X3 is I. In some embodiments, X2, X3, and X4 are L and X1 is I. In some embodiments, X1, X3, and X4 are L and X2 is I. In some embodiments, X1 and X2 are L and X3 and X4 are I. In some embodiments, X1 and X3 are L and X2 and X4 are I. In some embodiments, X1 and X4 are L and X2 and X3 are I. In some embodiments, X2 and X3 are L and X1 and X4 are I. In some embodiments, X2 and X4 are L and X1 and X3 are I. In some embodiments, X3 and X4 are L and X1 and X2 are I. In some embodiments, X1, X2, and X3 are L and X4 is I. In some embodiments, X2, X3, and X4 are L and X1 is I. In some embodiments, X1, X3, and X4 are L and X2 is I. In some embodiments, X1, X2, and X4 are L and X3 is I.


Each of the proteins may also be considered to have the C125S and the LALA and/or G237A mutations as provided for herein. The C125 substitution can also be C125A as described throughout the present application.


In an embodiment, an IL-2 mutein molecule comprises at least 60, 70, 80, 85, 90, 95, or 97% sequence identity or homology with a naturally occurring human IL-2 molecule, e.g., a naturally occurring IL-2 sequence disclosed herein or those that incorporated by reference.


As described herein the IL-2 muteins can be part of a bi-specific molecule with a tethering moiety, such as a MAdCAM antibody that will target the IL-2 mutein to a MAdCAM expressing cell. As described herein, the bispecific molecule can be produced from two polypeptide chains. In some embodiments, the following can be used:












Table of MAdCAM-IL-2 Mutein Bispecific Compounds










Chain 1 N-terminal to C-terminal Molecule
Chain 2 N-terminal



Component Sequence IDs
to C-terminal












Antibody


Molecule Component



Heavy


Sequence IDs















Chain

C-
Light
Light



Antibody VH
CH1-CH2-

terminal
Chain
Chain


Detail
Domain
CH3 Domains
Linker 1
Moiety
VK Domain
CK Domain





1. Anti-
Rat Anti-
SEQ ID
SEQ ID
SEQ ID
Rat Anti-
SEQ ID


MAdCam-Fc-
MAdCam -VH1
NO: 44
NO: 23
NO: 35
MAdCam -VK1
NO: 45


IL-2 N88D


V69A, Q74P


2. Anti-
Rat Anti-
SEQ ID
SEQ ID
SEQ ID
Rat Anti-
SEQ ID


MAdCam -
MAdCam-VH2
NO: 44
NO: 23
NO: 35
MAdCam -VK2
NO: 45


Fc-IL-2


N88D V69A,


Q74P


3. Anti-
Rat Anti-
SEQ ID
SEQ ID
SEQ ID
Rat Anti-
SEQ ID


MAdCam -
MAdCam -VH1
NO: 44
NO: 23
NO: 41
MAdCam -VK3
NO: 45


Fc-IL-2


L118I N88D


V69A, Q74P


4. TTJ2-
Human TTJ2-
SEQ ID
SEQ ID
SEQ ID
Human TTJ2-
SEQ ID


Fc-IL-2
VH
NO: 44
NO: 23
NO: 41
VK
NO: 45


L118I N88D


V69A, Q74P


5. anti
Anti-MAdCam
SEQ ID
SEQ ID
SEQ ID
Anti-MAdCam
SEQ ID


hu.MAdCAM-
Human VH3
NO: 44
NO: 23
NO: 41
Human VK3
NO: 45


Fc-IL-2


L118I N88D


V69A, Q74P


6. anti
Anti-MAdCam
SEQ ID
SEQ ID
SEQ ID
Anti-MAdCam
SEQ ID


hu.MAdCAM-
Human VH4
NO: 44
NO: 23
NO: 41
Human VK4
NO: 45


Fc-IL-2


L118I N88D


V69A, Q74P


7. anti
Anti-MAdCam
SEQ ID
SEQ ID
SEQ ID
Anti-MAdCam
SEQ ID


hu.MAdCAM-
Human VH5
NO: 44
NO: 23
NO: 41
Human VK5
NO: 45


Fc-IL-2


L118I N88D


V69A, Q74P









The proteins can be produced with or without a C125A or C125S mutation in the IL-2 mutein. Examples of IL-2 muteins that can be included are illustrated herein, such as, but not limited to, a sequence of SEQ ID NO: 59 or SEQ ID NO: 60.


In some embodiments, the constant kappa domain in any of the light chains can be replaced with a constant lambda domain.


GITR-Binders

GITR (CD357) is a cell surface marker present on Tregs. Blockade of the GITR-GITRL interaction maintains Treg function. In some embodiments, a therapeutic compound comprises an IIC binding entity that binds GITR-expressing Treg cells and a targeting moiety that targets the therapeutic compound to the target tissue of interest.


In some embodiments, a therapeutic compound comprises an anti-GITR antibody molecule, e.g., anti-GITR antibody molecule that inhibit binding of GITR to GITRL.


In some embodiments, a therapeutic compound comprises an anti-GITR antibody molecule, anti-GITR antibody molecule that inhibit binding of GITR to GITRL, and PD-1 agonist, IL-2 mutein molecule, or other effector described herein.


While not wishing to be bound by theory, it is believed that the therapeutic compound that comprises a GITR binder effects accumulation of GITR-expressing Tregs at the site targeted by the targeting moiety of the therapeutic compound, e.g., a transplant or site of organ injury.


Therapeutic Compounds Comprising an SM Binding/Modulating Moiety: Manipulation of Local Microenvironment

A therapeutic compound can comprise an effector binding/modulating moiety that promotes an immuno-suppressive local microenvironment, e.g., by providing in the proximity of the target, a substance that inhibits or minimizes attack by the immune system of the target, referred to herein a SM binding/modulating moiety.


In some embodiments, the SM binding/modulating moiety comprises a molecule that inhibits or minimizes attack by the immune system of the target (referred to herein as an SM binding/modulating moiety). In some embodiments, a therapeutic compound comprises an SM binding/modulating moiety that binds and accumulates a soluble substance, e.g., an endogenous or exogenous substance having immunosuppressive function. In some embodiments, a therapeutic compound comprises an SM binding/modulating moiety, e.g., a CD39 molecule or a CD73 molecule or alkaline phosphatase molecule, that binds, inhibits, sequesters, degrades or otherwise neutralizes a soluble substance, typically and endogenous soluble substance, e.g., ATP in the case of a CD39 molecule or alkaline phosphatase molecule, or AMP in the case of a CD73 molecule, that promotes immune attack. In some embodiments, a therapeutic compound comprises an SM binding/modulating moiety that comprises an immune-suppressive substance, e.g. a fragment of protein that is immunosuppressive.


Therapeutic Compounds Comprising an ICSM Binding/Modulating Moiety: Inhibition of Stimulation, e.g., Inhibition of Co-Stimulation of Immune Cells

A therapeutic compound can comprise an ICSM binding/modulating moiety that inhibits or antagonizes a stimulatory, e.g., co-stimulatory binding pair, e.g., OX40 and OX40L. The ICSM binding/modulating moiety can bind and antagonize either member of the pair.


In an embodiment, the ICSM binding/modulating moiety comprises an antibody molecule that binds and antagonizes either member of a stimulatory, e.g., co-stimulatory binding pair. In an embodiment the ICSM binding/modulating moiety comprises antagonistic analog of one of the members of the binding pair. In such embodiments the ICSM binding/modulating moiety can comprise a soluble fragment of one of the members that binds the other. Typically the analog will have at least 50, 60, 70, 80, 90, 95, or 98% homology or sequence identity with a naturally occurring member that binds the target member of the pair. In the case of an ICSM binding/modulating moiety that binds the member present on the surface of an immune cell, the ICSM binding/modulating moiety typically binds but does not activate, or allow endogenous counter member to bind and activate.


Thus, in the case of the binding pair that includes, for example, the OX40 immune cell member and the OX40L counter member, an ICSM binding/modulating member can comprise any of the following:

    • a) an antibody molecule that binds the OX40 immune cell member and antagonizes stimulation, e.g., by blocking binding of endogenous OX40L counter member;
    • b) an antibody molecule that binds OX40L counter member and antagonizes stimulation, e.g., by blocking effective binding of the endogenous OX40L counter member to the OX40 immune cell member;
    • c) a soluble fragment or analog of OX40L counter member which binds OX40 immune cell member and antagonizes stimulation; and
    • c) a soluble fragment or analog of OX40 immune cell member which binds OX40L counter member and antagonizes stimulation.


For example, the ICSM binding/modulating moiety, e.g., an antibody molecule or an antagonistic analog or of the counter member, can bind to CD2, ICOS, CD40L, CD28, LFA1, SLAM, TIM1, CD30, OX40 (CD134), 41BB (CD137), CD27, HVEM, DR3, GITR, BAFFR, TACI, BCMA, or CD30, CD40. In another embodiment, the ICSM binding/modulating moiety, e.g., an antibody molecule or an antagonistic analog or of the counter member, can bind to B7.1, B7.2, ICOSL (B7-H2, B7RP1), LFA3, CD48, CD58, ICAM1, SLAM, TIM4, CD40, CD30L, OX40L (CD252), 41BBL (CD137L), CD70, LIGHT, TL1A, GITRL, BAFF, APRIL, or CD30, CD40L.


In some embodiments, the ICSM binding/modulating molecule binds, and antagonizes, an activating or costimulatory molecule, e.g., a costimulatory molecule, present on an immune cell, or binds the counter member preventing the counter member from activating the costimulatory molecule present on the immune cell. In some embodiments, the ICSM comprises an antagonistic antibody molecule e.g., an antibody molecule that binds the costimulatory molecule on an immune cell or binds the counter member of the ICSM, preventing the counter member from activating the costimulatory molecule on the immune cell, and results in inhibiting the activity of the costimulatory molecule. In some embodiments, the ICSM comprises an antagonistic counterpart molecule, e.g., a fragment of a molecule that binds the costimulatory molecule, and results in the inhibition of the costimulatory molecule activity.


In some embodiments, one member of the binding pair will be on the surface of an immune cell, e.g., a T, B, or NK cell or dendritic cell, while the counter member will be on another immune cell, or an APC such as a dendritic cell or on non-immune cells such as smooth cells, or endothelial cells.


The following table provides non-limiting examples of costimulatory molecule and counter structure pairs:









TABLE 4





Costimulatory molecule and counterstructure pairs


















Costimulatory




Molecule (e.g. on T



cells)
Counterstructure







CD28
B7.1 or B7.2



ICOS
ICOSL (B7H-2, B7RP1)



CD2
LFA3, CD48, CD58



LFA1
ICAM1



SLAM
SLAM



TIM1
TIM4



CD40L
CD40



CD30
CD30L



OX40/CD134
OX40L (CD252)



41BB/CD137
41BBL (CD137L)



CD27
CD70



HVEM
LIGHT



DR3
TL1A



GITR
GITRL














Costimulatory




Molecule (e.g. on B



cells)
Counterstructure







BAFFR
BAFF



TACI
BAFF and APRIL



BCMA
BAFF and APRIL



CD40
CD40L



CD30L
CD30










Donor Tissue

Therapeutic compounds and methods described herein can be used in conjunction with a transplantation of donor tissue into a subject and can minimizes rejection of, minimizes immune effector cell mediated damage to, prolongs acceptance of, or prolongs the functional life of, donor transplant tissue. The tissue can be xenograft or allograft tissue. Transplanted tissue can comprise all or part of an organ, e.g., a liver, kidney, heart, pancreas, thymus, skin or lung. In embodiments, therapeutic compounds described herein reduce, or eliminate the need for systemic immune suppression. Therapeutic compounds and methods described herein can also be used to treat GVHD. In some embodiments, host cells are coated with a therapeutic compound that comprises, as an effector binding/modulating moiety, a PD-L1 molecule.


Table 5 provides target molecules for transplant indications. A target molecule is the target to which a targeting moiety binds. As discussed elsewhere herein, In some embodiments, a targeting moiety is selected that binds a product of an allele present on donor tissue and which is not expressed by the subject (recipient) or at expressed at a different level (e.g. reduced or substantially reduced).









TABLE 5







Target Molecules for Transplant Indications










Organ/




cell


Indication
type
Target





Allograft transplant tissue,
All
HLA-A, HLA-B, HLA-C,


e.g., allograft solid organ

HLA-DP, HLA-DQ or HLA-


transplant, GvHD

DR


Transplant
Kidney
Antigens expressed in the




kidney where immune cells




infiltrate, for example




including but not limited to




the tubular interstitial




region e.g. Uromodulin,




SLC22A2, SLC22A6, FXYD4,




SLC5A10, SLC6A13, AQP6,




SLC13A3, TMEM72, BSND,




NPR3, and the proximal and




distal tubular epithelium,




such as OAT1, OCT2









Auto-Immune Disorders

Therapeutic compounds and methods described herein can be used to treat a subject having or at risk for having an unwanted autoimmune response, e.g., an auto immune response in Type 1 Diabetes, Multiple Sclerosis, Cardiomyositis, vitiligo, alopecia, inflammatory bowel disease (IBD, e.g. Crohn's disease or ulcerative colitis), Sjogren's syndrome, focal segmented glomerular sclerosis (FSGS), scleroderma/systemic sclerosis (SSc) or rheumatoid arthritis. In some embodiments, the treatment minimizes rejection of, minimizes immune effector cell mediated damage to, prolongs the survival of subject tissue undergoing, or a risk for, autoimmune attack. Table 2 provides target molecules for several autoimmune indications and organ/cell types. A target molecule is the target to which a targeting moiety binds.









TABLE 2







Target Molecules for autoimmune indications









Indication
Organ/cell type
Target Molecule





Type 1 Diabetes and
Pancreas/Pancreatic islets,
SEZ6L2, LRP11, DISP2,


Transplant
beta cells
SLC30A8, FXYD2 TSPAN7




TMEM27 (reference Hald et




al. 2012 Diabetelogia




55: 154); FXYD2; GPR119;




HEPACAM2,




DPP6, or MAdCAM


Multiple Sclerosis
CNS/myelin sheath of
MOG, PLP, MBP



oligodendrocytes


Cardiomyositis, rheumatoid
Cardiomyocytes, monocytes,
SIRPA (CD172a)


arthritis
macrophages, myeloid cells


Inflammatory bowel disease
Intestine
MAdCAM


(ulcerative colitis, Crohn's


disease) or GVHD; Celiac


disease


Autoimmune hepatitis (AIH);
liver
MAdCAM


Primary Sclerosing


Cholangitis (PSC);


Primary Biliary Sclerosis;


(PBC);


transplant


Focal Segmented Glomerular
Kidney, podocytes, tubules,
COL1A1, Cadherin 2,


Sclerosis (FSGS) and other
epithelial cells
VCAM-1, Thy1, Podocin,


diseases that can affect

KIM1 (Hodgin et al, Am J


kidney for example lupus

Pathol 177: 1675 2010);


nephritis, systemic

PLA2R; OAT1; OCT2; K-


scleroderma, membranous

cadherin 6; CDH16


glomerular nephropathy


(MGN); Membranous


nephropathy (MN); Minimal


Change Disease (MCD); IgA


nephropathy; ANCA-


associated vasculitis (AAV)


Sjogren's syndrome
Salivary glands, epithelial
FCGR3B, HLAB, KIM1 (Hu



cells, kidney
et al Arth and Rheum




56: 3588 2007


Scleroderma, systemic
skin, kidney, lung,
Collagen I, III, VI, VII,


sclerosis (SSc)
Fibroblasts, connective tissue
fibronectin (Wang et al Arth




and Rheum 54: 2271 2006)


vitiligo
Skin, epidermis, Langerhans
COL17A1, CD1A, CD207,



cells, keratinocytes,
desmoglein 1-4, keratin 1



melanocytes


Alopecia areata
Skin, Hair follicle/hair bulb,
CD133 (Yang and Cotsarelis,



dermis
J Dermatol Sci 57: 2 2010)









Other examples of autoimmune disorders and diseases that can be treated with the compounds described herein include, but are not limited to, Myocarditis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Subacute bacterial endocarditis, Anti-Glomerular Basement Membrane nephritis, Interstitial cystitis, Lupus nephritis, membranous glomerulonephropathy, Chronic Kidney Disease (“CKD”), Autoimmune hepatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Antisynthetase syndrome, alopecia areata, autoimmune angioedema, autoimmune progesterone dermatitis, autoimmune urticaria, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, discoid lupus erythematosus, epidermolysis bullosa acquisita, erythema nodosum, gestational pemphigoid, hidradenitis suppurativa, lichen planus, lichen sclerosus, linear iga disease (lad), morphea, Pemphigus vulgaris, Pityriasis lichenoides et varioliformis acuta, mucha-habermann disease, psoriasis, systemic scleroderma, vitiligo, Addison's disease, Autoimmune polyendocrine syndrome (APS) type 1, Autoimmune polyendocrine syndrome (APS) type 2, Autoimmune polyendocrine syndrome (APS) type 3, Autoimmune pancreatitis (AIP), Diabetes mellitus type 1, Autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, Autoimmune Oophoritis, Endometriosis, Autoimmune orchitis, Sjogren's syndrome, Autoimmune enteropathy, Coeliac disease, Crohn's disease, Microscopic colitis, Ulcerative colitis, thrombocytopenia, Adiposis, dolorosa, Adult-onset Still's, disease, Ankylosing, Spondylitis, CREST syndrome, Drug-induced lupus, Enthesitis-related arthritis, Eosinophilic fasciitis, Felty syndrome, IgG4-related disease, Juvenile, Arthritis, Lyme disease (Chronic), Mixed connective tissue disease (MCTD), Palindromic rheumatism, Parry Romberg syndrome, Parsonage-Turner syndrome, Psoriatic arthritis, Reactive arthritis, Relapsing polychondritis, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schnitzler syndrome, Systemic Lupus Erythematosus (SLE), Undifferentiated connective tissue disease (UCTD), Dermatomyositis, Fibromyalgia, Inclusion body myositis, Myositis, Myasthenia gravis, Neuromyotonia, Paraneoplastic cerebellar degeneration, Polymyositis, Acute disseminated encephalomyelitis (ADEM), Acute motor axonal neuropathy, Anti-N-Methyl-D-Aspartate (anti-NMDA) Receptor Encephalitis, Balo concentric sclerosis, Bickerstaff's encephalitis, Chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, Hashimoto's encephalopathy, Idiopathic inflammatory demyelinating diseases, Lambert-Eaton myasthenic syndrome, Multiple sclerosis, Oshtoran syndrome, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS), Progressive inflammatory neuropathy, Restless leg syndrome, Stiff person syndrome, Sydenham chorea, Transverse myelitis, Autoimmune retinopathy, Autoimmune uveitis, Cogan syndrome, Graves ophthalmopathy, Intermediate uveitis, Ligneous conjunctivitis, Mooren's ulcer, Neuromyelitis optica, Opsoclonus myoclonus syndrome, Optic neuritis, Scleritis, Susac's syndrome, Sympathetic ophthalmia, Tolosa-Hunt syndrome, Autoimmune inner ear disease (AIED), Ménière's disease, Behcet's disease, Eosinophilic granulomatosis with polyangiitis (EGPA), Giant cell arteritis, Granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), Kawasaki's disease, Leukocytoclastic vasculitis, Lupus vasculitis, Rheumatoid vasculitis, Microscopic polyangiitis (MPA), Polyarteritis nodosa (PAN), Polymyalgia rheumatica, Vasculitis, Primary Immune Deficiency, and the like.


Other examples of potential autoimmune disorders and diseases, as well as autoimmune comorbidities that can be treated with the compounds described herein include, but are not limited to, Chronic fatigue syndrome, Complex regional pain syndrome, Eosinophilic esophagitis, Gastritis, Interstitial lung disease, POEMS syndrome, Raynaud's phenomenon, Primary immunodeficiency, Pyoderma gangrenosum, Agammaglobulinemia, Amyloidosis, Amyotrophic lateral sclerosis, Anti-tubular basement membrane nephritis, Atopic allergy, Atopic dermatitis, Autoimmune peripheral neuropathy, Blau syndrome, Castleman's disease, Chagas disease, Chronic obstructive pulmonary disease, Chronic recurrent multifocal osteomyelitis, Complement component 2 deficiency, Contact dermatitis, Cushing's syndrome, Cutaneous leukocytoclastic angiitis, Dego' deiase, Eczema, Eosinophilic gastroenteritis, Eosinophilic pneumonia, Erythroblastosis fetalsis, Fibrodysplasia ossificans progressive, Gastrointestinal pemphigoid, Hypogammaglobulinemia, Idiopathic giant-cell myocarditis, Idiopathic pulmonary fibrosis, IgA nephropathy, Immunoregulatory lipoproteins, IPEX syndrome, Ligenous conjunctivitis, Majeed syndrome, Narcolepsy, Rasmussen's encephalitis, Schizophrenia, Serum sickness, Spondyloarthropathy, Sweet's syndrome, Takayasu's arteritis, and the like.


In some embodiments, the autoimmune disorder does not comprise Pemphigus vulgaris, Pemphigus. In some embodiments, the autoimmune disorder does not comprise Pemphigus foliaceus. In some embodiments, the autoimmune disorder does not comprise bullous pemphigoid. In some embodiments, the autoimmune disorder does not comprise Goodpasture's Disease. In some embodiments, the autoimmune disorder does not comprise psoriasis. In some embodiments, the autoimmune disorder does not comprise a skin disorder. In some embodiments, the disorder does not comprise a neoplastic disorder, e.g., cancer.


Therapeutic Compounds

A therapeutic compound comprises a specific targeting moiety functionally associated with an effector binding/modulating moiety. In some embodiments, the specific targeting moiety and effector binding/modulating moiety are linked to one another by a covalent or noncovalent bond, e.g., a covalent or non-covalent bond directly linking the one to the other. In other embodiments, a specific targeting moiety and effector binding/modulating moiety are linked, e.g., covalently or noncovalently, through a linker moiety. E.g., in the case of a fusion polypeptide, a polypeptide sequence comprising the specific targeting moiety and a polypeptide sequence can be directly linked to one another or linked through one or more linker sequences. In some embodiments, the linker moiety comprises a polypeptide. Linkers are not, however, limited to polypeptides. In some embodiments, a linker moiety comprises other backbones, e.g., a non-peptide polymer, e.g., a PEG polymer. In some embodiments, a linker moiety can comprise a particle, e.g., a nanoparticle, e.g., a polymeric nanoparticle. In some embodiments, a linker moiety can comprise a branched molecule, or a dendrimer. However, in embodiments where the effector binding/modulating moiety comprises an ICIM binding/modulating moiety (which binds an effector like PD-1) structures that result in clustering in the absence of target binding should be avoided as they may cause clustering in the absence of target binding. Thus in embodiments, the therapeutic compound has a structure, e.g., the copies of an WWI are sufficiently limited, such that clustering in the absence of target binding is minimized or substantially eliminated, or eliminated, or is sufficiently minimized that substantial systemic immune suppression does not occur.


In some embodiments, the disclosure provides for use of a polypeptide or antibody as provided for herein, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of inflammatory bowel disease.


In some embodiments, the disclosure provides for use of a polypeptide or antibody as provided for herein, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of inflammatory bowel disease, such as Crohn's disease, or ulcerative colitis.


In some embodiments, the disclosure provides for use of a polypeptide or antibody as provided for herein, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of Crohn's disease, or ulcerative colitis.


In some embodiments, the disclosure provides for use of a polypeptide or antibody as provided for herein, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of an auto-immune hepatitis, a primary sclerosing cholangitis, a Type 1 diabetes, a transplant, a GVHD, an elevated risk, or a risk, for having, an autoimmune disorder.


In some embodiments, the disclosure provides for use of a polypeptide or antibody as provided for herein, or a pharmaceutical composition comprising the same, for the treatment of inflammatory bowel disease.


In some embodiments, the disclosure provides for use of a polypeptide or antibody as provided for herein, or a pharmaceutical composition comprising the same, for the treatment of an auto-immune hepatitis, a primary sclerosing cholangitis, a Type 1 diabetes, a transplant, a GVHD, an elevated risk, or a risk, for having, an autoimmune disorder.


In some embodiments, a therapeutic compound comprises a polypeptide comprising a specific targeting moiety covalently or non-covalently conjugated to an effector binding/modulating moiety. In some embodiments, a therapeutic molecule comprises a fusion protein having comprising a specific targeting moiety fused, e.g., directly or through a linking moiety comprising one or more amino acid residues, to an effector binding/modulating moiety. In some embodiments, a therapeutic molecule comprises a polypeptide comprising a specific targeting moiety linked by a non-covalent bond or a covalent bond, e.g., a covalent bond other than a peptide bond, e.g., a sulfhydryl bond, to an effector binding/modulating moiety.


In some embodiments, a therapeutic compound comprises polypeptide, e.g., a fusion polypeptide, comprising:

    • 1.a) a specific targeting moiety comprising a target specific binding polypeptide;
    • 1.b) a specific targeting moiety comprising a target ligand binding molecule;
    • 1.c) a specific targeting moiety comprising an antibody molecule;
    • 1.d) a specific targeting moiety comprising a single chain antibody molecule, e.g., a scFv domain; or
    • 1.e) a specific targeting moiety comprising a first of the light or heavy chain variable region of an antibody molecule, and wherein the other variable region is covalently or non-covalently associated with the first; and
    • 2.a) an effector binding/modulating moiety comprising an effector specific binding polypeptide;
    • 2.b) an effector binding/modulating moiety comprising an effector ligand binding molecule;
    • 2.c) an effector binding/modulating moiety comprising an antibody molecule;
    • 2.d) an effector binding/modulating moiety comprising a single chain antibody molecule, e.g., a scFv domain; or
    • 2.e) an effector binding/modulating moiety comprising a first of the light or heavy chain variable region of an antibody molecule, and wherein the other variable region is covalently or non-covalently associated with the first.


In some embodiments, a therapeutic compound comprises 1.a and 2.a.


In some embodiments, a therapeutic compound comprises 1.a and 2.b.


In some embodiments, a therapeutic compound comprises 1.a and 2.c.


In some embodiments, a therapeutic compound comprises 1.a and 2.d.


In some embodiments, a therapeutic compound comprises 1.a and 2.e.


In some embodiments, a therapeutic compound comprises 1.b and 2.a.


In some embodiments, a therapeutic compound comprises 1.b and 2.b.


In some embodiments, a therapeutic compound comprises 1.b and 2.c.


In some embodiments, a therapeutic compound comprises 1.b and 2.d.


In some embodiments, a therapeutic compound comprises 1.b and 2.e.


In some embodiments, a therapeutic compound comprises 1.c and 2.a.


In some embodiments, a therapeutic compound comprises 1.c and 2.b.


In some embodiments, a therapeutic compound comprises 1.c and 2.c.


In some embodiments, a therapeutic compound comprises 1.c and 2.d.


In some embodiments, a therapeutic compound comprises 1.c and 2.e.


In some embodiments, a therapeutic compound comprises 1.d and 2.a.


In some embodiments, a therapeutic compound comprises 1.d and 2.b.


In some embodiments, a therapeutic compound comprises 1.d and 2.c.


In some embodiments, a therapeutic compound comprises 1.d and 2.d.


In some embodiments, a therapeutic compound comprises 1.d and 2.e.


In some embodiments, a therapeutic compound comprises 1.e and 2.a.


In some embodiments, a therapeutic compound comprises 1.e and 2.b.


In some embodiments, a therapeutic compound comprises 1.e and 2.c.


In some embodiments, a therapeutic compound comprises 1.e and 2.d.


In some embodiments, a therapeutic compound comprises 1.e and 2.e.


Therapeutic compounds disclosed herein can, for example, comprise a plurality of effector binding/modulating and specific targeting moieties. Any suitable linker or platform can be used to present the plurality of moieties. The linker is typically coupled or fused to one or more effector binding/modulating and targeting moieties.


In some embodiments, two (or more) linkers associate, either covalently or non-covalently, e.g., to form a hetero or homo-dimeric therapeutic compound. E.g., the linker can comprise an Fc region and two Fc regions associate with one another. In some embodiments of a therapeutic compound comprising two linker regions, the linker regions can self-associate, e.g., as two identical Fc regions. In some embodiments of a therapeutic compound comprising two linker regions, the linker regions are not capable of, or not capable of substantial, self-association, e.g., the two Fc regions can be members of a knob and hole pair.


Non-limiting exemplary configurations of therapeutic compounds comprise the following (e.g., in N to C terminal order):

    • R1—Linker Region A—R2
    • R3—Linker Region B—R4,


      wherein,


R1, R2, R3, and R4, each independently comprises an effector binding/modulating moiety, e.g., an ICIM binding/modulating moiety, an IIC binding/modulating moiety, ICSM binding/modulating moiety, or an SM binding/modulating moiety; a specific targeting moiety; or is absent, provided that at least one of R1 and R2 is not absent, and at least one of R3 and R4 is not absent;


Linker Region A and Linker B comprise moieties that can associate with one another, e.g., Linker A and Linker B each comprises an Fc moiety provided that an effector binding/modulating moiety and a specific targeting moiety are present.


In some embodiments, the polypeptide having the formula of R1—Linker Region A—R2 and the polypeptide having the formula of R3—Linker Region B—R4 interact with one another to form a polypeptide complex. In some embodiment, the polypeptide having the formula of R1—Linker Region A—R2 and the polypeptide having the formula of R3—Linker Region B—R4 do not interact with one another to form a polypeptide complex.


In Some Embodiments:

    • R1 comprises an effector binding/modulating moiety, e.g., an ICIM binding/modulating moiety, an IIC binding/modulating moiety, ICSM binding/modulating moiety, or an SM binding/modulating moiety, or is absent;
    • R2 comprises a specific targeting moiety, or is absent;
    • R3 comprises an effector binding/modulating moiety, e.g., an ICIM binding/modulating moiety, an IIC binding/modulating moiety, ICSM binding/modulating moiety, or an SM binding/modulating moiety, or is absent;
    • R4 comprises a specific targeting moiety, or is absent;


Linker Region A and Linker B comprise moieties that can associate with one another, e.g., Linker A and Linker B each comprises an Fc moiety, provided that one of R1 or R3 is present and one of R2 or R4 is present.


In Some Embodiments:

    • R1 comprises a specific targeting moiety, or is absent;
    • R2 comprises an effector binding/modulating moiety, e.g., an ICIM binding/modulating moiety, an IIC binding/modulating moiety, ICSM binding/modulating moiety, or an SM binding/modulating moiety, or is absent;
    • R3 comprises a specific targeting moiety, or is absent;
    • R4 comprises an effector binding/modulating moiety, e.g., an ICIM binding/modulating moiety, an IIC binding/modulating moiety, ICSM binding/modulating moiety, or an SM binding/modulating moiety, or is absent;


Linker Region A and Linker B comprise moieties that can associate with one another, e.g., Linker A and Linker B each comprises an Fc moiety, provided that one of R1 or R3 is present and one of R2 or R4 is present.


Non-limiting examples include, but are not limited to:



















Linker


Linker Region




R1
Region A
R2
R3
B
R4
Other







HCVR and
Fc Region
scFv
HCVR
Fc Region
scFv
Self-Pairing


LCVR


and


Linker Regions





LCVR


HCVR and
Fc Region
scFv
HCVR
Fc Region
scFv
Non-Self


LCVR


and


Pairing linker





LCVR


regions


HCVR and
Fc Region
scFv
HCVR
Fc Region
scFv
Self-Pairing


LCVR (or


and


Linker Regions


absent)


LCVR


One of R1 or





(or


R3 is absent.





absent)


HCVR and
Fc Region
scFv
HCVR
Fc Region
scFv
Non-Self


LCVR (or


and


Pairing Linker


absent)


LCVR


Regions





(or


One of R1 or





absent)


R3 is absent.


HCVR and
Fc Region
scFv (or
HCVR
Fc Region
scFv (or
Self-Pairing


LCVR

absent)
and

absent)
linker regions





LCVR


One of R2 or








R4 is absent.


HCVR and
Fc Region
scFv (or
HCVR
Fc Region
scFv (or
Non-Self


LCVR

absent)
and

absent)
Pairing linker





LCVR


regions








One of R2 or








R4 is absent.


HCVR and
Fc Region
scFv
HCVR
Fc Region
scFv
Self-Pairing


LCVR


and


Linker Regions





LCVR


R1 and R3 are








the same


HCVR and
Fc Region
scFv
HCVR
Fc Region
scFv
Non-Self


LCVR


and


Pairing linker





LCVR


regions








Rland R3 are








different


HCVR and
Fc Region
scFv
HCVR
Fc Region
scFv
Self-Pairing


LCVR


and


Linker Regions





LCVR


R2 and R4 are








the same


HCVR and
Fc Region
scFv
HCVR
Fc Region
scFv
Non-Self


LCVR


and


Pairing linker





LCVR


regions








R2and R4 are








different





HCVR and LCVR: refers to an moiety comprising an antigen binding portion of a heavy and light chain variable region, typically with the heavy chain fused to the Linker region.


Self-pairing: wherein a liker region can pair with itself, e.g., an Fc region that can pair a copy of itself.


Non-Self Pairing: wherein a Linker Region does not pair with itself, or does not substantially pair with itself, e.g., an Fc region does not or does not significantly pair with itself, e.g., wherein Linker Region A and Linker Region B are members of a knob and hole pair.






In Some Embodiments:

    • R1, R2, R3 and R4 each independently comprise: an effector binding modulating moiety that activates an inhibitory receptor on an immune cell, e.g., a T cell or a B cell, e.g., a PD-L1 molecule or a functional anti-PD-1 antibody molecule (an agonist of PD-1); a specific targeting moiety; or is absent, provided that at least one of R1 and R2 is not absent, and at least one of R3 and R4 is not absent;
    • provided that an effector binding moiety and a specific targeting moiety are present.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties).


In Some Embodiments:

    • R1 and R3 independently comprise an effector binding modulating moiety that activates an inhibitory receptor on an immune cell, e.g., a T cell or a B cell, e.g., a PD-L1 molecule or an functional anti-PD-1 antibody molecule (an agonist of PD-1); and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties).


In Some Embodiments:

    • R1 and R3 independently comprise a functional anti-PD-1 antibody molecule (an agonist of PD-1); and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties).


In Some Embodiments:

    • R1 and R3 independently comprise specific targeting moieties, e.g., an anti-tissue antigen antibody; and
    • R2 and R4 independently comprise a functional anti-PD-1 antibody molecule (an agonist of PD-1), e.g., an scFv molecule.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties).


In Some Embodiments:

    • R1 and R3 independently comprise a PD-L1 molecule (an agonist of PD-1); and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen; and


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties).


In Some Embodiments:

    • R1 and R3 independently comprise specific targeting moieties, e.g., an anti-tissue antigen antibody; and
    • R2 and R4 independently comprise a PD-L1 molecule (an agonist of PD-1).


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties).


In Some Embodiments:

    • R1, R2, R3 and R4 each independently comprise: an SM binding/modulating moiety which modulates, e.g., binds and inhibits, sequesters, degrades or otherwise neutralizes a substance, e.g., a soluble molecule that modulates an immune response, e.g., ATP or AMP, e.g., a CD39 molecule or a CD73 molecule; a specific targeting moiety; or is absent, provided that at least one of R1 and R2 is not absent, and at least one of R3 and R4 is not absent; provided that an SM binding/modulating moiety and a specific targeting moiety are present.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • R1 and R3 independently comprise an SM binding/modulating moiety which modulates, e.g., binds and inhibits, sequesters, degrades or otherwise neutralizes a substance, e.g., a soluble molecule that modulates an immune response, e.g., ATP or AMP, e.g., a CD39 molecule or a CD73 molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • R1 and R3 independently comprise a CD39 molecule or a CD73 molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • R1 and R3 each comprises a CD39 molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen; and
    • In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • R1 and R3 each comprises a CD73 molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • One of R1 and R3 comprises a CD39 molecule and the other comprises a CD73 molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • R1, R2, R3 and R4 each independently comprise: an HLA-G molecule; a specific targeting moiety; or is absent;
    • provided that an HLA-G molecule and a specific targeting moiety are present.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • R1 and R3 each comprise an HLG-A molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • R1 and R3 each comprise an agonistic anti-LILRB1 antibody molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • R1 and R3 each comprise an agonistic anti-KIR2DL4 antibody molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • R1 and R3 each comprise an agonistic anti-LILRB2 antibody molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • R1 and R3 each comprise an agonistic anti-NKG2A antibody molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • one of R1 and R3 comprises a first moiety chosen from, and the other comprises a different moiety chosen from: an antagonistic anti-LILRB1 antibody molecule, an agonistic anti-KR2DL4 antibody molecule, and an agonistic anti-NKG2A antibody molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • one of R1 and R3 comprises an antagonistic anti-LILRB1 antibody molecule and the other comprises an agonistic anti-KR2DL4 antibody molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • one of R1 and R3 comprises an antagonistic anti-LILRB1 antibody molecule and the other comprises an agonistic anti-NKG2A antibody molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In an Embodiment:

    • R1, R2, R3 and R4 each independently comprise: an IL-2 mutein molecule; a specific targeting moiety; or is absent;
    • provided that an IL-2 mutein molecule and a specific targeting moiety are present.


In an embodiment Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


One of R1, R2, R3 and R4 comprises an IL-2 mutein molecule, one comprises an anti-GITR antibody molecule, e.g., an anti-GITR antibody molecule that inhibits binding of GITRL to GITR, and one comprises a specific targeting moiety;


In an embodiment Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In an Embodiment:

    • R1 and R3 each comprise an IL-2 mutein molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In an embodiment Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In an Embodiment:

    • one of R1 and R3 comprises a GARP binding molecule, e.g., an anti-GARP antibody molecule or a GITR binding molecule, e.g., an anti-GITR antibody molecule and the other comprises an IL-2 mutein molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In an embodiment Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In an Embodiment:

    • one of R1 and R3 comprises a GARP binding molecule, e.g., an anti-GARP antibody molecule and the other comprises an IL-2 mutein molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In an embodiment Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In an Embodiment:

    • one of R1 and R3 comprises a GITR binding molecule, e.g., an anti-GITR antibody molecule, and the other comprises an IL-2 mutein molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In an embodiment Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In Some Embodiments:

    • R1, R2, R3 and R4 each independently comprise: an effector binding modulating moiety that activates an inhibitory receptor on a B cell, e.g., an anti-FCRL antibody molecule, e.g., an agonistic anti-FCRL antibody molecule; a specific targeting moiety; or is absent; provided that an effector binding moiety and a specific targeting moiety are present. In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In embodiment the anti-FCRL molecule comprises: an anti-FCRL antibody molecule, e.g., an agonistic anti-FCRL antibody molecule, directed to FCRL1, FCRL2, FCRL3, FCRL4, FCRL5, or FCRL6.


In Some Embodiments:

    • R1 and R3 each comprises an agonistic anti-FCRL antibody molecule; and
    • R2 and R4 independently comprise specific targeting moieties, e.g., scFv molecules against a tissue antigen.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In embodiment the anti-FCRL molecule comprises: an anti-FCRL antibody molecule, e.g., an agonistic anti-FCRL antibody molecule directed to FCRL1, FCRL2, FCRL3, FCRL4, FCRL5, or FCRL6.


In Some Embodiments:

    • R1 and R3 independently comprise specific targeting moieties, e.g., antibody molecules against a tissue antigen; and
    • R2 and R4 each comprises an anti-FCRL antibody molecule, e.g., an agonistic anti-FCRL antibody molecule, e.g., an scFv molecule.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In embodiment the anti-FCRL molecule comprises: an anti-FCRL antibody molecule, e.g., an agonistic anti-FCRL antibody molecule directed to FCRL1, FCRL2, FCRL3, FCRL4, FCRL5, or FCRL6.


In Some Embodiments:


One of R1, R2, R3 and R4 comprises an anti-BCR antibody molecule, e.g., an antagonistic anti-BCR antibody molecule, one comprises an anti FCRL antibody molecule, and one comprises a specific targeting moiety.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In some embodiments, the anti-FCRL molecule comprises: an anti-FCRL antibody molecule, e.g., an agonistic anti-FCRL antibody molecule directed to FCRL1, FCRL2, FCRL3, FCRL4, FCRL5, or FCRL6.


In Some Embodiments:


One of R1, R2, R3 and R4 comprises a bispecific antibody molecule comprising an anti-BCR antibody molecule, e.g., an antagonistic anti-BCR antibody molecule, and an anti FCRL antibody molecule, and one comprises a specific targeting moiety;


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties or Fc moieties that do not, or do not substantially self-pair).


In embodiment the anti-FCRL molecule comprises: an anti-FCRL antibody molecule, e.g., an agonistic anti-FCRL antibody molecule directed to FCRL1, FCRL2, FCRL3, FCRL4, FCRL5, or FCRL6.


In Some Embodiments:

    • R1, R2, R3 and R4 each independently comprise:
      • i) an effector binding/modulating moiety, e.g., an ICIM binding/modulating moiety, an IIC binding/modulating moiety, ICSM binding/modulating moiety, or an SM binding/modulating moiety, that minimizes or inhibits T cell activity, expansion, or function (a T cell effector binding/modulating moiety);
      • ii) an effector binding/modulating moiety, e.g., an ICIM binding/modulating moiety, an IIC binding/modulating moiety, ICSM binding/modulating moiety, or an SM binding/modulating moiety, that minimizes or inhibits B cell activity, expansion, or function (a B cell effector binding/modulating moiety);
      • iii) a specific targeting moiety; or
      • iv) is absent;
    • provided that, a T cell effector binding/modulating moiety, a B cell effector binding/modulating moiety, and a specific targeting moiety are present.


In some embodiments, Linker A and Linker B comprise Fc moieties (e.g., self-pairing Fc moieties).


In some embodiments, one of R1, R2, R3, and R4 comprises an agonistic anti-PD-1 antibody and one comprises an HLA-G molecule.


In some embodiments, one of R1, R2, R3, and R4 comprises an SM binding/modulating moiety, e.g., a CD39 molecule or a CD73 molecule. In some embodiments, one of R1, R2, R3, and R4 comprises an entity that binds, activates, or maintains, a regulatory immune cell, e.g., a Treg cell or a Breg cell, for example, an IL-2 mutein molecule.


In some embodiments, one of R1, R2, R3, and R4 comprises an agonistic anti-PD-1 antibody, or one comprises an HLA-G molecule, and one comprises an IL-2 mutein molecule. In some embodiments, the PD-1 antibody is replaced with a IL-2 mutein molecule. In some embodiments, one of R1, R2, R3, and R4 comprises an agonistic anti-PD-1 antibody, one comprises an HLA-G molecule, and one comprises CD39 molecule or a CD73 molecule. In some embodiments, the PD-1 antibody is replaced with a IL-2 mutein molecule.


Linker Regions

As discussed elsewhere herein specific targeting and effector binding/modulating moieties can be linked by linker regions. Any linker region described herein can be used as a linker. For example, linker Regions A and B can comprise Fc regions. In some embodiments, a therapeutic compound comprises a Linker Region that can self-associate. In some embodiments, a therapeutic compound comprises a Linker Region that has a moiety that minimizes self-association, and typically Linker Region A and Linker Region B are heterodimers. Linkers also include glycine/serine linkers. In some embodiments, the linker can comprise one or more repeats of GGGGS (SEQ ID NO: 23). In some embodiments, the linker comprises 1, 2, 3, 4, or 5 repeats of SEQ ID NO: 23. In some embodiments, the linker comprises GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22), or GGGGSGGGGSGGGGS (SEQ ID NO: 30). These linkers can be used in any of the therapeutic compounds or compositions provided herein.


The linker region can comprise a Fc region that has been modified (e.g. mutated) to produce a heterodimer. In some embodiments, the CH3 domain of the Fc region can be mutated. Examples of such Fc regions can be found in, for example, U.S. Pat. No. 9,574,010, which is hereby incorporated by reference in its entirety. The Fc region as defined herein comprises a CH3 domain or fragment thereof, and may additionally comprise one or more addition constant region domains, or fragments thereof, including hinge, CH1, or CH2. It will be understood that the numbering of the Fc amino acid residues is that of the EU index as in Kabat et al., 1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va. The “EU index as set forth in Kabat” refers to the EU index numbering of the human IgG1 Kabat antibody. For convenience, Table B of U.S. Pat. No. 9,574,010 provides the amino acids numbered according to the EU index as set forth in Kabat of the CH2 and CH3 domain from human IgG1, which is hereby incorporated by reference. Table 1.1 of U.S. Pat. No. 9,574,010 provides mutations of variant Fc heterodimers that can be used as linker regions. Table 1.1 of U.S. Pat. No. 9,574,010 is hereby incorporated by reference.


In some embodiments, the Linker Region A comprises a first CH3 domain polypeptide and a the Linker Region B comprises a second CH3 domain polypeptide, the first and second CH3 domain polypeptides independently comprising amino acid modifications as compared to a wild-type CH3 domain polypeptide, wherein the first CH3 domain polypeptide comprises amino acid modifications at positions T350, L351, F405, and Y407, and the second CH3 domain polypeptide comprises amino acid modifications at positions T350, T366, K392 and T394, wherein the amino acid modification at position T350 is T350V, T3501, T350L or T350 M; the amino acid modification at position L351 is L351Y; the amino acid modification at position F405 is F405A, F405V, F405T or F405S; the amino acid modification at position Y407 is Y407V, Y407A or Y4071; the amino acid modification at position T366 is T366L, T366I, T366V, or T366 M, the amino acid modification at position K392 is K392F, K392L or K392 M, and the amino acid modification at position T394 is T394W, and wherein the numbering of amino acid residues is according to the EU index as set forth in Kabat.


In some embodiments, the amino acid modification at position K392 is K392 M or K392L. In some embodiments, the amino acid modification at position T350 is T350V. In some embodiments, the first CH3 domain polypeptide further comprises one or more amino acid modifications selected from Q347R and one of S400R or S400 E. In some embodiments, the second CH3 domain polypeptide further comprises one or more amino acid modifications selected from L351Y, K360 E, and one of N390R, N390D or N390 E. In some embodiments, the first CH3 domain polypeptide further comprises one or more amino acid modifications selected from Q347R and one of S400R or S400 E, and the second CH3 domain polypeptide further comprises one or more amino acid modifications selected from L351Y, K360 E, and one of N390R, N390D or N390 E. In some embodiments, the amino acid modification at position T350 is T350V. In some embodiments, the amino acid modification at position F405 is F405A. In some embodiments, the amino acid modification at position Y407 is Y407V. In some embodiments, the amino acid modification at position T366 is T366L or T366I. In some embodiments, the amino acid modification at position F405 is F405A, the amino acid modification at position Y407 is and Y407V, the amino acid modification at position T366 is T366L or T366I, and the amino acid modification at position K392 is K392 M or K392L. In some embodiments, the first CH3 domain polypeptide comprises the amino acid modifications T350V, L351Y, S400 E, F405V and Y407V, and the second CH3 domain polypeptide comprises the amino acid modifications T350V, T366L, N390R, K392 M and T394W. In some embodiments, the first CH3 domain polypeptide comprises the amino acid modifications T350V, L351Y, S400 E, F405T and Y407V, and the second CH3 domain polypeptide comprises the amino acid modifications T350V, T366L, N390R, K392 M and T394W. In some embodiments, the first CH3 domain polypeptide comprises the amino acid modifications T350V, L351Y, S400 E, F405S and Y407V, and the second CH3 domain polypeptide comprises the amino acid modifications T350V, T366L, N390R, K392 M and T394W. In some embodiments, the first CH3 domain polypeptide comprises the amino acid modifications T350V, L351Y, S400 E, F405A and Y407V, and the second CH3 domain polypeptide comprises the amino acid modifications T350V, L351Y, T366L, N390R, K392 M and T394W. In some embodiments, the first CH3 domain polypeptide comprises the amino acid modifications Q347R, T350V, L351Y, S400 E, F405A and Y407V, and the second CH3 domain polypeptide comprises the amino acid modifications T350V, K360 E, T366L, N390R, K392 M and T394W. In some embodiments, the first CH3 domain polypeptide comprises the amino acid modifications T350V, L351Y, S400R, F405A and Y407V, and the second CH3 domain polypeptide comprises the amino acid modifications T350V, T366L, N390D, K392 M and T394W. In some embodiments, the first CH3 domain polypeptide comprises the amino acid modifications T350V, L351Y, S400R, F405A and Y407V, and the second CH3 domain polypeptide comprises the amino acid modifications T350V, T366L, N390 E, K392 M and T394W. In some embodiments, the first CH3 domain polypeptide comprises the amino acid modifications T350V, L351Y, S400 E, F405A and Y407V, and the second CH3 domain polypeptide comprises the amino acid modifications T350V, T366L, N390R, K392L and T394W. In some embodiments, the first CH3 domain polypeptide comprises the amino acid modifications T350V, L351Y, S400 E, F405A and Y407V, and the second CH3 domain polypeptide comprises the amino acid modifications T350V, T366L, N390R, K392F and T394W.


In some embodiments, an isolated heteromultimer comprising a heterodimeric CH3 domain comprising a first CH3 domain polypeptide and a second CH3 domain polypeptide, the first CH3 domain polypeptide comprising amino acid modifications at positions F405 and Y407, and the second CH3 domain polypeptide comprising amino acid modifications at positions T366 and T394, wherein: (i) the first CH3 domain polypeptide further comprises an amino acid modification at position L351, and (ii) the second CH3 domain polypeptide further comprises an amino acid modification at position K392, wherein the amino acid modification at position F405 is F405A, F405T, F405S or F405V; and the amino acid modification at position Y407 is Y407V, Y407A, Y407L or Y4071; the amino acid modification at position T394 is T394W; the amino acid modification at position L351 is L351Y; the amino acid modification at position K392 is K392L, K392 M, K392V or K392F, and the amino acid modification at position T366 is T366I, T366L, T366 M or T366V, wherein the heterodimeric CH3 domain has a melting temperature (Tm) of about 70.degree. C. or greater and a purity greater than about 90%, and wherein the numbering of amino acid residues is according to the EU index as set forth in Kabat.


In some embodiments, the Linker Region A comprises a first CH3 domain polypeptide and at Linker Region B comprises a second CH3 domain polypeptide, wherein the first CH3 domain polypeptide comprising amino acid modifications at positions F405 and Y407, and the second CH3 domain polypeptide comprising amino acid modifications at positions T366 and T394, wherein: (i) the first CH3 domain polypeptide further comprises an amino acid modification at position L351, and (ii) the second CH3 domain polypeptide further comprises an amino acid modification at position K392, wherein the amino acid modification at position F405 is F405A, F405T, F405S or F405V; and the amino acid modification at position Y407 is Y407V, Y407A, Y407L or Y4071; the amino acid modification at position T394 is T394W; the amino acid modification at position L351 is L351Y; the amino acid modification at position K392 is K392L, K392 M, K392V or K392F, and the amino acid modification at position T366 is T366I, T366L, T366 M or T366V, wherein the heterodimeric CH3 domain has a melting temperature (Tm) of about 70° C. or greater and a purity greater than about 90%, and wherein the numbering of amino acid residues is according to the EU index as set forth in Kabat. In some embodiments, the amino acid modification at position F405 is F405A. In some embodiments, the amino acid modification at position T366 is T366I or T366L. In some embodiments, the amino acid modification at position Y407 is Y407V. In some embodiments, the amino acid modification at position F405 is F405A, the amino acid modification at position Y407 is Y407V, the amino acid modification at position T366 is T366I or T366L, and the amino acid modification at position K392 is K392L or K392 M. In some embodiments, the amino acid modification at position F405 is F405A, the amino acid modification at position Y407 is Y407V, the amino acid modification at position T366 is T366L, and the amino acid modification at position K392 is K392 M. In some embodiments, the amino acid modification at position F405 is F405A, the amino acid modification at position Y407 is Y407V, the amino acid modification at position T366 is T366L, and the amino acid modification at position K392 is K392L. In some embodiments, the amino acid modification at position F405 is F405A, the amino acid modification at position Y407 is Y407V, the amino acid modification at position T366 is T366I, and the amino acid modification at position K392 is K392 M. In some embodiments, the amino acid modification at position F405 is F405A, the amino acid modification at position Y407 is Y407V, the amino acid modification at position T366 is T366I, and the amino acid modification at position K392 is K392L. In some embodiments, the first CH3 domain polypeptide further comprises an amino acid modification at position 5400 selected from S400D and S400 E, and the second CH3 domain polypeptide further comprises the amino acid modification N390R. In some embodiments, the amino acid modification at position F405 is F405A, the amino acid modification at position Y407 is Y405V, the amino acid modification at position 5400 is S400 E, the amino acid modification at position T366 is T366L, and the amino acid modification at position K392 is K392 M.


In some embodiments, the modified first and second CH3 domains are comprised by an Fc construct based on a type G immunoglobulin (IgG). The IgG can be an IgG1, IgG2, IgG3 or IgG4.


Other Linker Region A and Linger Region B comprising variant CH3 domains are described in U.S. Pat. Nos. 9,499,634 and 9,562,109, each of which is incorporated by reference in its entirety.


A Linker Region A and Linker Region B can be complementary fragments of a protein, e.g., a naturally occurring protein such as human serum albumin. In embodiments, one of Linker Region A and Linker Region B comprises a first, e.g., an N terminal fragment of the protein, e.g., hSA, and the other comprises a second, e.g., a C terminal fragment of the protein, e.g., has. In an embodiment the fragments comprise an N terminal and a C terminal fragment. In an embodiment the fragments comprise two internal fragments. Typically the fragments do not overlap. In an embodiment the First and second fragment, together, provide the entire sequence of the original protein, e.g., hSA. The first fragment provides a N terminus and a C terminus for linking, e.g., fusing, to other sequences, e.g., sequences of R1, R2, R3, or R4 (as defined herein).


The Linker Region A and the Linker Region B can be derived from albumin polypeptide. In some embodiments, the albumin polypeptide is selected from native human serum albumin polypeptide and human alloalbumin polypeptide. The albumin polypeptide can be modified such that the Linker Region A and Linker Region B interact with one another to form heterodimers. Examples of modified albumin polypeptides are described in U.S. Pat. Nos. 9,388,231 and 9,499,605, each of which is hereby incorporated by reference in its entirety. Accordingly, provided herein are multifunctional heteromultimer proteins of the formula R1—Linker Region A—R2 and R3—Linker Region B—R4, wherein the Linker Region A and Linker Region B form a heteromultimer. In some embodiments, the Linker Region A comprises a first polypeptide and the Linker Region B comprises a second polypeptide; wherein each of said first and second polypeptides comprises an amino acid sequence comprising a segment of an albumin polypeptide selected from native human serum albumin polypeptide and human alloalbumin polypeptide; wherein said first and second polypeptides are obtained by segmentation of said albumin polypeptide at a segmentation site, such that the segmentation results in a deletion of zero to 3 amino acid residues at the segmentation site; wherein said first polypeptide comprises at least one mutation selected from A194C, L198C, W214C, A217C, L331C and A335C, and said second polypeptide comprises at least one mutation selected from L331C, A335C, V343C, L346C, A350C, V455C, and N458C; and wherein said first and second polypeptides self-assemble to form a quasi-native structure of the monomeric form of the albumin polypeptide.


In some embodiments, the segmentation site resides on a loop of the albumin polypeptide that has a high solvent accessible surface area (SASA) and limited contact with the rest of the albumin structure, b) the segmentation results in a complementary interface between the transporter polypeptides. These segmentation sites are described, for example, in U.S. Pat. No. 9,388,231, which is hereby incorporated by reference in its entirety.


In some embodiments, the first polypeptide comprises residues 1-337 or residues 1-293 of the albumin polypeptide with one or more of the mutations described herein. In some embodiments, the second polypeptide comprises residues of 342-585 or 304-585 of the albumin polypeptide with one or more of the mutations described herein. In some embodiments, the first polypeptide comprises residues 1-339, 1-300, 1-364, 1-441, 1-83, 1-171, 1-281, 1-293, 1-114, 1-337, or 1-336 of the albumin protein. In some embodiments, the second polypeptide comprises residues 301-585, 365-585, 442-585, 85-585, 172-585, 282-585, or 115-585, 304-585, 340-585, or 342-585 of the albumin protein.


In some embodiments, the first and second polypeptide comprise the residues of the albumin protein as shown in the table below. The sequence of the albumin protein is described below.
















First Polypeptide Residues
Second Polypeptide Residues









1-300
301-585



1-364
365-585



1-441
442-585



1-83 
 85-585



1-171
172-585



1-281
282-585



1-114
115-585



1-339
340-585



1-337
342-585



1-293
304-585



1-336
342-585










In some embodiments, the first and second polypeptides comprise a linker that can form a covalent bond with one another, such as a disulfide bond. A non-limiting example of the linker is a peptide linker. In some embodiments, the peptide linker comprises GGGGS (SEQ ID NO: 23). The linker can be fused to the C-terminus of the first polypeptide and the N-terminus of the second polypeptide. The linker can also be used to attach the moieties described herein without abrogating the ability of the linkers to form a disulfide bond. In some embodiments, the first and second polypeptides do not comprise a linker that can form a covalent bond. In some embodiments, the first and second polypeptides have the following substitutions.
















First Polypeptide Substitution
Second Polypeptide Substitution









A217C
V343C



L331C
A350C



A217C
L346C



W214C
V343C



A335C
L346C



L198C
V455C



A217C
A335C



A217C
L331C



L198C
N458C



A194C
V455C










The sequence of the albumin polypeptide can be The sequence of human albumin is as shown, in the post-protein form with the N-terminal signaling residues removed











(MKWVTFISLLFLFSSAYSRGVFRR (SEQ ID NO: 1437))







(human albumin, SEQ ID NO: 42)



DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHV







KLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVATL







RETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEV







DVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRY







KAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCA







SLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKV







HTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKP







LLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEA







KDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCA







AADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKF







QNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEA







KRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVN







RRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKK







QTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDK







ETCFAEEGKKLVAASQAALGL 






In some embodiments, the Linker Region A and the Linker Region B form a heterodimer as described herein.


In some embodiments, the polypeptide comprises at the N-terminus an antibody comprised of F(ab′)2 on an IgG1 Fc backbone fused with scFvs on the C-terminus of the IgG Fc backbone. In some embodiments, the IgG Fc backbone is a IgG1 Fc backbone. In some embodiments, the IgG1 backbone is replaced with a IgG4 backbone, IgG2 backbone, or other similar IgG backbone. The IgG backbones described in this paragraph can be used throughout this application where a Fc region is referred to as part of the therapeutic compound. Thus, in some embodiments, the antibody comprised of F(ab′)2 on an IgG1 Fc backbone can be an anti-MAdCAM antibody or an anti-PD-1 antibody on an IgG1 Fc or any other targeting moiety or effector binding/modulating moiety provided herein. In some embodiments, the scFv segments fused to the C-terminus could be an anti-PD-1 antibody, if the N-terminus region is an anti-MAdCAM antibody, or anti-MAdCAM antibody, if the N-terminus region is an anti-PD-1 antibody. In this non-limiting example, the N-terminus can be the targeting moiety, such as any one of the ones provided for herein, and the C-terminus can be the effector binding/modulating moiety, such as any of the ones provided for herein. Alternatively, in some embodiments, the N-terminus can be the effector binding/modulating moiety, such as any one of the ones provided for herein, and the C-terminus can be the targeting moiety, such as any of the ones provided for herein.


In some embodiments, the N-terminus can be the targeting moiety, such as any one of the ones provided for herein, and the C-terminus can be the effector binding/modulating moiety, such as any of the ones provided for herein.


In some embodiments, the therapeutic compound comprises two polypeptides that homodimerize. In some embodiments, the N-terminus of the polypeptide comprises an effector binding/modulating moiety that is fused to a human IgG1 Fc domain (e.g. CH2 and/or CH3 domains). In some embodiments, the C-terminus of the Fc domain is another linker that is fused to the targeting moiety. Thus, in some embodiments, the molecule could be represented using the formula of R1-Linker A-Fc Region-Linker B—R2, wherein R1 can be an effector binding/modulating moiety, R2 is a targeting moiety, Linker A and Linker B are independently linkers as provided for herein. In some embodiments, Linker 1 and Linker 2 are different.


In some embodiments, the molecule could be represented using the formula of R1-Linker A-Fc Region-Linker B—R2, wherein R1 can be a targeting moiety, R2 is an effector binding/modulating moiety, Linker A and Linker B are independently linkers as provided for herein. In some embodiments, Linker A and Linker B are different. The linkers can be chosen from the non-limiting examples provided for herein. In some embodiments, R1 and R2 are independently selected from F(ab′)2 and scFv antibody domains. In some embodiments, R1 and R2 are different antibody domains. In some embodiments, the scFv is in the VL-VH domain orientation.


In some embodiments, the therapeutic compound is a bispecific antibody. In some embodiments, the bispecific antibodies are comprised of four polypeptide chains comprising the following:

    • Chain 1: nt-VH1-CH1-CH2-CH3-Linker A-scFv[VL2-Linker B—VH2]-ct
    • Chain 2: nt-VH1-CH1-CH2-CH3-Linker A-scFv[VL2-Linker B—VH2]-ct
    • Chain 3: nt-VL1-CL-ct
    • Chain 4: nt-VL1-CL-ct,
    • wherein chains 1 and 2 are identical to each other, and chains 3 and 4 are identical to each other,
    • wherein chain 1 forms a homodimer with chain 2; and chain 3 and 4 associate with chain 1 and chain 2. That is, when each light chain associates with each heavy chain, VL1 associates with VH1 and CL associates with CH1 to form two functional Fab units. Without being bound to any particular theory, each scFv unit is intrinsically functional since VL2 and VH2 are covalently linked in tandem with a linker as provided herein, e.g., GGGGS (SEQ ID NO: 23), GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22), or GGGGSGGGGSGGGGS (SEQ ID NO: The sequences of Linker A and Linker B, which are independent of one another can be the same or different and as otherwise described throughout the present application. Thus, in some embodiments, Linker A comprises GGGGS (SEQ ID NO: 23), or two repeats thereof, GGGGSGGGGSGGGGS (SEQ ID NO: 30), or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22). In some embodiments, Linker B comprises GGGGS (SEQ ID NO: 23), or two repeats thereof, GGGGSGGGGSGGGGS (SEQ ID NO: 30), or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22). The scFv may be arranged in the NT-VH2-VL2-CT or NT-VL2-VH2-CT orientation. NT or nt stands for N-terminus and CT or ct stands for C-terminus of the protein. CH1, CH2, and CH3 are the domains from the IgG Fc region, and CL stands for Constant Light chain, which can be either kappa or lambda family light chains. The other definitions stand for the way they are normally used in the art.


In some embodiments, the VH1 and VL1 domains are derived from the effector molecule and the VH2 and VL2 domains are derived from the targeting moiety. In some embodiments the VH1 and VL1 domains are derived from a targeting moiety and the VH2 and VL2 domains are derived from an effector binding/modulating moiety.


In some embodiments, the VH1 and VL1 domains are derived from an anti-PD-1 antibody, and the VH2 and VL2 domains are derived from an anti-MAdCAM antibody. In some embodiments the VH1 and VL1 domains are derived from an anti-MAdCAM antibody and the VH2 and VL2 domains are derived from an anti-PD-1 antibody.


In some embodiments, Linker A comprises 1, 2, 3, 4, or 5 GGGGS (SEQ ID NO: 23) repeats (repeats disclosed as SEQ ID NO: 1549). In some embodiments, Linker B comprises 1, 2, 3, 4, or 5 GGGGS (SEQ ID NO: 23) repeats (repeats disclosed as SEQ ID NO: 1549). For the avoidance of doubt, the sequences of Linker A and Linker B, which are used throughout this application, are independent of one another. Therefore, in some embodiments, Linker A and Linker B can be the same or different. In some embodiments, Linker A comprises GGGGS (SEQ ID NO: 23), or two repeats thereof, GGGGSGGGGSGGGGS (SEQ ID NO: 30), or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22). In some embodiments, Linker B comprises GGGGS (SEQ ID NO: 23), or two repeats thereof, GGGGSGGGGSGGGGS (SEQ ID NO: 30), or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22).


In some embodiments, the therapeutic compound comprises a light chain and a heavy chain. In some embodiments, the light and heavy chain begin at the N-terminus with the VH domain of a targeting moiety followed by the CH1 domain of a human IgG1, which is fused to a Fc region (e.g. CH2-CH3) of human IgG1. In some embodiments, at the c-terminus of the Fc region is fused to a linker as provided herein, such as but not limited to, GGGGS (SEQ ID NO: 23), or two or three repeats thereof, or GGGGSGGGGSGGGGS (SEQ ID NO: 30). The linker can then be fused to an effector binding/modulating moiety, such as any one of the effector moieties provided for herein. The polypeptides can homodimerize because through the heavy chain homodimerization, which results in a therapeutic compound having two effector moieties, such as two anti-PD-1 antibodies. In this orientation, the targeting moiety is an IgG format, there are two Fab arms that each recognize binding partner of the targeting moiety, for example, MAdCAM being bound by the anti-MAdCAM targeting moiety.


In some embodiments, the therapeutic or polypeptide comprises a formula of: An antibody (targeting moiety) with a variable heavy chain and a variable light chain, in an IgG isotype, for example, with an effector molecule, such as an IL-2 mutein. In some embodiments, the IL-2 mutein is fused at the c-terminus of the variable heavy chain. This can be represented by the formula of VL and VH-IgGConstantDomain-L1-E, wherein L1 is a linker, such as a glycine/serine linker as provided herein, E is an effector molecule, such as an IL-2 mutein and VL and VH are the variable light and heavy chains. The VL domain can be a kappa domain. In some embodiments, the IgG Constant domain comprises the sequence of:









(SEQ ID NO: 44)


ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG





VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV





EPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVV





DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW





LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ





VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT





VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG






In some embodiments, the linker comprises GGGGS (SEQ ID NO: 23). In some embodiments, the IL-2 mutein comprises the IL-2 muteins provided herein, such as one of SEQ ID NOs: 31-41, which can also have a Fc molecule appended to the N- or C-terminus of the IL-2 mutein. The Fc domain can comprise SEQ ID NO: 21 or 43. In some embodiments, the IL-2 mutein comprises one of SEQ ID NO: 47-60. In some embodiments, the IL-2 mutein comprises SEQ ID NO: 41 or SEQ ID NO: 56. In some embodiments, the IL-2 mutein comprises SEQ ID NO: 40 or SEQ ID NO: 55.


In some embodiments, the targeting moiety is a MAdCAM antibody. In some embodiments, the MAdCAM antibody is selected from the following table:
















TABLE 6





Clone









ID
HCDR1
HCDR2
HCDR3
LCDR1
LCDR2
LCDR3
ScFv







 1.
FTFS
AVIS
CTTS
QASQDI
AASSLQS
CQQGYSTPLTF
EVQLLESGGGLVQPGGSLRLSCAA



SYGM
DDGS
KYYY
SKSLN
(SEQ ID
(SEQ ID NO:
SGFTFSSYGMHWVRQAPGKGLEWV



H
DKYY
YYGM
(SEQ
NO: 65)
66)
AVISDDGSDKYYADSVKGRFTISR



(SEQ
A
DVW
ID NO:


DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
64)


TTSKYYYYYGMDVWGQGTTVTVSS



NO:
ID
ID



GGGGSGGGGSGGGGSGGGGSDIQM



61)
NO:
NO:



TQSPSSLSASVGDRVTITCQASQD




62)
63)



ISKSLNWYQQKPGKAPKLLIYAAS









SLQSGVPSRFSGSGSGTDFTLTIS









SLQPEDFATYYCQQGYSTPLTFGG









GTKVEIK (SEQ ID NO: 67)





 2.
YPFI
GIIN
CARE
RASQSI
GASTLES
CQQTWGPPFTF
QVQLVQSGAEVKKPGASVKVSCKA



GYYL
PSGG
GRLS
SSYLA
(SEQ ID
(SEQ ID NO:
SGYPFIGYYLHWVRQAPGQGLEWM



H
STSY
YGMD
(SEQ
NO: 72)
73)
GIINPSGGSTSYAQKFQGRVTMTR



(SEQ
A
AW
ID NO:


DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
71)


AREGRLSYGMDAWGQGTLVTVSSG



NO:
ID
ID



GGGSGGGGSGGGGSGGGGSDIQMT



68)
NO:
NO:



QSPSSLSASVGDRVTITCRASQSI




69)
70)



SSYLAWYQQKPGKAPKLLIYGAST









LESGVPSRFSGSGSGTDFTLTISS









LQPEDFATYYCQQTWGPPFTFGQG









TKLEIK (SEQ ID NO: 74)





 3.
YPFI
GIIN
CARE
RASQSI
GASTLES
CQQTWGPPFTF
QVQLVQSGAEVKKPGASVKVSCKA



GQYL
PSGG
GRLS
SSYLA
(SEQ ID
(SEQ ID NO:
SGYPFIGQYLHWVRQAPGQGLEWM



H
STSY
YGMD
(SEQ
NO: 72)
73)
GIINPSGGSTSYAQKFQGRVTMTR



(SEQ
A
AW
ID NO:


DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
71)


AREGRLSYGMDAWGQGTLVTVSSG



NO:
ID
ID



GGGSGGGGSGGGGSGGGGSDIQMT



75)
NO:
NO:



QSPSSLSASVGDRVTITCRASQSI




69)
70)



SSYLAWYQQKPGKAPKLLIYGAST









LESGVPSRFSGSGSGTDFTLTISS









LQPEDFATYYCQQTWGPPFTFGQG









TKLEIK (SEQ ID NO: 76)





 4.
GTFS
GSIN
CAKD
QASQDI
AASSLQS
CQQSYSSVITF
QVQLVQSGAEVKKPGASVKVSCKA



SYAI
PSGD
KAQW
SNSLN
(SEQ ID
(SEQ ID NO:
SGGTFSSYAISWVRQAPGQGLEWM



S
TTSY
LVGY
(SEQ
NO: 65)
81)
GSINPSGDTTSYAQKFQGRVTMTR



(SEQ
A
FDYW
ID NO:


DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
80)


AKDKAQWLVGYFDYWGQGTLVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



77)
NO:
NO:



MTQSPSSLSASVGDRVTITCQASQ




78)
79)



DISNSLNWYQQKPGKAPKLLIYAA









SSLQSGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQSYSSVITFG









QGTKVEIK (SEQ ID NO: 82)





 5.
FTFS
SSIS
CARE
RASQGI
GASSLQS
CQQANSFPFTE
EVQLLESGGGLVQPGGSLRLSCAA



SYWM
PGGS
VQLS
SNSLA
(SEQ ID
(SEQ ID NO:
SGFTFSSYWMHWVRQAPGKGLEWV



H
NIDY
HYDY
(SEQ
NO: 87)
88)
SSISPGGSNIDYADSVKGRFTISR



(SEQ
A
W
ID NO:


DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
86)


AREVQLSHYDYWGQGTLVTVSSGG



NO:
ID
ID



GGSGGGGSGGGGSGGGGSDIQMTQ



83)
NO:
NO:



SPSSLSASVGDRVTITCRASQGIS




84)
85)



NSLAWYQQKPGKAPKLLIYGASSL









QSGVPSRFSGSGSGTDFTLTISSL









QPEDFATYYCQQANSFPFTFGQGT









KVEIK (SEQ ID NO: 89)





 6.
FTEN
SRIN
CARE
RASQII
GASSLQS
CQQSYRLPFTF
EVQLLESGGGLVQPGGSLRLSCAA



NYAF
SYGT
GPVA
GTNLA
(SEQ ID
(SEQ ID NO:
SGFTFNNYAFHWVRQAPGKGLEWV



H
STTY
GYWY
(SEQ
NO: 87)
94)
SRINSYGTSTTYADSVKGRFTISR



(SEQ
A
FDLW
ID NO:


DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
93)


AREGPVAGYWYFDLWGQGTLVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



90)
NO:
NO:



MTQSPSSLSASVGDRVTITCRASQ




91)
92)



IIGTNLAWYQQKPGKAPKLLIYGA









SSLQSGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQSYRLPFTFG









QGTKVEIK (SEQ ID NO: 95)





 7.
YTFT
GIIN
CAKD
RASQNI
AASSLQS
CQQSYTTPYTF
QVQLVQSGAEVKKPGASVKVSCKA



GYHI
PSGG
WSSW
SSSLN
(SEQ ID
(SEQ ID NO:
SGYTFTGYHIHWVRQAPGQGLEWM



H
STIY
YLGP
(SEQ
NO: 65)
100)
GIINPSGGSTIYAQKFQGRVTMTR



(SEQ
A
FDYW
ID NO:


DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
99)


AKDWSSWYLGPFDYWGQGTLVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



96)
NO:
NO:



MTQSPSSLSASVGDRVTITCRASQ




97)
98)



NISSSLNWYQQKPGKAPKLLIYAA









SSLQSGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQSYTTPYTFG









QGTKVEIK (SEQ ID NO:









101)





 8.
FMFG
SAIS
CAKD
RASQGI
DASSLES
CQQTHSFPSTF
EVQLLESGGGLVQPGGSLRLSCAA



DYAM
GSGG
LVVA
SNNLN
(SEQ ID
(SEQ ID NO:
SGFMFGDYAMHWVRQAPGKGLEWV



H
STYY
GIWY
(SEQ
NO:
107)
SAISGSGGSTYYADSVKGRFTISR



(SEQ
A
FDLW
ID NO:
106)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
105)


AKDLVVAGIWYFDLWGRGTLVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



102)
NO:
NO:



MTQSPSSLSASVGDRVTITCRASQ




103)
104)



GISNNLNWYQQKPGKAPKLLIYDA









SSLESGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQTHSFPSTFG









QGTKLEIK (SEQ ID NO:









108)





 9.
FTFS
SVIG
CAAD
RASQGI
AASTLQS
CQQSYSTPWTF
EVQLLESGGGLVQPGGSLRLSCAA



DYYM
ESGG
PVSR
SSSLA
(SEQ ID
(SEQ ID NO:
SGFTFSDYYMNWVRQAPGKGLEWV



N
STYY
WPKH
(SEQ
NO:
114)
SVIGESGGSTYYADSVKGRFTISR



(SEQ
A
GGGD
ID NO:
113)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
YW
112)


AADPVSRWPKHGGGDYWGQGTLVT



NO:
ID
(SEQ



VSSGGGGSGGGGSGGGGSGGGGSD



109)
NO:
ID



IQMTQSPSSLSASVGDRVTITCRA




110)
NO:



SQGISSSLAWYQQKPGKAPKLLIY





111)



AASTLQSGVPSRFSGSGSGTDFTL









TISSLQPEDFATYYCQQSYSTPWT









FGQGTKVEIK (SEQ ID NO:









115)





10.
YTLT
GWIN
CAKG
RASDNI
AASSLQS
CQQGYSTPPTF
QVQLVQSGAEVKKPGASVKVSCKA



TWYM
PNRG
DLWG
GSWLA
(SEQ ID
(SEQ ID NO:
SGYTLTTWYMYWVRQAPGQGLEWM



Y
ATNY
AMDV
(SEQ
NO: 65)
120)
GWINPNRGATNYAQKFQGRVTMTR



(SEQ
A
W
ID NO:


DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
119)


AKGDLWGAMDVWGQGTLVTVSSGG



NO:
ID
ID



GGSGGGGSGGGGSGGGGSDIQMTQ



116)
NO:
NO:



SPSSLSASVGDRVTITCRASDNIG




117)
118)



SWLAWYQQKPGKAPKLLIYAASSL









QSGVPSRFSGSGSGTDFTLTISSL









QPEDFATYYCQQGYSTPPTFGQGT









KVEIK (SEQ ID NO: 121)





11.
YTFT
GGFD
CARH
RASESI
AASTLQS
CQQSYSVPFTF
QVQLVQSGAEVKKPGASVKVSCKA



TYYM
PEDG
AVAG
SNWLA
(SEQ ID
(SEQ ID NO:
SGYTFTTYYMHWVRQAPGQGLEWM



H
ETIY
AVGA
(SEQ
NO:
126)
GGFDPEDGETIYAQKFQGRVTMTR



(SEQ
A
GYYY
ID NO:
113)

DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
YGMD
125)


ARHAVAGAVGAGYYYYGMDVWGQG



NO:
ID
VW



TMVTVSSGGGGSGGGGSGGGGSGG



122)
NO:
(SEQ



GGSDIQMTQSPSSLSASVGDRVTI




123)
ID



TCRASESISNWLAWYQQKPGKAPK





NO:



LLIYAASTLQSGVPSRFSGSGSGT





124)



DFTLTISSLQPEDFATYYCQQSYS









VPFTFGPGTKVDIK (SEQ ID









NO: 127)





12.
YTFT
GWIG
CARD
RSSQSL
SSSNRAP
CMQALHIPLTF
QVQLVQSGAEVKKPGASVKVSCKA



GYYM
PNSG
LDHN
LHSNGY
(SEQ ID
(SEQ ID NO:
SGYTFTGYYMHWVRQAPGQGLEWM



H
DTNY
WYFD
NYLD
NO:
133)
GWIGPNSGDTNYAQKFQGRVTMTR



(SEQ
A
LW
(SEQ
132)

DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
ID NO:


ARDLDHNWYFDLWGRGTLVTVSSG



NO:
ID
ID
131)


GGGSGGGGSGGGGSGGGGSDIVMT



128)
NO:
NO:



QSPLSLPVTPGEPASISCRSSQSL




129)
130)



LHSNGYNYLDWYLQKPGQSPQLLI









YSSSNRAPGVPDRFSGSGSGTDFT









LKISRVEAEDVGVYYCMQALHIPL









TFGGGTKVEIK (SEQ ID NO:









134)





13.
FTFD
SYID
CAKD
QASQDI
KASTLES
CQQSYSTPITF
EVQLLESGGGLVQPGGSLRLSCAA



DYAM
ASGT
QAAA
SNYLN
(SEQ ID
(SEQ ID NO:
SGFTFDDYAMHWVRQAPGKGLEWV



H
TIYY
GYWY
(SEQ
NO:
140)
SYIDASGTTIYYADSVKGRFTISR



(SEQ
A
FDLW
ID NO:
139)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
138)


AKDQAAAGYWYFDLWGRGTLVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



135)
NO:
NO:



MTQSPSSLSASVGDRVTITCQASQ




136)
137)



DISNYLNWYQQKPGKAPKLLIYKA









STLESGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQSYSTPITFG









QGTRLEIK (SEQ ID NO:









141)





14.
YTFT
GGIV
CAKD
RSSQSL
SAYNRAS
CMQALQTPLTF
QVQLVQSGAEVKKPGSSVKVSCKA



DYHI
PRSG
ESSG
LHSNGY
(SEQ ID
(SEQ ID NO:
SGYTFTDYHIHWVRQAPGQGLEWM



H
STTY
WYYF
NYLD
NO:
146)
GGIVPRSGSTTYAQKFQGRVTITA



(SEQ
A
DYW
(SEQ


DESTSTAYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
ID NO:
145)

AKDESSGWYYFDYWGQGTLVTVSS



NO:
ID
ID
131)


GGGGSGGGGSGGGGSGGGGSDIVM



142)
NO:
NO:



TQSPLSLPVTPGEPASISCRSSQS




143)
144)



LLHSNGYNYLDWYLQKPGQSPQLL









IYSAYNRASGVPDRFSGSGSGTDF









TLKISRVEAEDVGVYYCMQALQTP









LTFGQGTKVEIK (SEQ ID NO:









147)





15.
YTFT
GGII
CAKG
QANQDI
RASKLEA
CQQSSEIPYSF
QVQLVQSGAEVKKPGSSVKVSCKA



NYYM
PIVD
RYTV
SNYLN
(SEQ ID
(SEQ ID NO:
SGYTFTNYYMHWVRQAPGQGLEWM



H
RVKY
NYYY
(SEQ
NO:
153)
GGIIPIVDRVKYAQKFQGRVTITA



(SEQ
A
GMDV
ID NO:
152)

DESTSTAYMELSSLRSEDTAVYYC



ID
(SEQ
W
151)


AKGRYTVNYYYGMDVWGQGTTVTV



NO:
ID
(SEQ



SSGGGGSGGGGSGGGGSGGGGSDI



148)
NO:
ID



QMTQSPSSLSASVGDRVTITCQAN




149)
NO:



QDISNYLNWYQQKPGKAPKLLIYR





150)



ASKLEAGVPSRFSGSGSGTDFTLT









ISSLQPEDFATYYCQQSSEIPYSF









GQGTKLEIK (SEQ ID NO:









154)





16.
FTFE
SYLN
CAKD
RASQSI
DASNLET
CQQSYTIPITF
EVQLLESGGGLVQPGGSLRLSCAA



DYAM
SDGG
YCTN
STYLN
(SEQ ID
(SEQ ID NO:
SGFTFEDYAMHWVRQAPGKGLEWV



H
STSY
GVCA
(SEQ
NO:
160)
SYLNSDGGSTSYADSVKGRFTISR



(SEQ
A
FDYW
ID NO:
159)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
158)


AKDYCTNGVCAFDYWGQGTLVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



155)
NO:
NO:



MTQSPSSLSASVGDRVTITCRASQ




156)
157)



SISTYLNWYQQKPGKAPKLLIYDA









SNLETGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQSYTIPITFG









QGTRLEIK (SEQ ID NO:









161)





17.
FTFS
SAIS
CVSD
RASQSI
AASRLEG
CQQANSFPLTF
EVQLLESGGGLVQPGGSLRLSCAA



DSAM
GSGS
IAVA
STFLN
(SEQ ID
(SEQ ID NO:
SGFTFSDSAMHWVRQAPGKGLEWV



H
TIYY
GHWY
(SEQ
NO:
167)
SAISGSGSTIYYADSVKGRFTISR



(SEQ
A
FDLW
ID NO:
166)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
165)


VSDIAVAGHWYFDLWGRGTLVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



162)
NO:
NO:



MTQSPSSLSASVGDRVTITCRASQ




163)
164)



SISTFLNWYQQKPGKAPKLLIYAA









SRLEGGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQANSFPLTFG









PGTKVDIK (SEQ ID NO:









168)





18.
FTES
SYIS
CARA
RASQSI
AASSLQS
CQQSYSTPLTF
EVQLVESGGGLVKPGGSLRLSCAA



SYWM
GDSG
NSSG
SSYLN
(SEQ ID
(SEQ ID NO:
SGFTFSSYWMSWVRQAPGKGLEWV



S
YTNY
WYDW
(SEQ
NO: 65)
173)
SYISGDSGYTNYAAPVKGRFTISR



(SEQ
A
YFDL
ID NO:


DDSKNTLYLQMNSLKTEDTAVYYC



ID
(SEQ
W
172)


ARANSSGWYDWYFDLWGRGTLVTV



NO:
ID
(SEQ



SSGGGGSGGGGSGGGGSGGGGSDI



169)
NO:
ID



QMTQSPSSLSASVGDRVTITCRAS




170)
NO:



QSISSYLNWYQQKPGKAPKLLIYA





171)



ASSLQSGVPSRFSGSGSGTDFTLT









ISSLQPEDFATYYCQQSYSTPLTF









GGGTKVEIK (SEQ ID NO:









174)





19.
FTFD
SGIS
CAKD
QASQDI
DASNLET
CQQSYSTPLTF
EVQLLESGGGLVQPGGSLRLSCAA



DYAM
WNSG
IVAA
SNYLN
(SEQ ID
(SEQ ID NO:
SGFTFDDYAMHWVRQAPGKGLEWV



H
SIGY
GHYY
(SEQ
NO:
173)
SGISWNSGSIGYADSVKGRFTISR



(SEQ
A
YGMD
ID NO:
159)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
VW
138)


AKDIVAAGHYYYGMDVWGQGTTVT



NO:
ID
(SEQ



VSSGGGGSGGGGSGGGGSGGGGSD



135)
NO:
ID



IQMTQSPSSLSASVGDRVTITCQA




175)
NO:



SQDISNYLNWYQQKPGKAPKLLIY





176)



DASNLETGVPSRFSGSGSGTDFTL









TISSLQPEDFATYYCQQSYSTPLT









FGGGTKVEIK (SEQ ID NO:









177)





20.
FTFD
SYID
CARD
QAGQDI
DASNLET
CQQTYSTPITF
EVQLLESGGGLVQPGGSLRLSCAA



DYAM
TSSS
EAAA
SNYLN
(SEQ ID
(SEQ ID NO:
SGFTFDDYAMHWVRQAPGKGLEWV



H
HLYY
GYYG
(SEQ
NO:
181)
SYIDTSSSHLYYADSVKGRFTISR



(SEQ
A
MDVW
ID NO:
159)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
180)


ARDEAAAGYYGMDVWGQGTTVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



135)
NO:
NO:



MTQSPSSLSASVGDRVTITCQAGQ




178)
179)



DISNYLNWYQQKPGKAPKLLIYDA









SNLETGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQTYSTPITFG









QGTKLEIK (SEQ ID NO:









182)





21.
FTFS
STIV
CARD
RASQDI
AASSLQS
CQQSYSIPPTF
EVQLLESGGGLVQPGGSLRLSCAA



NAWM
GNGG
NPLR
SNYLN
(SEQ ID
(SEQ ID NO:
SGFTFSNAWMSWVRQAPGKGLEWV



S
ATYY
WQGM
(SEQ
NO: 65)
187)
STIVGNGGATYYADSVKGRFTISR



(SEQ
A
DVW
ID NO:


DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
186)


ARDNPLRWQGMDVWGQGTLVTVSS



NO:
ID
ID



GGGGSGGGGSGGGGSGGGGSDIQM



183)
NO:
NO:



TQSPSSLSASVGDRVTITCRASQD




184)
185)



ISNYLNWYQQKPGKAPKLLIYAAS









SLQSGVPSRFSGSGSGTDFTLTIS









SLQPEDFATYYCQQSYSIPPTFGP









GTKVDIK (SEQ ID NO: 188)





22.
FTFS
SYIS
CARA
RASQSI
AASSLQS
CQQSYSTPLTF
EVQLLESGGGLVQPGGSLRLSCAA



SYQM
SSST
NSSS
SSYLN
(SEQ ID
(SEQ ID NO:
SGFTFSSYQMSWVRQAPGKGLEWV



S
YTNY
WYDW
(SEQ
NO: 65)
173)
SYISSSSTYTNYADSVKGRFTISR



(SEQ
A
YFDL
ID NO:


DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
W
172)


ARANSSSWYDWYFDLWGQGTLVTV



NO:
ID
(SEQ



SSGGGGSGGGGSGGGGSGGGGSDI



189)
NO:
ID



QMTQSPSSLSASVGDRVTITCRAS




190)
NO:



QSISSYLNWYQQKPGKAPKLLIYA





191)



ASSLQSGVPSRFSGSGSGTDFTLT









ISSLQPEDFATYYCQQSYSTPLTF









GGGTKVEIK (SEQ ID NO:









192)





23.
FTFS
SGIS
CATS
RASQSI
AASNLQR
CQQSYSIPITE
EVQLLESGGGLVQPGGSLRLSCAA



SYAM
GSGG
QAPV
SSWLA
(SEQ ID
(SEQ ID NO:
SGFTFSSYAMHWVRQAPGKGLEWV



H
SAYY
DYYY
(SEQ
NO:
198)
SGISGSGGSAYYADSVKGRFTISR



(SEQ
A
YGMD
ID NO:
197)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
VW
196)


ATSQAPVDYYYYGMDVWGQGTTVT



NO:
ID
(SEQ



VSSGGGGSGGGGSGGGGSGGGGSD



193)
NO:
ID



IQMTQSPSSLSASVGDRVTITCRA




194)
NO:



SQSISSWLAWYQQKPGKAPKLLIY





195)



AASNLQRGVPSRFSGSGSGTDFTL









TISSLQPEDFATYYCQQSYSIPIT









FGQGTKVEIK (SEQ ID NO:









199)





24.
FTFS
SYIS
CARV
RASQSI
AASSLQS
CQQSYSTPLTF
EVQLVESGGGLVKPGGSLRLSCAA



SYWM
GSSS
GSSG
SSYLN
(SEQ ID
(SEQ ID NO:
SGFTFSSYWMSWVRQAPGKGLEWV



S
YTNY
WYDW
(SEQ
NO: 65)
173)
SYISGSSSYTNYAAPVKGRFTISR



(SEQ
A
YFDL
ID NO:


DDSKNTLYLQMNSLKTEDTAVYYC



ID
(SEQ
W
172)


ARVGSSGWYDWYFDLWGRGTLVTV



NO:
ID
(SEQ



SSGGGGSGGGGSGGGGSGGGGSDI



169)
NO:
ID



QMTQSPSSLSASVGDRVTITCRAS




200)
NO:



QSISSYLNWYQQKPGKAPKLLIYA





201)



ASSLQSGVPSRFSGSGSGTDFTLT









ISSLQPEDFATYYCQQSYSTPLTF









GQGTKVEIK (SEQ ID NO:









202)





25.
YTLT
GWIN
CAKG
RASDNI
AASSLQS
CQQGYSTPPTF
QVQLVQSGAEVKKPGASVKVSCKA



TWYM
PNRG
DLWG
GSWLA
(SEQ ID
(SEQ ID NO:
SGYTLTTWYMYWVRQAPGQGLEWM



Y
ATNY
AMDV
(SEQ
NO: 65)
120)
GWINPNRGATNYAQKFQGRVTMTR



(SEQ
A
W
ID NO:


DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
119)


AKGDLWGAMDVWGQGTLVTVSSGG



NO:
ID
ID



GGSGGGGSGGGGSGGGGSDIQMTQ



116)
NO:
NO:



SPSSLSASVGDRVTITCRASDNIG




117
118)



SWLAWYQQKPGKAPKLLIYAASSL









QSGVPSRFSGSGSGTDFTLTISSL









QPEDFATYYCQQGYSTPPTFGQGT









KVEIK (SEQ ID NO: 121)





26.
YTLT
GWIN
CAKG
RASDNI
AASSLQS
CQQGYSTPPTF
QVQLVQSGAEVKKPGASVKVSCKA



TWYM
PNRG
DLWG
GSWLA
(SEQ ID
(SEQ ID NO:
SGYTLTTWYMYWVRQAPGQGLEWM



Y
ATNY
AMDV
(SEQ
NO: 65)
120)
GWINPNRGATNYAQKFQGRVTMTR



(SEQ
A
W
ID NO:


DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
119)


AKGDLWGAMDVWGQGTTVTVSSGG



NO:
ID
ID



GGSGGGGSGGGGSGGGGSDIQMTQ



116)
NO:
NO:



SPSSLSASVGDRVTITCRASDNIG




117)
118)



SWLAWYQQKPGKAPKLLIYAASSL









QSGVPSRFSGSGSGTDFTLTISSL









QPEDFATYYCQQGYSTPPTFGQGT









KVEIK (SEQ ID NO: 203)





27.
YTFT
GWMN
CARD
RASQSI
AASSLQS
CQQSYTAPYTF
QVQLVQSGAEVKKPGASVKVSCKA



GYYI
PNSG
PGFL
SSYLH
(SEQ ID
(SEQ ID NO:
SGYTFTGYYIHWVRQAPGQGLEWM



H
NTGY
GYCS
(SEQ
NO: 65)
208)
GWMNPNSGNTGYAQKFQGRVTMTR



(SEQ
A
GGSC
ID NO:


DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
YDGW
207)


ARDPGFLGYCSGGSCYDGWFDPWG



NO:
ID
FDPW



QGTLVTVSSGGGGSGGGGSGGGGS



204)
NO:
(SEQ



GGGGSDIQMTQSPSSLSASVGDRV




205)
ID



TITCRASQSISSYLHWYQQKPGKA





NO:



PKLLIYAASSLQSGVPSRFSGSGS





206)



GTDFTLTISSLQPEDFATYYCQQS









YTAPYTFGQGTKLEIK (SEQ ID









NO: 209)





28.
YTFT
GWMN
CARE
RASQGI
DASNLET
CQQSYSTPLTF
QVQLVQSGAEVKKPGASVKVSCKA



DYFL
PTSG
GEGS
NSWLA
(SEQ ID
(SEQ ID NO:
SGYTFTDYFLHWVRQAPGQGLEWM



H
NTGY
GFDY
(SEQ
NO:
173)
GWMNPTSGNTGYAQKFQGRVTMTR



(SEQ
A
W
ID NO:
159)

DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
213)


AREGEGSGFDYWGQGTLVTVSSGG



NO:
ID
ID



GGSGGGGSGGGGSGGGGSDIQMTQ



210)
NO:
NO:



SPSSLSASVGDRVTITCRASQGIN




211)
212)



SWLAWYQQKPGKAPKLLIYDASNL









ETGVPSRFSGSGSGTDFTLTISSL









QPEDFATYYCQQSYSTPLTFGGGT









KVEIK (SEQ ID NO: 214)





29.
YTFT
AWMN
CARD
RASQGI
AASSLQS
CQQSYSTPWTF
QVQLVQSGAEVKKPGASVKVSCKA



SYYM
PNSG
YDFW
SNYLA
(SEQ ID
(SEQ ID NO:
SGYTFTSYYMHWVRQAPGQGLEWM



H
NTGY
SGSL
(SEQ
NO: 65)
114)
AWMNPNSGNTGYAQKFQGRVTMTR



(SEQ
A
GYW
ID NO:


DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
218)


ARDYDFWSGSLGYWGQGTLVTVSS



NO:
ID
ID



GGGGSGGGGSGGGGSGGGGSDIQM



215)
NO:
NO:



TQSPSSLSASVGDRVTITCRASQG




216)
217)



ISNYLAWYQQKPGKAPKLLIYAAS









SLQSGVPSRFSGSGSGTDFTLTIS









SLQPEDFATYYCQQSYSTPWTFGQ









GTKVEIK (SEQ ID NO: 219)





30.
YTLT
GWIN
CAKG
RASDNI
AASSLQS
CQQGYSTPPTF
QVQLVQSGAEVKKPGASVKVSCKA



TWYM
PNRG
DLWG
GSWLA
(SEQ ID
(SEQ ID NO:
SGYTLTTWYMYWVRQAPGQGLEWM



Y
ATNY
AMDV
SEQ
NO: 65)
120)
GWINPNRGATNYAQKFQGRVTMTR



(SEQ
A
W
ID NO:


DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
119)


AKGDLWGAMDVWGQGTLVTVSSGG



NO:
ID
ID



GGSGGGGSGGGGSGGGGSDIQMTQ



116)
NO:
NO:



SPSSLSASVGDRVTITCRASDNIG




117)
118)



SWLAWYQQKPGKAPKLLIYAASSL









QSGVPSRFSGSGSGTDFTLTISSL









QPEDFATYYCQQGYSTPPTFGQGT









KVEIK (SEQ ID NO: 121)





31.
YTFT
GIIN
CARD
RASQSI
DASNLQS
CQQSYSIPITE
QVQLVQSGAEVKKPGASVKVSCKA



SYYM
PSGG
TGYS
GRWLA
(SEQ ID
(SEQ ID NO:
SGYTFTSYYMHWVRQAPGQGLEWM



H
STSY
YGRY
(SEQ
NO:
198)
GIINPSGGSTSYAQKFQGRVTMTR



(SEQ
A
YYYG
ID NO:
222)

DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
MDVW
221)


ARDTGYSYGRYYYYGMDVWGQGTL



NO:
ID
(SEQ



VTVSSGGGGSGGGGGGGGSGGGG



215)
NO:
ID



SDIQMTQSPSSLSASVGDRVTITC




69)
NO:



RASQSIGRWLAWYQQKPGKAPKLL





220)



IYDASNLQSGVPSRFSGSGSGTDF









TLTISSLQPEDFATYYCQQSYSIP









ITFGQGTKVEIK (SEQ ID NO:









223)





32.
YTLT
GIIN
CARE
RASQGI
AASSLQS
CQQSYSTPLTF
QVQLVQSGAEVKKPGASVKVSCKA



DYYM
PSGG
EYSS
SSWLA
(SEQ ID
(SEQ ID NO:
SGYTLTDYYMHWVRQAPGQGLEWM



H
STSY
SSGY
(SEQ
NO: 65)
173)
GIINPSGGSTSYAQKFQGRVTMTR



(SEQ
A
FDYW
ID NO:


DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
226)


AREEYSSSSGYFDYWGQGTLVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



224)
NO:
NO:



MTQSPSSLSASVGDRVTITCRASQ




69)
225)



GISSWLAWYQQKPGKAPKLLIYAA









SSLQSGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQSYSTPLTFG









QGTKVEIK (SEQ ID NO:









227)





33.
YTFT
GWMH
CARD
RASQSI
AASSLQS
CQQSYSVPITF
QVQLVQSGAEVKKPGASVKVSCKA



SYGI
PKSG
TPYY
SSWLA
(SEQ ID
(SEQ ID NO:
SGYTFTSYGISWVRQAPGQGLEWM



S
DTGL
YYGM
(SEQ
NO: 65)
231)
GWMHPKSGDTGLTQKFQGRVTMTR



(SEQ
T
DVW
ID NO:


DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
196)


ARDTPYYYYGMDVWGQGTTVTVSS



NO:
ID
ID



GGGGSGGGGSGGGGSGGGGSDIQM



228)
NO:
NO:



TQSPSSLSASVGDRVTITCRASQS




229)
230)



ISSWLAWYQQKPGKAPKLLIYAAS









SLQSGVPSRFSGSGSGTDFTLTIS









SLQPEDFATYYCQQSYSVPITFGQ









GTKVEIK (SEQ ID NO: 232)





34.
FTFG
SYIS
CARD
RASQSI
AASSLQS
CQQSYSTPLTF
EVQLVESGGGLVKPGGSLRLSCAA



DYAM
GDIG
VAAT
SSYLN
(SEQ ID
(SEQ ID NO:
SGFTFGDYAMSWVRQAPGKGLEWV



S
YTNY
GNWY
(SEQ
NO: 65)
173)
SYISGDIGYTNYAAPVKGRFTISR



(SEQ
A
FDLW
ID NO:


DDSKNTLYLQMNSLKTEDTAVYYC



ID
(SEQ
(SEQ
172)


ARDVAATGNWYFDLWGRGTLVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



233)
NO:
NO:



MTQSPSSLSASVGDRVTITCRASQ




234)
235)



SISSYLNWYQQKPGKAPKLLIYAA









SSLQSGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQSYSTPLTFG









GGTKVEIK (SEQ ID NO:









236)





35.
FSFS
SFIT
CARD
RASQSV
GASTRAT
CQQYGSSPLTE
EVQLLESGGGLVQPGGSLRLSCAA



SYTM
SSSR
RRGD
RNYLA
(SEQ ID
(SEQ ID NO:
SGFSFSSYTMNWVRQAPGKGLEWV



N
TIYY
YGDS
(SEQ
NO:
242)
SFITSSSRTIYYADSVKGRFTISR



(SEQ
A
WYFD
ID NO:
241)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
LW
240)


ARDRRGDYGDSWYFDLWGRGTLVT



NO:
ID
(SEQ



VSSGGGGSGGGGSGGGGSGGGGSE



237)
NO:
ID



IVMTQSPATLSVSPGERATLSCRA




238)
NO:



SQSVRNYLAWYQQKPGQAPRLLIY





239)



GASTRATGIPARFSGSGSGTEFTL









TISSLQSEDFAVYYCQQYGSSPLT









FGGGTKVEIK (SEQ ID NO:









243)





36.
YTFT
GIIN
CARD
RASQSI
DASNLQS
CQQSYSIPITE
QVQLVQSGAEVKKPGASVKVSCKA



GHYM
PSGG
TGYS
GRWLA
(SEQ ID
(SEQ ID NO:
SGYTFTGHYMHWVRQAPGQGLEWM



H
STSY
YGRY
(SEQ
NO:
198)
GIINPSGGSTSYAQKFQGRVTMTR



(SEQ
A
YYYG
ID NO:
222)

DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
MDVW
221)


ARDTGYSYGRYYYYGMDVWGQGTT



NO:
ID
(SEQ



VTVSSGGGGSGGGGSGGGGSGGGG



244)
NO:
ID



SDIQMTQSPSSLSASVGDRVTITC




69)
NO:



RASQSIGRWLAWYQQKPGKAPKLL





220)



IYDASNLQSGVPSRFSGSGSGTDF









TLTISSLQPEDFATYYCQQSYSIP









ITFGGGTKVEIK (SEQ ID NO:









245)





37.
YTFS
GWMN
CARG
RASQSI
AASTLQS
CQQSYSTPWTF
QVQLVQSGAEVKKPGASVKVSCKA



KHFV
PNSG
EGGY
SSWLA
(SEQ ID
(SEQ ID NO:
SGYTFSKHFVHWVRQAPGQGLEWM



H
NSGY
YYYG
(SEQ
NO:
114)
GWMNPNSGNSGYAQKFQGRVTMTR



(SEQ
A
MDVW
ID NO:
113)

DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
196)


ARGEGGYYYYGMDVWGQGTLVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



246)
NO:
NO:



MTQSPSSLSASVGDRVTITCRASQ




247)
248)



SISSWLAWYQQKPGKAPKLLIYAA









STLQSGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQSYSTPWTFG









QGTKVEIK (SEQ ID NO:









249)





38.
FTFG
SAIG
CAKG
RASQPL
AASSLQS
CQQAISFPLTF
EVQLLESGGGLVQPGGSLRLSCAA



SYSM
TGGG
TPYY
SNWLA
(SEQ ID
(SEQ ID NO:
SGFTFGSYSMSWVRQAPGKGLEWV



S
TYYA
YYYG
(SEQ
NO: 65)
254)
SAIGTGGGTYYADSVKGRFTISRD



(SEQ
(SEQ
MDVW
ID NO:


NSKNTLYLQMNSLRAEDTAVYYCA



ID
ID
(SEQ
253)


KGTPYYYYYGMDVWGQGTMVTVSS



NO:
NO:
ID



GGGGSGGGGSGGGGSGGGGSDIQM



250)
251)
NO:



TQSPSSLSASVGDRVTITCRASQP





252)



LSNWLAWYQQKPGKAPKLLIYAAS









SLQSGVPSRFSGSGSGTDFTLTIS









SLQPEDFATYYCQQAISFPLTFGG









GTKVEIK (SEQ ID NO: 255)





39.
YTFT
GWMN
CARD
QSSEDI
AASSLQI
CQQTYSTPYTF
QVQLVQSGAEVKKPGASVKVSCKA



SYYM
PNSG
LGYY
SSSLN
(SEQ ID
(SEQ ID NO:
SGYTFTSYYMHWVRQAPGQGLEWM



H
NTGY
DSSG
(SEQ
NO:
259)
GWMNPNSGNTGYAQKFQGRVTMTR



(SEQ
A
YFGA
ID NO:
258)

DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
FDIW
257)


ARDLGYYDSSGYFGAFDIWGQGTT



NO:
ID
(SEQ



VTVSSGGGGSGGGGSGGGGSGGGG



215)
NO:
ID



SDIQMTQSPSSLSASVGDRVTITC




205)
NO:



QSSEDISSSLNWYQQKPGKAPKLL





256)



IYAASSLQIGVPSRFSGSGSGTDF









TLTISSLQPEDFATYYCQQTYSTP









YTFGQGTKVEIK (SEQ ID NO:









260)





40.
YTFT
GIIN
CARG
RASQGI
AASNLET
CQQIHSYPLTF
QVQLVQSGAEVKKPGASVKVSCKA



SYGI
PRGG
TRSS
GNWLA
(SEQ ID
(SEQ ID NO:
SGYTFTSYGISWVRQAPGQGLEWM



S
STIF
GWYG
(SEQ
NO:
265)
GIINPRGGSTIFAQKFQGRVTMTR



(SEQ
A
WFDP
ID NO:
264)

DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
W
263)


ARGTRSSGWYGWFDPWGQGTLVTV



NO:
ID
(SEQ



SSGGGGSGGGGSGGGGSGGGGSDI



228)
NO:
ID



QMTQSPSSLSASVGDRVTITCRAS




261)
NO:



QGIGNWLAWYQQKPGKAPKLLIYA





262)



ASNLETGVPSRFSGSGSGTDFTLT









ISSLQPEDFATYYCQQIHSYPLTF









GGGTKVEIK (SEQ ID NO:









266)





41.
FTFD
SYIS
CARE
RASQSI
AASSLQS
CQQSYSTPLTF
EVQLLESGGGLVQPGGSLRLSCAA



DYGM
SSSS
IAAA
SSYLN
(SEQ ID
(SEQ ID NO:
SGFTFDDYGMSWVRQAPGKGLEWV



S
YIYY
GFYG
(SEQ
NO: 65)
173)
SYISSSSSYIYYADSVKGRFTISR



(SEQ
A
MDVW
ID NO:


DNSKNTLYLQMNSLRAEDTAVYYC



ID
( SEQ
(SEQ
172)


AREIAAAGFYGMDVWGQGTTVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



267)
NO:
NO:



MTQSPSSLSASVGDRVTITCRASQ




268)
269)



SISSYLNWYQQKPGKAPKLLIYAA









SSLQSGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQSYSTPLTFG









GGTKVEIK (SEQ ID NO:









270)





42.
GTLS
GGII
CARD
RASQSV
GASTRAT
CQQYGSSPITF
QVQLVQSGAEVKKPGSSVKVSCKA



RYGV
PIFG
RVYY
SSSYLA
(SEQ ID
(SEQ ID NO:
SGGTLSRYGVSWVRQAPGQGLEWM



S
TTNY
DSSG
(SEQ
NO:
275)
GGIIPIFGTTNYAQKFQGRVTITA



(SEQ
A
YPTW
ID NO:
241)

DESTSTAYMELSSLRSEDTAVYYC



ID
(SEQ
YFDL
274)


ARDRVYYDSSGYPTWYFDLWGRGT



NO:
ID
W



LVTVSSGGGGSGGGGSGGGGSGGG



271)
NO:
(SEQ



GSEIVMTQSPATLSVSPGERATLS




272)
ID



CRASQSVSSSYLAWYQQKPGQAPR





NO:



LLIYGASTRATGIPARFSGSGSGT





273)



EFTLTISSLQSEDFAVYYCQQYGS









SPITFGQGTKVEIK (SEQ ID









NO: 276)





43.
FTFD
SGIS
CARD
QASQDI
KASTLES
CQQANSFPLTF
EVQLLESGGGLVQPGGSLRLSCAA



DFAM
GNGD
ASYG
RNYLN
(SEQ ID
(SEQ ID NO:
SGFTFDDFAMHWVRQAPGKGLEWV



H
SRYY
GNYG
(SEQ
NO:
167)
SGISGNGDSRYYADSVKGRFTISR



(SEQ
A
MDVW
ID NO:
139)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
SEQ
280)


ARDASYGGNYGMDVWGQGTTVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



277)
NO:
NO:



MTQSPSSLSASVGDRVTITCQASQ




278)
279)



DIRNYLNWYQQKPGKAPKLLIYKA









STLESGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQANSFPLTFG









PGTKVDIK (SEQ ID NO:









281)





44.
FTFS
SAIG
CARE
RASQSI
GASNLQS
CQQSYSTPWTF
EVQLVESGGGLVKPGGSLRLSCAA



SYWM
TGGG
WLVP
SRWLA
(SEQ ID
(SEQ ID NO:
SGFTFSSYWMSWVRQAPGKGLEWV



S
TYYA
YYGM
(SEQ
NO:
114)
SAIGTGGGTYYAAPVKGRFTISRD



(SEQ
(SEQ
DVW
ID NO:
284)

DSKNTLYLQMNSLKTEDTAVYYCA



ID
ID
(SEQ
283)


REWLVPYYGMDVWGQGTTVTVSSG



NO:
NO:
ID



GGGSGGGGSGGGGSGGGGSDIQMT



169)
251)
NO:



QSPSSLSASVGDRVTITCRASQSI





282)



SRWLAWYQQKPGKAPKLLIYGASN









LQSGVPSRFSGSGSGTDFTLTISS









LQPEDFATYYCQQSYSTPWTFGQG









TKVEIK (SEQ ID NO: 285)





45.
FSVS
AGIS
CARS
KSSQSV
WASTRQS
CHQYYGHPPTF
EVQLLESGGGLVQPGGSLRLSCAA



SNYM
YDGS
RGIA
LYSSNN
(SEQ ID
(SEQ ID NO:
SGFSVSSNYMSWVRQAPGKGLEWV



S
SKPY
ARPL
KNYLA
NO:
291)
AGISYDGSSKPYADSVKGRFTISR



(SEQ
A
QHW
(SEQ
290)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
ID NO:


ARSRGIAARPLQHWGQGTLVTVSS



NO:
ID
ID
289)


GGGGSGGGGSGGGGSGGGGSDIVM



286)
NO:
NO:



TQSPDSLAVSLGERATINCKSSQS




287)
288)



VLYSSNNKNYLAWYQQKPGQPPKL









LIYWASTRQSGVPDRFSGSGSGTD









FTLTISSLQAEDVAVYYCHQYYGH









PPTFGGGTKVEIK (SEQ ID









NO: 292)





46.
FSVS
AGIS
CARS
KSSQSV
QASTRQS
CHQYYGHPPTF
EVQLLESGGGLVQPGGSLRLSCAA



SNYM
YDGS
RGIA
LYSSNN
(SEQ ID
(SEQ ID NO:
SGFSVSSNYMSWVRQAPGKGLEWV



S
SKPY
ARPL
KNYLA
NO:
291)
AGISYDGSSKPYADSVKGRFTISR



(SEQ
A
QHW
(SEQ
293)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
ID NO:


ARSRGIAARPLQHWGQGTLVTVSS



NO:
ID
ID
289)


GGGGSGGGGSGGGGSGGGGSDIVM



286)
NO:
NO:



TQSPDSLAVSLGERATINCKSSQS




287)
288)



VLYSSNNKNYLAWYQQKPGQPPKL









LIYQASTRQSGVPDRFSGSGSGTD









FTLTISSLQAEDVAVYYCHQYYGH









PPTFGGGTKVEIK (SEQ ID









NO: 294)





47.
FSFS
SAIS
CARD
RASQGI
DASNLET
CQQSYSTPLTF
EVQLLESGGGLVQPGGSLRLSCAA



DYGM
GSGG
GGWQ
SNNLN
(SEQ ID
(SEQ ID NO:
SGFSFSDYGMHWVRQAPGKGLEWV



H
STYY
PAAI
(SEQ
NO:
173)
SAISGSGGSTYYADSVKGRFTISR



(SEQ
A
LDYW
ID NO:
159)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
105)


ARDGGWQPAAILDYWGQGTLVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



295)
NO:
NO:



MTQSPSSLSASVGDRVTITCRASQ




103)
296)



GISNNLNWYQQKPGKAPKLLIYDA









SNLETGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQSYSTPLTFG









GGTKVEIK (SEQ ID NO:









297)





48.
FTFS
SVIY
CARD
RASQGI
DASNLET
CQQSYSTCYTF
EVQLLESGGGLVQPGGSLRLSCAA



DHGM
GGES
PAVA
SNYLA
(SEQ ID
(SEQ ID NO:
SGFTFSDHGMHWVRQAPGKGLEWV



H
TYYA
GGGI
(SEQ
NO:
301)
SVIYGGESTYYADSVKGRFTISRD



(SEQ
(SEQ
FDYW
ID NO:
159)

NSKNTLYLQMNSLRAEDTAVYYCA



ID
ID
(SEQ
218)


RDPAVAGGGIFDYWGQGTLVTVSS



NO:
NO:
ID



GGGGSGGGGSGGGGSGGGGSDIQM



298)
299)
NO:



TQSPSSLSASVGDRVTITCRASQG





300)



ISNYLAWYQQKPGKAPKLLIYDAS









NLETGVPSRFSGSGSGTDFTLTIS









SLQPEDFATYYCQQSYSTCYTFGQ









GTKLEIK (SEQ ID NO: 302)





49.
DTFT
GWIN
CARS
RASQTI
DASTLQS
CQQYSSYPLTF
QVQLVQSGAEVKKPGASVKVSCKA



GYYI
PNSG
GLWL
SIWLA
(SEQ ID
(SEQ ID NO:
SGDTFTGYYIHWVRQAPGQGLEWM



H
GTNY
GSYY
(SEQ
NO:
308)
GWINPNSGGTNYAQKFQGRVTMTR



(SEQ
A
GMDV
ID NO:
307)

DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
W
306)


ARSGLWLGSYYGMDVWGQGTLVTV



NO:
ID
(SEQ



SSGGGGSGGGGSGGGGSGGGGSDI



303)
NO:
ID



QMTQSPSSLSASVGDRVTITCRAS




304)
NO:



QTISIWLAWYQQKPGKAPKLLIYD





305)



ASTLQSGVPSRFSGSGSGTDFTLT









ISSLQPEDFATYYCQQYSSYPLTF









GQGTKVEIK (SEQ ID NO:









309)





50.
YTFT
GWIN
CARS
RASHFI
AASTLQS
CQQSYSGISF
QVQLVQSGAEVKKPGASVKVSCKA



SYDI
PNSG
PYYY
SRWVA
(SEQ ID
(SEQ ID NO:
SGYTFTSYDINWVRQAPGQGLEWM



N
TTGY
YGMD
(SEQ
NO:
314)
GWINPNSGTTGYAQKFQGRVTMTR



(SEQ
A
VW
ID NO:
113)

DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
313)


ARSPYYYYGMDVWGQGTTVTVSSG



NO:
ID
ID



GGGSGGGGSGGGGSGGGGSDIQMT



310)
NO:
NO:



QSPSSLSASVGDRVTITCRASHFI




311)
312)



SRWVAWYQQKPGKAPKLLIYAAST









LQSGVPSRFSGSGSGTDFTLTISS









LQPEDFATYYCQQSYSGISFGPGT









KVDIK (SEQ ID NO: 315)





51.
FTEN
SRIN
CARG
RASQSV
ATSSRAS
CQQYYSGLTF
EVQLLESGGGLVQPGGSLRLSCAA



NYGM
SDGS
AYYY
SGSYLA
(SEQ ID
(SEQ ID NO:
SGFTFNNYGMNWVRQAPGKGLEWV



N
STSY
YYMD
(SEQ
NO:
321)
SRINSDGSSTSYADSVKGRFTISR



(SEQ
A
VW
ID NO:
320)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
319)


ARGAYYYYYMDVWGQGTLVTVSSG



NO:
ID
ID



GGGSGGGGSGGGGSGGGGSEIVMT



316)
NO:
NO:



QSPATLSVSPGERATLSCRASQSV




317)
318)



SGSYLAWYQQKPGQAPRLLIYATS









SRASGIPARFSGSGSGTEFTLTIS









SLQSEDFAVYYCQQYYSGLTFGQG









TKVEIK (SEQ ID NO: 322)





52.
FTFS
AHIW
CARD
RASQDI
DASSLET
CQQATSLPLTF
EVQLLESGGGLVQPGGSLRLSCAA



NSDM
NDGS
RTDP
RNYLG
(SEQ ID
(SEQ ID NO:
SGFTFSNSDMNWVRQAPGKGLEWV



N
QKYY
GYSS
(SEQ
NO:
328)
AHIWNDGSQKYYADSVKGRFTISR



(SEQ
A
AMDV
ID NO:
327)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
W
326)


ARDRTDPGYSSAMDVWGQGTTVTV



NO:
ID
(SEQ



SSGGGGSGGGGSGGGGSGGGGSDI



323)
NO:
ID



QMTQSPSSLSASVGDRVTITCRAS




324)
NO:



QDIRNYLGWYQQKPGKAPKLLIYD





325)



ASSLETGVPSRFSGSGSGTDFTLT









ISSLQPEDFATYYCQQATSLPLTF









GGGTKVEIK (SEQ ID NO:









329)





53.
YTFT
GWMN
CAKD
RASQDI
QASSLES
CQQSYTIPLTF
QVQLVQSGAEVKKPGASVKVSCKA



SYDI
PNSG
SDYS
TNDLG
(SEQ ID
(SEQ ID NO:
SGYTFTSYDINWVRQAPGQGLEWM



N
NTGY
NLLW
(SEQ
NO:
333)
GWMNPNSGNTGYAQKFQGRVTMTR



(SEQ
A
DYW
ID NO:
332)

DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
331)


AKDSDYSNLLWDYWGQGTLVTVSS



NO:
ID
ID



GGGGSGGGGSGGGGSGGGGSDIQM



310)
NO:
NO:



TQSPSSLSASVGDRVTITCRASQD




205)
330)



ITNDLGWYQQKPGKAPKLLIYQAS









SLESGVPSRFSGSGSGTDFTLTIS









SLQPEDFATYYCQQSYTIPLTFGQ









GTKVEIK (SEQ ID NO: 334)





54.
FTFG
AVVS
CAKD
RASQNI
DASNLET
CQQANSFPPTF
EVQLLESGGGLVQPGGSLRLSCAA



DYAM
YDGT
ICSS
NNYVN
(SEQ ID
(SEQ ID NO:
SGFTFGDYAMSWVRQAPGKGLEWV



S
NKYY
TSCY
(SEQ
NO:
338)
AVVSYDGTNKYYADSVKGRFTISR



(SEQ
A
FDLW
ID NO:
159)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
337)


AKDICSSTSCYFDLWGRGTLVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



233)
NO:
NO:



MTQSPSSLSASVGDRVTITCRASQ




335)
336)



NINNYVNWYQQKPGKAPKLLIYDA









SNLETGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQANSFPPTFG









QGTRLEIK (SEQ ID NO:









339)





55.
YTFT
GIID
CARE
RASQGI
ATSSLQT
CQQTYSIPITF
QVQLVQSGAEVKKPGASVKVSCKA



SYYM
PSGG
EWSS
SSYLA
(SEQ ID
(SEQ ID NO:
SGYTFTSYYMHWVRQAPGQGLEWM



H
STSY
GGVG
(SEQ
NO:
344)
GIIDPSGGSTSYAQKFQGRVTMTR



(SEQ
A
YFDY
ID NO:
343)

DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
W
342)


AREEWSSGGVGYFDYWGQGTLVTV



NO:
ID
(SEQ



SSGGGGSGGGGSGGGGSGGGGSDI



215)
NO:
ID



QMTQSPSSLSASVGDRVTITCRAS




340)
NO:



QGISSYLAWYQQKPGKAPKLLIYA





341)



TSSLQTGVPSRFSGSGSGTDFTLT









ISSLQPEDFATYYCQQTYSIPITE









GQGTRLEIK (SEQ ID NO:









345)





56.
FTFD
SAIS
CARD
QASQDI
KASSLES
CQQANSYPVTF
EVQLLESGGGLVQPGGSLRLSCAA



DYAM
GGGE
ASYG
RNYLN
(SEQ ID
(SEQ ID NO:
SGFTFDDYAMHWVRQAPGKGLEWV



H
DTYY
GNYG
(SEQ
NO:
348)
SAISGGGEDTYYADSVKGRFTISR



(SEQ
A
MDVW
ID NO:
347)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
280)


ARDASYGGNYGMDVWGQGTTVTVS



NO:
ID
ID



SGGGGSGGGGSGGGGSGGGGSDIQ



135)
NO:
NO:



MTQSPSSLSASVGDRVTITCQASQ




346)
279)



DIRNYLNWYQQKPGKAPKLLIYKA









SSLESGVPSRFSGSGSGTDFTLTI









SSLQPEDFATYYCQQANSYPVTFG









GGTKVEIK (SEQ ID NO:









349)





57.
YTFT
GIIN
CARD
RASQGI
AASSLQG
CQQSYSLPYTF
QVQLVQSGAEVKKPGASVKVSCKA



SYYM
PSGG
SVAG
SNYFA
(SEQ ID
(SEQ ID NO:
SGYTFTSYYMHWVRQAPGQGLEWM



H
STSY
TGGR
(SEQ
NO:
353)
GIINPSGGSTSYAQKFQGRVTMTR



(SEQ
A
YYGM
ID NO:
352)

DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
DVW
351)


ARDSVAGTGGRYYGMDVWGQGTLV



NO:
ID
(SEQ



TVSSGGGGSGGGGSGGGGSGGGGS



215)
NO:
ID



DIQMTQSPSSLSASVGDRVTITCR




69)
NO:



ASQGISNYFAWYQQKPGKAPKLLI





350)



YAASSLQGGVPSRFSGSGSGTDFT









LTISSLQPEDFATYYCQQSYSLPY









TFGQGTKLEIK (SEQ ID NO:









354)





58.
YTFT
GIIN
CTTA
RASQGI
AASSLQS
CQQYYSNADF
QVQLVQSGAEVKKPGASVKVSCKA



GYYM
PSGG
DYYY
SNYLA
(SEQ ID
(SEQ ID NO:
SGYTFTGYYMHWVRQAPGQGLEWM



H
NTKY
YMDV
(SEQ
NO: 65)
357)
GIINPSGGNTKYAQKFQGRVTMTR



(SEQ
A
W
ID NO:


DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
218)


TTADYYYYMDVWGKGTTVTVSSGG



NO:
ID
ID



GGSGGGGSGGGGSGGGGSDIQMTQ



128)
NO:
NO:



SPSSLSASVGDRVTITCRASQGIS




355)
356)



NYLAWYQQKPGKAPKLLIYAASSL









QSGVPSRFSGSGSGTDFTLTISSL









QPEDFATYYCQQYYSNADFGQGTK









VEIK (SEQ ID NO: 358)





59.
FTFS
SYIS
CARD
RASQSV
SSLQS
QQYKSYPVT
EVQLLESGGGLVQPGGSLRLSCAA



DFWM
GDSG
RPYY
SRSLA
(SEQ ID
(SEQ ID NO:
SGFTFSDFWMHWVRQAPGKGLEWI



H
YTNY
YYMD
(SEQ
NO:
363)
SYISGDSGYTNYADSVKGRFTISR



(SEQ
A
VW
ID NO:
362)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
361)


ARDRPYYYYMDVWGKGTTVTVSSG



NO:
ID
ID



GGGSGGGGSGGGGSGGGGSDIQMT



359)
NO:
NO:



QSPSSLSASVGDRVTITCRASQSV




170)
360)



SRSLAWYQQKPGKAPKLLIYAASS









LQSGVPSRFSGSGSGTDFTLTISS









LQPEDFATYYCQQYKSYPVTFGQG









TKVEIK (SEQ ID NO: 364)





60.
FTFD
SDIS
CAKD
QASQDI
SYLQS
QQAHNYPIT
EVQLLESGGGLVQPGGSLRLSCAA



DYTM
GSGG
VVVA
SNYLN
(SEQ ID
(SEQ ID NO:
SGFTFDDYTMHWVRQAPGKGLEWV



H
STYY
GTPL
(SEQ
NO:
369)
SDISGSGGSTYYADSVKGRFTISR



(SEQ
A
HFDY
ID NO:
368)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
W
138)


AKDVVVAGTPLHFDYWGQGTLVTV



NO:
ID
(SEQ



SSGGGGSGGGGSGGGGSGGGGSDI



365)
NO:
ID



QMTQSPSSLSASVGDRVTITCQAS




366)
NO:



QDISNYLNWYQQKPGKAPKLLIYA





367)



ASYLQSGVPSRFSGSGSGTDFTLT









ISSLQPEDFATYYCQQAHNYPITF









GQGTRLEIK (SEQ ID NO:









370)





61.
FTFS
ASIS
CARE
RASQSI
SSLQS
QQANAFPPT
EVQLLESGGGLVQPGGSLRLSCAA



NAWM
STSA
VVGA
STWLA
(SEQ ID
(SEQ ID NO:
SEFTFSNAWMSWVRQAPGKGLEWV



S
YIDY
TTFD
(SEQ
NO:
374)
ASISSTSAYIDYADSVKGRFTISR



(SEQ
A
YW
ID NO:
362)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
373)


AREVVGATTFDYWGQGTLVTVSSG



NO:
ID
ID



GGGSGGGGSGGGGSGGGGSDIQMT



183)
NO:
NO:



QSPSSLSASVGDRVTITCRASQSI




371)
372)



STWLAWYQQKPGKAPKLLIYAASS









LQSGVPSRFSGSGSGTDFTLTISS









LQPEDFATYYCQQANAFPPTFGQG









TRLEIK (SEQ ID NO: 375)





62.
GTFS
GWME
CAKG
KSSQSV
STRES
QQYYSTPPT
QVQLVQSGAEVKKPGSSVKVSCKA



SYAI
PHTG
GFSW
LYSSNN
(SEQ ID
(SEQ ID NO:
SGGTFSSYAISWVRQAPGQGLEWM



S
NTRY
FDPW
KNYLA
NO:
379)
GWMEPHTGNTRYAQKFQGRVTITA



(SEQ
A
(SEQ
(SEQ
378)

DESTSTAYMELSSLRSEDTAVYYC



ID
(SEQ
ID
ID NO:


AKGGFSWFDPWGQGTLVTVSSGGG



NO:
ID
NO:
289)


GSGGGGSGGGGSGGGGSDIVMTQS



77)
NO:
377)



PDSLAVSLGERATINCKSSQSVLY




376)




SSNNKNYLAWYQQKPGQPPKLLIY









WASTRESGVPDRFSGSGSGTDFTL









TISSLQAEDVAVYYCQQYYSTPPT









FGQGTRLEIK (SEQ ID NO:









380)





63.
FTFD
ASIT
CARE
RASQGI
STRAT
QQYYTYPPT
EVQLLESGGGLVKPGGSLRLSCAA



DYAM
SSSA
RVDW
SNSYLA
(SEQ ID
(SEQ ID NO:
SGFTFDDYAMHWVRQAPGKGLEWV



H
FIDY
NSYF
(SEQ
NO:
385)
ASITSSSAFIDYAASVKGRFTISR



(SEQ
A
DLW
ID NO:
384)

DDSKNTLYLQMNSLKTEDTAVYYC



ID
(SEQ
(SEQ
383)


ARERVDWNSYFDLWGRGTLVTVSS



NO:
ID
ID



GGGGSGGGGSGGGGSGGGGSEIVM



135)
NO:
NO:



TQSPATLSVSPGERATLSCRASQG




381)
382)



ISNSYLAWYQQKPGQAPRLLIYGA









STRATGIPARFSGSGSGTEFTLTI









SSLQSEDFAVYYCQQYYTYPPTFG









PGTKVDIK (SEQ ID NO:









386)





64.
FAFS
AGTS
CARE
RASQGI
ANLEG
QQSDIFPPT
EVQLLESGGGLVKPGGSLRLSCAA



SHWM
GSGE
TYYY
SNYLA
(SEQ ID
(SEQ ID NO:
SGFAFSSHWMHWVRQAPGKGLEWV



H
SRDY
YYMD
(SEQ
NO:
391)
AGTSGSGESRDYADFVKGRFTISR



(SEQ
A
VW
ID NO:
390)

DDSKNTLYLQMNSLKTEDTAVYYC



ID
(SEQ
(SEQ
218)


ARETYYYYYMDVWGKGTTVTVSSG



NO:
ID
ID



GGGSGGGGSGGGGSGGGGSDIQMT



387)
NO:
NO:



QSPSSLSASVGDRVTITCRASQGI




388)
389)



SNYLAWYQQKPGKAPKLLIYDAAN









LEGGVPSRFSGSGSGTDFTLTISS









LQPEDFATYYCQQSDIFPPTFGQG









TKVEIK (SEQ ID NO: 392)





65.
YTFT
GWIN
CARE
RASQSI
SSLQS
QQSNSFPLT
QVQLVQSGAEVKKPGASVKVSCKA



RHWI
VKTG
SSGW
SNYLA
(SEQ ID
(SEQ ID NO:
SGYTFTRHWIHWVRQAPGQGLEWM



H
GAGY
YGTD
(SEQ
NO:
397)
GWINVKTGGAGYAQKFQGRVTMTR



(SEQ
A
VW
ID NO:
362)

DTSTSTVYMELSSLRSEDTAVYYC



ID
(SEQ
(SEQ
396)


ARESSGWYGTDVWGQGTTVTVSSG



NO:
ID
ID



GGGSGGGGSGGGGSGGGGSDIQMT



393)
NO:
NO:



QSPSSLSASVGDRATITCRASQSI




394)
395)



SNYLAWYQQKPGKAPKLLIYAASS









LQSGVPSRFSGSGSGTDFTLTISS









LQPEDFATYYCQQSNSFPLTFGGG









TKVEIK (SEQ ID NO: 398)





66.
FTFS
AAIS
CARE
QASQDI
NLRS
QQANSFPVT
EVQLLESGGGLVQPGGSLRLSCAA



SYWM
YDGK
NKQW
SNFVN
(SEQ ID
(SEQ ID NO:
SGFTFSSYWMHWVRQAPGKGLEWV



H
YKDY
LASF
(SEQ
NO:
403)
AAISYDGKYKDYEDSVKGRFTISR



(SEQ
E
DYW
ID NO:
402)

DNSKNTLYLQMNSLRAEDTAVYYC



ID
(SEQ
(SEQ
401)


ARENKQWLASFDYWGQGTLVTVSS



NO:
ID
ID



GGGGSGGGGSGGGGSGGGGSDIQM



83)
NO:
NO:



TQSPSSLSASVGDRVTITCQASQD




399)
400)



ISNFVNWYQQKPGKAPKLLIYAAN









LRSGVPSRFSGSGSGTDFTLTISS









LQPEDFATYYCQQANSFPVTFGPG









TKVDIK (SEQ ID NO: 404)









In some embodiments, the antibody comprises a CDR set as set forth in Table 6 or Table 7. In some embodiments, the antibody comprises the CDRs of Clone ID: 6, Clone ID: 59, or Clone ID: 63 of Table 6.


The antibodies, can be in a scFv format, which are also illustrated in a non-limiting embodiment in Table 6.


In some embodiments, the MAdCAM antibody is selected from the following table, which can be in a IgG format as illustrated in Table 7.

















TABLE 7





Clone










ID
HCDR1
HCDR2
HCDR3
LCDR1
LCDR2
LCDR3
VH
VK























1.
FTFSS
AVISD
CTTSK
QASQD
AASSLQ
CQQGY
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YGMH
DGSDK
YYYYY
ISKSL
S (SEQ
STPLT
PGGSLRLSCAASG
GDRVTITCQASQDIS



(SEQ
YYA
GMDVW
N
ID NO:
F
FTFSSYGMHWVRQ
KSLNWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
65)
(SEQ
APGKGLEWVAVIS
LLIYAASSLQSGVPS



NO:
ID
ID
ID

ID
DDGSDKYYADSVK
RFSGSGSGTDFTLTI



61)
NO:
NO:
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




62)
63)
64)

66)
LYLQMNSLRAEDT
GYSTPLTFGGGTKVE









AVYYCTTSKYYYY
IK (SEQ ID NO:









YGMDVWGQGTTVT
406)









VSS (SEQ ID










NO: 405)






2.
YPFIG
GIINP
CAREG
RASQS
GASTLE
CQQTW
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYLH
SGGST
RLSYG
ISSYL
S
GPPFT
PGASVKVSCKASG
GDRVTITCRASQSIS



(SEQ
SYA
MDAW
A
(SEQ
F
YPFIGYYLHWVRQ
SYLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
ID NO:
(SEQ
APGQGLEWMGIIN
LLIYGASTLESGVPS



NO:
ID
ID
ID
72)
ID
PSGGSTSYAQKFQ
RFSGSGSGTDFTLTI



68)
NO:
NO:
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




69)
70)
71)

73)
VYMELSSLRSEDT
TWGPPFTFGQGTKLE









AVYYCAREGRLSY
IK (SEQ ID NO:









GMDAWGQGTLVTV
408)









SS (SEQ ID










NO: 407)






3.
YPFIG
GIINP
CAREG
RASQS
GASTLE
CQQTW
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



QYLH
SGGST
RLSYG
ISSYL
S (SEQ
GPPFT
PGASVKVSCKASG
GDRVTITCRASQSIS



(SEQ
SYA
MDAW
A
ID NO:
F
YPFIGQYLHWVRQ
SYLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
72)
(SEQ
APGQGLEWMGIIN
LLIYGASTLESGVPS



NO:
ID
ID
ID

ID
PSGGSTSYAQKFQ
RFSGSGSGTDFTLTI



75
NO:
NO:
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




69)
70)
71)

73)
VYMELSSLRSEDT
TWGPPFTFGQGTKLE









AVYYCAREGRLSY
IK (SEQ ID NO:









GMDAWGQGTLVTV
408)









SS (SEQ ID










NO: 409)






4.
GTFSS
GSINP
CAKDK
QASQD
AASSLQ
CQQSY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YAIS
SGDTT
AQWLV
ISNSL
S (SEQ
SSVIT
PGASVKVSCKASG
GDRVTITCQASQDIS



(SEQ
SYA
GYFDY
N
ID NO:
F
GTFSSYAISWVRQ
NSLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
65)
(SEQ
APGQGLEWMGSIN
LLIYAASSLQSGVPS



NO:
ID
(SEQ
ID

ID
PSGDTTSYAQKFQ
RFSGSGSGTDFTLTI



77)
NO:
ID
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




78)
NO:
80)

81)
VYMELSSLRSEDT
SYSSVITFGQGTKVE





79)



AVYYCAKDKAQWL
IK (SEQ ID NO:









VGYFDYWGQGTLV
411)









TVSS (SEQ ID










NO: 410)






5.
FTFSS
SSISP
CAREV
RASQG
GASSLQ
CQQAN
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YWMH
GGSNI
QLSHY
ISNSL
S (SEQ
SFPFT
PGGSLRLSCAASG
GDRVTITCRASQGIS



(SEQ
DYA
DYW
A
ID NO:
F
FTFSSYWMHWVRQ
NSLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
87)
(SEQ
APGKGLEWVSSIS
LLIYGASSLQSGVPS



NO:
ID
ID
ID

ID
PGGSNIDYADSVK
RFSGSGSGTDFTLTI



83)
NO:
NO:
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




84)
85)
86)

88)
LYLQMNSLRAEDT
ANSFPFTFGQGTKVE









AVYYCAREVQLSH
IK (SEQ ID NO:









YDYWGQGTLVTVS
413)









S (SEQ ID NO:










412)






6.
FTFNN
SRINS
CAREG
RASQI
GASSLQ
CQQSY
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YAFH
YGTST
PVAGY
IGTNL
S (SEQ
RLPFT
PGGSLRLSCAASG
GDRVTITCRASQIIG



(SEQ
TYA
WYFDL
A
ID NO:
F
FTFNNYAFHWVRQ
TNLAWYQQKPGKAPK



ID
(SEQ
W
(SEQ
87)
(SEQ
APGKGLEWVSRIN
LLIYGASSLQSGVPS



NO:
ID
(SEQ
ID

ID
SYGTSTTYADSVK
RFSGSGSGTDFTLTI



90)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




91)
NO:
93)

94)
LYLQMNSLRAEDT
SYRLPFTFGQGTKVE





92)



AVYYCAREGPVAG
IK (SEQ ID NO:









YWYFDLWGQGTLV
415)









TVSS (SEQ ID










NO: 414)






7.
FTFSD
AIISH
CAKPY
RASRG
STLQS
QQAYS
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YQMS
ADGGF
SSGWS
ITNDL
(SEQ
FPWT
PGGSLRLSCAASG
GDRVTITCRASRGIT



(SEQ
KDYA
AVYYF
G
ID NO:
(SEQ
FTFSDYQMSWVRQ
NDLGWYQQKPGKAPK



ID
(SEQ
DYW
(SEQ
420)
ID
APGKGLEWVAIIS
LLIYAASTLQSGVPS



NO:
ID
(SEQ
ID

NO:
HADGGFKDYADSV
RFSGSGSGTDFTLTI



416)
NO:
ID
NO:

421)
KGRFTISRDNSKN
SSLQPEDFATYYCQQ




417)
NO:
419)


TLYLQMNSLRAED
AYSFPWTFGQGTKVE





418)



TAVYYCAKPYSSG
IK (SEQ ID NO:









WSAVYYFDYWGQG
423)









TLVTVSS (SEQ










ID NO: 422)






8.
YTFTG
GIINP
CAKDW
RASQN
AASSLQ
CQQSY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YHIH
SGGST
SSWYL
ISSSL
S (SEQ
TTPYT
PGASVKVSCKASG
GDRVTITCRASQNIS



(SEQ
IYA
GPFDY
N
ID NO:
F
YTFTGYHIHWVRQ
SSLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
65)
(SEQ
APGQGLEWMGIIN
LLIYAASSLQSGVPS



NO:
ID
(SEQ
ID

ID
PSGGSTIYAQKFQ
RFSGSGSGTDFTLTI



96)
NO:
ID
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




97)
NO:
99)

100)
VYMELSSLRSEDT
SYTTPYTFGQGTKVE





98)



AVYYCAKDWSSWY
IK (SEQ ID NO:









LGPFDYWGQGTLV
425)









TVSS (SEQ ID










NO: 424)






9.
YTFTS
GIINH
CARPY
RASQS
STLQS
QQSYS
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
SGGST
SGWYF
ISSSL
(SEQ
TPLT
PGASVKVSCKASG
GDRVTITCRASQSIS



(SEQ
SYA
AFDIW
N
ID NO:
(SEQ
YTFTSYYMHWVRQ
SSLNWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
420)
ID
APGQGLEWMGIIN
LLIYAASTLQSGVPS



NO:
ID
ID
ID

NO:
HSGGSTSYAQKFQ
RFSGSGSGTDFTLTI



215)
NO:
NO:
NO:

429)
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




426)
427)
428)


VYMELSSLRSEDT
SYSTPLTFGQGTKVE









AVYYCARPYSGWY
IK (SEQ ID NO:









FAFDIWGQGTLVT
431)









VSS (SEQ ID










NO: 430)






10.
FMFGD
SAISG
CAKDL
RASQG
DASSLE
CQQTH
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YAMH
SGGST
VVAGI
ISNNL
S (SEQ
SFPST
PGGSLRLSCAASG
GDRVTITCRASQGIS



(SEQ
YYA
WYFDL
N
ID NO:
F
FMFGDYAMHWVRQ
NNLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
106)
(SEQ
APGKGLEWVSAIS
LLIYDASSLESGVPS



NO:
ID
(SEQ
ID

ID
GSGGSTYYADSVK
RFSGSGSGTDFTLTI



102)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




103)
NO:
105)

107)
LYLQMNSLRAEDT
THSFPSTFGQGTKLE





104)



AVYYCAKDLVVAG
IK (SEQ ID NO:









IWYFDLWGRGTLV
433)









TVSS (SEQ ID










NO: 432)






11.
FTFSD
SVIGE
CAADP
RASQG
AASTLQ
CQQSY
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YYMN
SGGST
VSRWP
ISSSL
S (SEQ
STPWT
PGGSLRLSCAASG
GDRVTITCRASQGIS



(SEQ
YYA
KHGGG
A
ID NO:
F
FTFSDYYMNWVRQ
SSLAWYQQKPGKAPK



ID
(SEQ
DYW
(SEQ
113)
(SEQ
APGKGLEWVSVIG
LLIYAASTLQSGVPS



NO:
ID
(SEQ
ID

ID
ESGGSTYYADSVK
RFSGSGSGTDFTLTI



109)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




110)
NO:
112)

114)
LYLQMNSLRAEDT
SYSTPWTFGQGTKVE





111)



AVYYCAADPVSRW
IK (SEQ ID NO:









PKHGGGDYWGQGT
435)









LVTVSS (SEQ










ID NO: 434)






12.
YTLTT
GWINP
CAKGD
RASDN
AASSLQ
CQQGY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



WYMY
NRGAT
LWGAM
IGSWL
S (SEQ
STPPT
PGASVKVSCKASG
GDRVTITCRASDNIG



(SEQ
NYA
DVW
A
ID NO:
F
YTLTTWYMYWVRQ
SWLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
65)
(SEQ
APGQGLEWMGWIN
LLIYAASSLQSGVPS



NO:
ID
ID
ID

ID
PNRGATNYAQKFQ
RFSGSGSGTDFTLTI



116)
NO:
NO:
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




117)
118)
119)

120)
VYMELSSLRSEDT
GYSTPPTFGQGTKVE









AVYYCAKGDLWGA
IK (SEQ ID NO:









MDVWGQGTLVTVS
437)









S (SEQ ID NO:










436)






13.
YTFTT
GGFDP
CARHA
RASES
AASTLQ
CQQSY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
EDGET
VAGAV
ISNWL
S (SEQ
SVPFT
PGASVKVSCKASG
GDRVTITCRASESIS



(SEQ
IYA
GAGYY
A
ID NO:
F
YTFTTYYMHWVRQ
NWLAWYQQKPGKAPK



ID
(SEQ
YYGMD
(SEQ
113)
(SEQ
APGQGLEWMGGFD
LLIYAASTLQSGVPS



NO:
ID
VW
ID

ID
PEDGETIYAQKFQ
RFSGSGSGTDFTLTI



122)
NO:
(SEQ
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




123)
ID
125)

126)
VYMELSSLRSEDT
SYSVPFTFGPGTKVD





NO:



AVYYCARHAVAGA
IK (SEQ ID NO:





124)



VGAGYYYYGMDVW
439)









GQGTMVTVSS










(SEQ ID NO:










438)






14.
YTFTN
GGIIP
CAKGQ
QANQD
SKLEA
QQSSE
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
IVDGV
FTGNY
ISNYL
(SEQ
IPYS
PGSSVKVSCKASG
GDRVTITCQANQDIS



(SEQ
KYA
YYGMD
N
ID NO:
(SEQ
YTFTNYYMHWVRQ
NYLNWYQQKPGKAPK



ID
(SEQ
YW
(SEQ
442)
ID
APGQGLEWMGGII
LLIYRASKLEAGVPS



NO:
ID
(SEQ
ID

NO:
PIVDGVKYAQKFQ
RFSGSGSGTDFTLTI



148)
NO:
ID
NO:

443)
GRVTITADESTST
SSLQPEDFATYYCQQ




440)
NO:
151)


AYMELSSLRSEDT
SSEIPYSFGQGTKVE





441)



AVYYCAKGQFTGN
IK (SEQ ID NO:









YYYGMDYWGQGTL
445)









VTVSS (SEQ ID










NO: 444)






15.
YTFTG
GWIGP
CARDL
RSSQS
SSSNRA
CMQAL
QVQLVQSGAEVKK
DIVMTQSPLSLPVTP



YYMH
NSGDT
DHNWY
LLHSN
P (SEQ
HIPLT
PGASVKVSCKASG
GEPASISCRSSQSLL



(SEQ
NYA
FDLW
GYNYL
ID NO:
F
YTFTGYYMHWVRQ
HSNGYNYLDWYLQKP



ID
(SEQ
(SEQ
D
132)
(SEQ
APGQGLEWMGWIG
GQSPQLLIYSSSNRA



NO:
ID
ID
(SEQ

ID
PNSGDTNYAQKFQ
PGVPDRFSGSGSGTD



128)
NO:
NO:
ID

NO:
GRVTMTRDTSTST
FTLKISRVEAEDVGV




129)
130)
NO:

133)
VYMELSSLRSEDT
YYCMQALHIPLTFGG






131)


AVYYCARDLDHNW
GTKVEIK (SEQ ID









YFDLWGRGTLVTV
NO: 447)









SS (SEQ ID










NO: 446)






16.
FTFDD
SYIDA
CAKDQ
QASQD
KASTLE
CQQSY
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YAMH
SGTTI
AAAGY
ISNYL
S (SEQ
STPIT
PGGSLRLSCAASG
GDRVTITCQASQDIS



(SEQ
YYA
WYFDL
N
ID NO:
F
FTFDDYAMHWVRQ
NYLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
139)
(SEQ
APGKGLEWVSYID
LLIYKASTLESGVPS



NO:
ID
(SEQ
ID

ID
ASGTTIYYADSVK
RFSGSGSGTDFTLTI



135)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




136)
NO:
138)

140)
LYLQMNSLRAEDT
SYSTPITFGQGTRLE





137)



AVYYCAKDQAAAG
IK (SEQ ID NO:









YWYFDLWGRGTLV










TVSS (SEQ ID
449)









NO: 448)






17.
YTFTD
GGIVP
CAKDE
RSSQS
SAYNRA
CMQAL
QVQLVQSGAEVKK
DIVMTQSPLSLPVTP



YHIH
RSGST
SSGWY
LLHSN
S (SEQ
QTPLT
PGSSVKVSCKASG
GEPASISCRSSQSLL



(SEQ
TYA
YFDYW
GYNYL
ID NO:
F
YTFTDYHIHWVRQ
HSNGYNYLDWYLQKP



ID
(SEQ
(SEQ
D
145)
(SEQ
APGQGLEWMGGIV
GQSPQLLIYSAYNRA



NO:
ID
ID
(SEQ

ID
PRSGSTTYAQKFQ
SGVPDRFSGSGSGTD



142)
NO:
NO:
ID

NO:
GRVTITADESTST
FTLKISRVEAEDVGV




143)
144)
NO:

146)
AYMELSSLRSEDT
YYCMQALQTPLTFGQ






131)


AVYYCAKDESSGW
GTKVEIK (SEQ ID









YYFDYWGQGTLVT
NO: 451)









VSS (SEQ ID










NO: 450)






18.
YTFTN
GGIIP
CAKGR
QANQD
RASKLE
CQQSS
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
IVDRV
YTVNY
ISNYL
A (SEQ
EIPYS
PGSSVKVSCKASG
GDRVTITCQANQDIS



(SEQ
KYA
YYGMD
N
ID NO:
F
YTFTNYYMHWVRQ
NYLNWYQQKPGKAPK



ID
(SEQ
VW
(SEQ
152)
(SEQ
APGQGLEWMGGII
LLIYRASKLEAGVPS



NO:
ID
(SEQ
ID

ID
PIVDRVKYAQKFQ
RFSGSGSGTDFTLTI



148)
NO:
ID
NO:

NO:
GRVTITADESTST
SSLQPEDFATYYCQQ




149)
NO:
151)

153)
AYMELSSLRSEDT
SSEIPYSFGQGTKLE





150)



AVYYCAKGRYTVN
IK (SEQ ID NO:









YYYGMDVWGQGTT
453)









VTVSS (SEQ ID










NO: 452)






19.
FTFED
SYLNS
CAKDY
RASQS
DASNLE
CQQSY
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YAMH
DGGST
CTNGV
ISTYL
T (SEQ
TIPIT
PGGSLRLSCAASG
GDRVTITCRASQSIS



(SEQ
SYA
CAFDY
N
ID NO:
F
FTFEDYAMHWVRQ
TYLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
159)
(SEQ
APGKGLEWVSYLN
LLIYDASNLETGVPS



NO:
ID
(SEQ
ID

ID
SDGGSTSYADSVK
RFSGSGSGTDFTLTI



155)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




156)
NO:
158)

160)
LYLQMNSLRAEDT
SYTIPITFGQGTRLE





157)



AVYYCAKDYCTNG
IK (SEQ ID NO:









VCAFDYWGQGTLV
455)









TVSS (SEQ ID










NO: 454)






20.
FTFSD
SAISG
CVSDI
RASQS
AASRLE
CQQAN
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



SAMH
SGSTI
AVAGH
ISTFL
G (SEQ
SFPLT
PGGSLRLSCAASG
GDRVTITCRASQSIS



(SEQ
YYA
WYFDL
N
ID NO:
F
FTFSDSAMHWVRQ
TFLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
166)
(SEQ
APGKGLEWVSAIS
LLIYAASRLEGGVPS



NO:
ID
(SEQ
ID

ID
GSGSTIYYADSVK
RFSGSGSGTDFTLTI



162)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




163)
NO:
165)

167)
LYLQMNSLRAEDT
ANSFPLTFGPGTKVD





164)



AVYYCVSDIAVAG
IK (SEQ ID NO:









HWYFDLWGRGTLV
457)









TVSS (SEQ ID










NO: 456)






21.
FTFSS
SYISG
CARAN
RASQS
AASSLQ
CQQSY
EVQLVESGGGLVK
DIQMTQSPSSLSASV



YWMS
DSGYT
SSGWY
ISSYL
S (SEQ
STPLT
PGGSLRLSCAASG
GDRVTITCRASQSIS



(SEQ
NYA
DWYFD
N
ID NO:
F
FTFSSYWMSWVRQ
SYLNWYQQKPGKAPK



ID
(SEQ
LW
(SEQ
65)
(SEQ
APGKGLEWVSYIS
LLIYAASSLQSGVPS



NO:
ID
(SEQ
ID

ID
GDSGYTNYAAPVK
RFSGSGSGTDFTLTI



169)
NO:
ID
NO:

NO:
GRFTISRDDSKNT
SSLQPEDFATYYCQQ




170)
NO:
172)

173)
LYLQMNSLKTEDT
SYSTPLTFGGGTKVE





171)



AVYYCARANSSGW
IK (SEQ ID NO:









YDWYFDLWGRGTL
459)









VTVSS (SEQ ID










NO: 458)






22.
FTFDD
SGISW
CAKDI
QASQD
DASNLE
CQQSY
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YAMH
NSGSI
VAAGH
ISNYL
T (SEQ
STPLT
PGGSLRLSCAASG
GDRVTITCQASQDIS



(SEQ
GYA
YYYGM
N
ID NO:
F
FTFDDYAMHWVRQ
NYLNWYQQKPGKAPK



ID
(SEQ
DVW
(SEQ
159)
(SEQ
APGKGLEWVSGIS
LLIYDASNLETGVPS



NO:
ID
(SEQ
ID

ID
WNSGSIGYADSVK
RFSGSGSGTDFTLTI



135)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




175)
NO:
138)

173)
LYLQMNSLRAEDT
SYSTPLTFGGGTKVE





176)



AVYYCAKDIVAAG
IK (SEQ ID NO:









HYYYGMDVWGQGT
461)









TVTVSS (SEQ










ID NO: 460)






23.
FTFDD
SYIDT
CARDE
QAGQD
DASNLE
CQQTY
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YAMH
SSSHL
AAAGY
ISNYL
T (SEQ
STPIT
PGGSLRLSCAASG
GDRVTITCQAGQDIS



(SEQ
YYA
YGMDV
N
ID NO:
F
FTFDDYAMHWVRQ
NYLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
159)
(SEQ
APGKGLEWVSYID
LLIYDASNLETGVPS



NO:
ID
(SEQ
ID

ID
TSSSHLYYADSVK
RFSGSGSGTDFTLTI



135)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




178)
NO:
180)

181)
LYLQMNSLRAEDT
TYSTPITFGQGTKLE





179)



AVYYCARDEAAAG
IK (SEQ ID NO:









YYGMDVWGQGTTV
463)









TVSS (SEQ ID










NO: 462)






24.
FTFSS
SRISS
CARGT
RASQS
SNLQS
QQSYS
EVQLVESGGGLVK
DIQMTQSPSSLSASV



YWMS
DGRIT
SYCTG
IGRNL
(SEQ
IPLT
PGGSLRLSCAASG
GDRVTITCRASQSIG



(SEQ
TYA
GVCDI
N
ID NO:
(SEQ
FTFSSYWMSWVRQ
RNLNWYQQKPGKAPK



ID
(SEQ
DYW
(SEQ
467)
ID
APGKGLEWVSRIS
LLIYSASNLQSGVPS



NO:
ID
(SEQ
ID

NO:
SDGRITTYAAPVK
RFSGSGSGTDFTLTI



169)
NO:
ID
NO:

468)
GRFTISRDDSKNT
SSLQPEDFATYYCQQ




464)
NO:
466)


LYLQMNSLKTEDT
SYSIPLTFGPGTKVD





465)



AVYYCARGTSYCT
IK (SEQ ID NO:









GGVCDIDYWGQGT
470)









LVTVSS (SEQ










ID NO: 469)






25.
FTFSN
STIVG
CARDN
RASQD
AASSLQ
CQQSY
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



AWMS
NGGAT
PLRWQ
ISNYL
S (SEQ
SIPPT
PGGSLRLSCAASG
GDRVTITCRASQDIS



(SEQ
YYA
GMDVW
N
ID NO:
F
FTFSNAWMSWVRQ
NYLNWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
65)
(SEQ
APGKGLEWVSTIV
LLIYAASSLQSGVPS



NO:
ID
ID
ID

ID
GNGGATYYADSVK
RFSGSGSGTDFTLTI



183)
NO:
NO:
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




184)
185)
186)

187)
LYLQMNSLRAEDT
SYSIPPTFGPGTKVD









AVYYCARDNPLRW
IK (SEQ ID NO:









QGMDVWGQGTLVT
472)









VSS (SEQ ID










NO: 471)






26.
FTFSS
SYISS
CARAN
RASQS
SGLQS
QQSYS
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YAMS
SSTYT
SSSWY
ISSYL
(SEQ
TPLT
PGGSLRLSCAASG
GDRVTITCRASQSIS



(SEQ
NYA
DWYFD
N
ID NO:
(SEQ
FTFSSYAMSWVRQ
SYLNWYQQKPGKAPK



ID
(SEQ
LW
(SEQ
474)
ID
APGKGLEWVSYIS
LLIYAASGLQSGVPS



NO:
ID
(SEQ
ID

NO:
SSSTYTNYADSVK
RFSGSGSGTDFTLTI



473)
NO:
ID
NO:

429)
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




190)
NO:
172)


LYLQMNSLRAEDT
SYSTPLTFGGGTKVE





191)



AVYYCARANSSSW
IK (SEQ ID NO:









YDWYFDLWGQGTL
476)









VTVSS (SEQ ID










NO: 475)






27.
FTFSS
SYISS
CARAN
RASQS
SGLQS
QQSYS
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YQMS
SSTYT
SSSWY
ISSYL
(SEQ
TPLT
PGGSLRLSCAASG
GDRVTITCRASQSIS



(SEQ
NYA
DWYFD
N
ID NO:
(SEQ
FTFSSYQMSWVRQ
SYLNWYQQKPGKAPK



ID
(SEQ
LW
(SEQ
474)
ID
APGKGLEWVSYIS
LLIYAASGLQSGVPS



NO:
ID
(SEQ
ID

NO:
SSSTYTNYADSVK
RFSGSGSGTDFTLTI



189)
NO:
ID
NO:

429)
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




190)
NO:
172)


LYLQMNSLRAEDT
SYSTPLTFGGGTKVE





191)



AVYYCARANSSSW
IK (SEQ ID NO:









YDWYFDLWGQGTL
476)









VTVSS (SEQ ID










NO: 477)






28.
FTFSS
SYISS
CARAN
RASQS
SSLQS
QQSYS
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YAMS
SSTYT
SSSWY
ISSYL
(SEQ
TPLT
PGGSLRLSCAASG
GDRVTITCRASQSIS



(SEQ
NYA
DWYFD
N
ID NO:
(SEQ
FTFSSYAMSWVRQ
SYLNWYQQKPGKAPK



ID
(SEQ
LW
(SEQ
362)
ID
APGKGLEWVSYIS
LLIYAASSLQSGVPS



NO:
ID
(SEQ
ID

NO:
SSSTYTNYADSVK
RFSGSGSGTDFTLTI



473)
NO:
ID
NO:

429)
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




190)
NO:
172)


LYLQMNSLRAEDT
SYSTPLTFGGGTKVE





191)



AVYYCARANSSSW
IK (SEQ ID NO:









YDWYFDLWGQGTL
459)









VTVSS (SEQ ID










NO: 475)






29.
FTFSS
SYISS
CARAN
RASQS
AASSLQ
CQQSY
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YQMS
SSTYT
SSSWY
ISSYL
S (SEQ
STPLT
PGGSLRLSCAASG
GDRVTITCRASQSIS



(SEQ
NYA
DWYFD
N
ID NO:
F
FTFSSYQMSWVRQ
SYLNWYQQKPGKAPK



ID
(SEQ
LW
(SEQ
65)
(SEQ
APGKGLEWVSYIS
LLIYAASSLQSGVPS



NO:
ID
(SEQ
ID

ID
SSSTYTNYADSVK
RFSGSGSGTDFTLTI



189)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




190)
NO:
172)

173)
LYLQMNSLRAEDT
SYSTPLTFGGGTKVE





191)



AVYYCARANSSSW
IK (SEQ ID NO:









YDWYFDLWGQGTL
459)









VTVSS (SEQ ID










NO: 477)






30.
FTFSS
SGISG
CATSQ
RASQS
AASNLQ
CQQSY
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YAMH
SGGSA
APVDY
ISSWL
R (SEQ
SIPIT
PGGSLRLSCAASG
GDRVTITCRASQSIS



(SEQ
YYA
YYYGM
A
ID NO:
F
FTFSSYAMHWVRQ
SWLAWYQQKPGKAPK



ID
(SEQ
DVW
(SEQ
197)
(SEQ
APGKGLEWVSGIS
LLIYAASNLQRGVPS



NO:
ID
SEQ
ID

ID
GSGGSAYYADSVK
RFSGSGSGTDFTLTI



193)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




194)
NO:
196)

198)
LYLQMNSLRAEDT
SYSIPITFGQGTKVE





195)



AVYYCATSQAPVD
IK (SEQ ID NO:









YYYYGMDVWGQGT
479)









TVTVSS (SEQ










ID NO: 478)






31.
FTFSS
SYISG
CARVG
RASQS
AASSLQ
CQQSY
EVQLVESGGGLVK
DIQMTQSPSSLSASV



YWMS
SSSYT
SSGWY
ISSYL
S (SEQ
STPLT
PGGSLRLSCAASG
GDRVTITCRASQSIS



(SEQ
NYA
DWYFD
N
ID NO:
F
FTFSSYWMSWVRQ
SYLNWYQQKPGKAPK



ID
(SEQ
LW
(SEQ
65)
(SEQ
APGKGLEWVSYIS
LLIYAASSLQSGVPS



NO:
ID
(SEQ
ID

ID
GSSSYTNYAAPVK
RFSGSGSGTDFTLTI



169)
NO:
ID
NO:

NO:
GRFTISRDDSKNT
SSLQPEDFATYYCQQ




200)
NO:
172)

173)
LYLQMNSLKTEDT
SYSTPLTFGQGTKVE





201)



AVYYCARVGSSGW
IK (SEQ ID NO:









YDWYFDLWGRGTL
481)









VTVSS (SEQ ID










NO: 480)






32.
YTLTT
GWINP
CAKGD
RASDN
AASSLQ
CQQGY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



WYMY
NRGAT
LWGAM
IGSWL
S (SEQ
STPPT
PGASVKVSCKASG
GDRVTITCRASDNIG



(SEQ
NYA
DVW
A
ID NO:
F
YTLTTWYMYWVRQ
SWLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
65)
(SEQ
APGQGLEWMGWIN
LLIYAASSLQSGVPS



NO:
ID
ID
ID

ID
PNRGATNYAQKFQ
RFSGSGSGTDFTLTI



116)
NO:
NO:
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




117)
118)
119)

120)
VYMELSSLRSEDT
GYSTPPTFGQGTKVE









AVYYCAKGDLWGA
IK (SEQ ID NO:









MDVWGQGTLVTVS
437)









S (SEQ ID NO:










436)






33.
YTLTT
GWINP
CAKGD
RASDN
AASSLQ
CQQGY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



WYMY
NRGAT
LWGAM
IGSWL
S (SEQ
STPPT
PGASVKVSCKASG
GDRVTITCRASDNIG



(SEQ
NYA
DVW
A
ID NO:
F
YTLTTWYMYWVRQ
SWLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
65)
(SEQ
APGQGLEWMGWIN
LLIYAASSLQSGVPS



NO:
ID
ID
ID

ID
PNRGATNYAQKFQ
RFSGSGSGTDFTLTI



116)
NO:
NO:
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




117)
118)
119)

120)
VYMELSSLRSEDT
GYSTPPTFGQGTKVE









AVYYCAKGDLWGA
IK (SEQ ID NO:









MDVWGQGTTVTVS
437)









S (SEQ ID NO:










482)






34.
YTFTG
GWMNP
CARDP
RASQS
AASSLQ
CQQSY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYIH
NSGNT
GFLGY
ISSYL
S (SEQ
TAPYT
PGASVKVSCKASG
GDRVTITCRASQSIS



(SEQ
GYA
CSGGS
H
ID NO:
F
YTFTGYYIHWVRQ
SYLHWYQQKPGKAPK



ID
(SEQ
CYDGW
(SEQ
65)
(SEQ
APGQGLEWMGWMN
LLIYAASSLQSGVPS



NO:
ID
FDPW
ID

ID
PNSGNTGYAQKFQ
RFSGSGSGTDFTLTI



204)
NO:
(SEQ
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




205)
ID
207)

208)
VYMELSSLRSEDT
SYTAPYTFGQGTKLE





NO:



AVYYCARDPGFLG
IK (SEQ ID NO:





206)



YCSGGSCYDGWFD
484)









PWGQGTLVTVSS










(SEQ ID NO:










483)






35.
YTFTG
GWMNP
CARDP
RASQS
AASSLQ
CQQSY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYIH
NSGNT
GFLGY
ISSYL
S (SEQ
TAPYT
PGASVKVSCKASG
GDRVTITCRASQSIS



(SEQ
GYA
SSGGS
H
ID NO:
F
YTFTGYYIHWVRQ
SYLHWYQQKPGKAPK



ID
(SEQ
CYDGW
(SEQ
65)
(SEQ
APGQGLEWMGWMN
LLIYAASSLQSGVPS



NO:
ID
FDPW
ID

ID
PNSGNTGYAQKFQ
RFSGSGSGTDFTLTI



204)
NO:
(SEQ
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




205)
ID
207)

208)
VYMELSSLRSEDT
SYTAPYTFGQGTKLE





NO:



AVYYCARDPGELG
IK (SEQ ID NO:





485)



YSSGGSSYDGWFD
484)









PWGQGTLVTVSS










(SEQ ID NO:










486)






36.
FTFDD
SAISG
CARDG
QASQD
SNLET
QQSYS
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YALH
DGRST
TVNGA
ISKYL
(SEQ
IPFT
PGGSLRLSCAASG
GDRVTITCQASQDIS



(SEQ
TYA
TGWFD
N
ID NO:
(SEQ
FTFDDYALHWVRQ
KYLNWYQQKPGKAPK



ID
(SEQ
PW
(SEQ
491)
ID
APGKGLEWVSAIS
LLIYDASNLETGVPS



NO:
ID
(SEQ
ID

NO:
GDGRSTTYADSVK
RFSGSGSGTDFTLTI



487)
NO:
ID
NO:

492)
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




488)
NO:
490)


LYLQMNSLRAEDT
SYSIPFTFGPGTKVD





489)



AVYYCARDGTVNG
IK (SEQ ID NO:









ATGWFDPWGQGTL
494)









VTVSS (SEQ ID










NO: 493)






37.
FTFSD
SAISG
CARDG
RASQG
SNLET
QQSYS
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YGMP
SGGST
GWQPA
ISNNL
(SEQ
TPLT
PGGSLRLSCAASG
GDRVTITCRASQGIS



(SEQ
YYA
AILDY
N
ID NO:
(SEQ
FTFSDYGMPWVRQ
NNLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
491)
ID
APGKGLEWVSAIS
LLIYDASNLETGVPS



NO:
ID
(SEQ
ID

NO:
GSGGSTYYADSVK
RFSGSGSGTDFTLTI



495)
NO:
ID
NO:

429)
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




103)
NO:
105)


LYLQMNSLRAEDT
SYSTPLTFGQGTKVE





296)



AVYYCARDGGWQP
IK (SEQ ID NO:









AAILDYWGQGTLV
497)









TVSS (SEQ ID










NO: 496)






38.
YTFTD
GWMNP
CAREG
RASQG
DASNLE
CQQSY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YFLH
TSGNT
EGSGF
INSWL
T (SEQ
STPLT
PGASVKVSCKASG
GDRVTITCRASQGIN



(SEQ
GYA
DYW
A
ID NO:
F
YTFTDYFLHWVRQ
SWLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
159)
(SEQ
APGQGLEWMGWMN
LLIYDASNLETGVPS



NO:
ID
ID
ID

ID
PTSGNTGYAQKFQ
RFSGSGSGTDFTLTI



210)
NO:
NO:
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




211)
212)
213)

173)
VYMELSSLRSEDT
SYSTPLTFGGGTKVE









AVYYCAREGEGSG
IK (SEQ ID NO:









FDYWGQGTLVTVS
499)









S (SEQ ID NO:










498)






39.
YTFTS
AWMNP
CARDY
RASQG
AASSLQ
CQQSY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
NSGNT
DFWSG
ISNYL
S (SEQ
STPWT
PGASVKVSCKASG
GDRVTITCRASQGIS



(SEQ
GYA
SLGYW
A
ID NO:
F
YTFTSYYMHWVRQ
NYLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
65)
(SEQ
APGQGLEWMAWMN
LLIYAASSLQSGVPS



NO:
ID
ID
ID

ID
PNSGNTGYAQKFQ
RFSGSGSGTDFTLTI



215)
NO:
NO:
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




216)
217)
218)

114)
VYMELSSLRSEDT
SYSTPWTFGQGTKVE









AVYYCARDYDFWS
IK (SEQ ID NO:









GSLGYWGQGTLVT
501)









VSS (SEQ ID










NO: 500)






40.
YTLTT
GWINP
CAKGD
RASDN
AASSLQ
CQQGY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



WYMY
NRGAT
LWGAM
IGSWL
S (SEQ
STPPT
PGASVKVSCKASG
GDRVTITCRASDNIG



(SEQ
NYA
DVW
A
ID NO:
F
YTLTTWYMYWVRQ
SWLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
65)
(SEQ
APGQGLEWMGWIN
LLIYAASSLQSGVPS



NO:
ID
ID
ID

ID
PNRGATNYAQKFQ
RFSGSGSGTDFTLTI



116)
NO:
NO:
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




117)
118)
119)

120)
VYMELSSLRSEDT
GYSTPPTFGQGTKVE









AVYYCAKGDLWGA
IK (SEQ ID NO:









MDVWGQGTLVTVS
437)









S (SEQ ID NO:










436)






41.
YTFTS
GIINP
CARDT
RASQS
DASNLQ
CQQSY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
SGGST
GYSYG
IGRWL
S (SEQ
SIPIT
PGASVKVSCKASG
GDRVTITCRASQSIG



(SEQ
SYA
RYYYY
A
ID NO:
F
YTFTSYYMHWVRQ
RWLAWYQQKPGKAPK



ID
(SEQ
GMDVW
(SEQ
222)
(SEQ
APGQGLEWMGIIN
LLIYDASNLQSGVPS



NO:
ID
(SEQ
ID

ID
PSGGSTSYAQKFQ
RFSGSGSGTDFTLTI



215)
NO:
ID
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




69)
NO:
221)

198)
VYMELSSLRSEDT
SYSIPITFGQGTKVE





220)



AVYYCARDTGYSY
IK (SEQ ID NO:









GRYYYYGMDVWGQ
503)









GTLVTVSS (SEQ










ID NO: 502)






42.
YTLTD
GIINP
CAREE
RASQG
AASSLQ
CQQSY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
SGGST
YSSSS
ISSWL
S (SEQ
STPLT
PGASVKVSCKASG
GDRVTITCRASQGIS



(SEQ
SYA
GYFDY
A
ID NO:
F
YTLTDYYMHWVRQ
SWLAWYQQKPGKAPK



ID
(SEQ
W
(SEQ
65)
(SEQ
APGQGLEWMGIIN
LLIYAASSLQSGVPS



NO:
ID
(SEQ
ID

ID
PSGGSTSYAQKFQ
RFSGSGSGTDFTLTI



224)
NO:
ID
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




69)
NO:
226)

173)
VYMELSSLRSEDT
SYSTPLTFGQGTKVE





225)



AVYYCAREEYSSS
IK (SEQ ID NO:









SGYFDYWGQGTLV
505)









TVSS (SEQ ID










NO: 504)






43.
YTFTS
GWMHP
CARDT
RASQS
AASSLQ
CQQSY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YGIS
KSGDT
PYYYY
ISSWL
S (SEQ
SVPIT
PGASVKVSCKASG
GDRVTITCRASQSIS



(SEQ
GLT
GMDVW
A
ID NO:
F
YTFTSYGISWVRQ
SWLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
65)
(SEQ
APGQGLEWMGWMH
LLIYAASSLQSGVPS



NO:
ID
ID
ID

ID
PKSGDTGLTQKFQ
RFSGSGSGTDFTLTI



228)
NO:
NO:
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




229)
230)
196)

231)
VYMELSSLRSEDT
SYSVPITFGQGTKVE









AVYYCARDTPYYY
IK (SEQ ID NO:









YGMDVWGQGTTVT
507)









VSS (SEQ ID










NO: 506)






44.
FTFSS
SAISG
CAKER
QASQD
SSLQS
QQTYS
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YAMS
SGGST
FIDYG
ISNYL
(SEQ
GWT
PGGSLRLSCAASG
GDRVTITCQASQDIS



(SEQ
YYA
MDVW
N
ID NO:
(SEQ
FTFSSYAMSWVRQ
NYLNWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
362)
ID
APGKGLEWVSAIS
LLIYAASSLQSGVPS



NO:
ID
ID
ID

NO:
GSGGSTYYADSVK
RFSGSGSGTDFTLTI



473)
NO:
NO:
NO:

509)
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




103)
508)
138)


LYLQMNSLRAEDT
TYSGWTFGPGTKVDI









AVYYCAKERFIDY
K (SEQ ID NO:









GMDVWGQGTTVTV
511)









SS (SEQ ID










NO: 510)






45.
FTFGD
SYISG
CARDV
RASQS
AASSLQ
CQQSY
EVQLVESGGGLVK
DIQMTQSPSSLSASV



YAMS
DIGYT
AATGN
ISSYL
S (SEQ
STPLT
PGGSLRLSCAASG
GDRVTITCRASQSIS



(SEQ
NYA
WYFDL
N
ID NO:
F
FTFGDYAMSWVRQ
SYLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
65)
(SEQ
APGKGLEWVSYIS
LLIYAASSLQSGVPS



NO:
ID
(SEQ
ID

ID
GDIGYTNYAAPVK
RFSGSGSGTDFTLTI



233)
NO:
ID
NO:

NO:
GRFTISRDDSKNT
SSLQPEDFATYYCQQ




234)
NO:
172)

173)
LYLQMNSLKTEDT
SYSTPLTFGGGTKVE





235)



AVYYCARDVAATG
IK (SEQ ID NO:









NWYFDLWGRGTLV
459)









TVSS (SEQ ID










NO: 512)






46.
FSFSS
SFITS
CARDR
RASQS
GASTRA
CQQYG
EVQLLESGGGLVQ
EIVMTQSPATLSVSP



YTMN
SSRTI
RGDYG
VRNYL
T (SEQ
SSPLT
PGGSLRLSCAASG
GERATLSCRASQSVR



(SEQ
YYA
DSWYF
A
ID NO:
F
FSFSSYTMNWVRQ
NYLAWYQQKPGQAPR



ID
(SEQ
DLW
(SEQ
241)
(SEQ
APGKGLEWVSFIT
LLIYGASTRATGIPA



NO:
ID
(SEQ
ID

ID
SSSRTIYYADSVK
RFSGSGSGTEFTLTI



237)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQSEDFAVYYCQQ




238)
NO:
240)

242)
LYLQMNSLRAEDT
YGSSPLTFGGGTKVE





239)



AVYYCARDRRGDY
IK (SEQ ID NO:









GDSWYFDLWGRGT
514)









LVTVSS (SEQ










ID NO: 513)






47.
YTFTG
GIINP
CARDT
RASQS
DASNLQ
CQQSY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



HYMH
SGGST
GYSYG
IGRWL
S (SEQ
SIPIT
PGASVKVSCKASG
GDRVTITCRASQSIS



(SEQ
SYA
RYYYY
A
ID NO:
F
YTFSKHFVHWVRQ
SWLAWYQQKPGKAPK



ID
(SEQ
GMDVW
(SEQ
222)
(SEQ
APGQGLEWMGWMN
LLIYAASTLQSGVPS



NO:
ID
(SEQ
ID

ID
PNSGNSGYAQKFQ
RFSGSGSGTDFTLTI



244)
NO:
ID
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




69)
NO:
221)

198)
VYMELSSLRSEDT
SYSTPWTFGQGTKVE





220)



AVYYCARGEGGYY
IK (SEQ ID NO:









YYGMDVWGQGTLV
516)









TVSS (SEQ ID










NO: 515)






48.
YTFSK
GWMNP
CARGE
RASQS
AASTLQ
CQQSY
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



HFVH
NSGNS
GGYYY
ISSWL
S (SEQ
STPWT
PGGSLRLSCAASG
GDRVTITCRASQPLS



(SEQ
GYA
YGMDV
A
ID NO:
F
FTFGSYSMSWVRQ
NWLAWYQQKPGKAPK



ID
(SEQ
W
(SEQ
113)
(SEQ
APGKGLEWVSAIG
LLIYAASSLQSGVPS



NO:
ID
(SEQ
ID

ID
TGGGTYYADSVKG
RFSGSGSGTDFTLTI



246)
NO:
ID
NO:

NO:
RFTISRDNSKNTL
SSLQPEDFATYYCQQ




247)
NO:
196)

114)
YLQMNSLRAEDTA
AISFPLTFGGGTKVE





248)



VYYCAKGTPYYYY
IK (SEQ ID NO:









YGMDVWGQGTMVT
518)









VSS (SEQ ID










NO: 517)






49.
FTFGS
SAIGT
CAKGT
RASQP
AASSLQ
CQQAI
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YSMS
GGGTY
PYYYY
LSNWL
S (SEQ
SFPLT
PGASVKVSCKASG
GDRVTITCQSSEDIS



(SEQ
YA
YGMDV
A
ID NO:
F
YTFTSYYMHWVRQ
SSLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
65)
(SEQ
APGQGLEWMGWMN
LLIYAASSLQIGVPS



NO:
ID
(SEQ
ID

ID
PNSGNTGYAQKFQ
RFSGSGSGTDFTLTI



250)
NO:
ID
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




251)
NO:
253)

254)
VYMELSSLRSEDT
TYSTPYTFGQGTKVE





252)



AVYYCARDLGYYD
IK (SEQ ID NO:









SSGYFGAFDIWGQ
520)









GTTVTVSS (SEQ










ID NO: 519)






50.
YTFTS
GWMNP
CARDL
QSSED
AASSLQ
CQQTY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
NSGNT
GYYDS
ISSSL
I (SEQ
STPYT
PGASVKVSCKASG
GDRVTITCRASQGIG



(SEQ
GYA
SGYFG
N
ID NO:
F
YTFTSYGISWVRQ
NWLAWYQQKPGKAPK



ID
(SEQ
AFDIW
(SEQ
258)
(SEQ
APGQGLEWMGIIN
LLIYAASNLETGVPS



NO:
ID
(SEQ
ID

ID
PRGGSTIFAQKFQ
RFSGSGSGTDFTLTI



215)
NO:
ID
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




205)
NO:
257)

259)
VYMELSSLRSEDT
IHSYPLTFGGGTKVE





256)



AVYYCARGTRSSG
IK (SEQ ID NO:









WYGWFDPWGQGTL
522)









VTVSS (SEQ ID










NO: 521)






51.
YTFTS
GIINP
CARGT
RASQG
AASNLE
CQQIH
EVQLVESGGGLVK
DIVMTQSPLSLPVTP



YGIS
RGGST
RSSGW
IGNWL
T (SEQ
SYPLT
PGGSLRLSCAASG
GEPASISCRSSQSLL



(SEQ
IFA
YGWFD
A
ID NO:
F
FIFQDSAIHWVRQ
HSNGYNYLDWYLQKP



ID
(SEQ
PW
(SEQ
264)
(SEQ
APGKGLEWVSAIG
GQSPQLLIYDASNLE



NO:
ID
(SEQ
ID

ID
TGGGTYYAAPVKG
TGVPDRFSGSGSGTD



228)
NO:
ID
NO:

NO:
RFTISRDDSKNTL
FTLKISRVEAEDVGV




261)
NO:
263)

265)
YLQMNSLKTEDTA
YYCMQALQTPLTFGQ





262)



VYYCARSYCSGGS
GTKVEIK (SEQ ID









CSLGSWGQGTLVT
NO: 524)









VSS (SEQ ID










NO: 523)






52.
FTFDD
SYISS
CAREI
RASQS
AASSLQ
CQQSY
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YGMS
SSSYI
AAAGF
ISSYL
S (SEQ
STPLT
PGGSLRLSCAASG
GDRVTITCRASQSIS



(SEQ
YYA
YGMDV
N
D NO:
F
FTFDDYGMSWVRQ
SYLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
65)
(SEQ
APGKGLEWVSYIS
LLIYAASSLQSGVPS



NO:
ID
(SEQ
ID

ID
SSSSYIYYADSVK
RFSGSGSGTDFTLTI



267)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




268)
NO:
172)

173)
LYLQMNSLRAEDT
SYSTPLTFGGGTKVE





269)



AVYYCAREIAAAG
IK (SEQ ID NO:









FYGMDVWGQGTTV
459)









TVSS (SEQ ID










NO: 525)






53.
YTFTS
GWMNP
CAREG
RASQG
SSLQS
QQSYS
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
NSGNT
LGYCT
ISSWL
(SEQ
TPYT
PGASVKVSCKASG
GDRVTITCRASQGIS



(SEQ
GYA
NGVCW
A
ID NO:
(SEQ
YTFTSYYMHWVRQ
SWLAWYQQKPGKAPK



ID
(SEQ
NYYGM
(SEQ
362)
ID
APGQGLEWMGWMN
LLIYGASSLQSGVPS



NO:
ID
DVW
ID

NO:
PNSGNTGYAQKFQ
RFSGSGSGTDFTLTI



215)
NO:
(SEQ
NO:

527)
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




205)
ID
226)


VYMELSSLRSEDT
SYSTPYTFGQGTKVE





NO:



AVYYCAREGLGYC
IK (SEQ ID NO:





526)



TNGVCWNYYGMDV
529)









WGQGTLVTVSS










(SEQ ID NO:










528)






54.
GTLSR
GGIIP
CARDR
RASQS
GASTRA
CQQYG
QVQLVQSGAEVKK
EIVMTQSPATLSVSP



YGVS
IFGTT
VYYDS
VSSSY
T (SEQ
SSPIT
PGSSVKVSCKASG
GERATLSCRASQSVS



(SEQ
NYA
SGYPT
LA
ID NO:
F
GTLSRYGVSWVRQ
SSYLAWYQQKPGQAP



ID
(SEQ
WYFDL
(SEQ
241)
(SEQ
APGQGLEWMGGII
RLLIYGASTRATGIP



NO:
ID
W
ID

ID
PIFGTTNYAQKFQ
ARFSGSGSGTEFTLT



271)
NO:
(SEQ
NO:

NO:
GRVTITADESTST
ISSLQSEDFAVYYCQ




272)
ID
274)

275)
AYMELSSLRSEDT
QYGSSPITFGQGTKV





NO:



AVYYCARDRVYYD
EIK (SEQ ID NO:





273)



SSGYPTWYFDLWG
531)









RGTLVTVSS










(SEQ ID NO:










530)






55.
FTFDD
SGISG
CARDA
QASQD
KASTLE
CQQAN
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



FAMH
NGDSR
SYGGN
IRNYL
S (SEQ
SFPLT
PGGSLRLSCAASG
GDRVTITCQASQDIR



(SEQ
YYA
YGMDV
N
ID NO:
F
FTFDDFAMHWVRQ
NYLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
139)
(SEQ
APGKGLEWVSGIS
LLIYKASTLESGVPS



NO:
ID
(SEQ
ID

ID
GNGDSRYYADSVK
RFSGSGSGTDFTLTI



277)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




278)
NO:
280)

167)
LYLQMNSLRAEDT
ANSFPLTFGPGTKVD





279)



AVYYCARDASYGG
IK (SEQ ID NO:









NYGMDVWGQGTTV
533)









TVSS (SEQ ID










NO: 532)






56.
FTFSS
SAIGT
CAREW
RASQS
GASNLQ
CQQSY
EVQLVESGGGLVK
DIQMTQSPSSLSASV



YWMS
GGGTY
LVPYY
ISRWL
S (SEQ
STPWT
PGGSLRLSCAASG
GDRVTITCRASQSIS



(SEQ
YA
GMDVW
A
ID NO:
F
FTFSSYWMSWVRQ
RWLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
284)
(SEQ
APGKGLEWVSAIG
LLIYGASNLQSGVPS



NO:
ID
ID
ID

ID
TGGGTYYAAPVKG
RFSGSGSGTDFTLTI



169)
NO:
NO:
NO:

NO:
RFTISRDDSKNTL
SSLQPEDFATYYCQQ




251)
282)
283)

114)
YLQMNSLKTEDTA
SYSTPWTFGQGTKVE









VYYCAREWLVPYY
IK (SEQ ID NO:









GMDVWGQGTTVTV
535)









SS (SEQ ID










NO: 534)






57.
FSVSS
AGISY
CARSR
KSSQS
WASTRQ
CHQYY
EVQLLESGGGLVQ
DIVMTQSPDSLAVSL



NYMS
DGSSK
GIAAR
VLYSS
S (SEQ
GHPPT
PGGSLRLSCAASG
GERATINCKSSQSVL



(SEQ
PYA
PLQHW
NNKNY
ID NO:
F
FSVSSNYMSWVRQ
YSSNNKNYLAWYQQK



ID
(SEQ
(SEQ
LA
290)
(SEQ
APGKGLEWVAGIS
PGQPPKLLIYWASTR



NO:
ID
ID
(SEQ

ID
YDGSSKPYADSVK
QSGVPDRFSGSGSGT



286)
NO:
NO:
ID

NO:
GRFTISRDNSKNT
DFTLTISSLQAEDVA




287)
288)
NO:

291)
LYLQMNSLRAEDT
VYYCHQYYGHPPTFG






289)


AVYYCARSRGIAA
GGTKVEIK (SEQ









RPLQHWGQGTLVT
ID NO: 537)









VSS (SEQ ID










NO: 536)






58.
FSVSS
AGISY
CARSR
KSSQS
QASTRQ
CHQYY
EVQLLESGGGLVQ
DIVMTQSPDSLAVSL



NYMS
DGSSK
GIAAR
VLYSS
S (SEQ
GHPPT
PGGSLRLSCAASG
GERATINCKSSQSVL



(SEQ
PYA
PLQHW
NNKNY
ID NO:
F
FSVSSNYMSWVRQ
YSSNNKNYLAWYQQK



ID
(SEQ
(SEQ
LA
293)
(SEQ
APGKGLEWVAGIS
PGQPPKLLIYQASTR



NO:
ID

(SEQ

ID
YDGSSKPYADSVK
QSGVPDRFSGSGSGT



286)
NO:
ID
ID

NO:
GRFTISRDNSKNT
DFTLTISSLQAEDVA




287)
NO:
NO:

291)
LYLQMNSLRAEDT
VYYCHQYYGHPPTFG





288)
289)


AVYYCARSRGIAA
GGTKVEIK (SEQ









RPLQHWGQGTLVT
ID NO: 538)









VSS (SEQ ID










NO: 536)






59.
FSFSD
SAISG
CARDG
RASQG
DASNLE
CQQSY
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YGMH
SGGST
GWQPA
ISNNL
T (SEQ
STPLT
PGGSLRLSCAASG
GDRVTITCRASQGIS



(SEQ
YYA
AILDY
N
ID NO:
F
FSFSDYGMHWVRQ
NNLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
159)
(SEQ
APGKGLEWVSAIS
LLIYDASNLETGVPS



NO:
ID
(SEQ
ID

ID
GSGGSTYYADSVK
RFSGSGSGTDFTLTI



295)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




103)
NO:
105)

173)
LYLQMNSLRAEDT
SYSTPLTFGGGTKVE





296)



AVYYCARDGGWQP
IK (SEQ ID NO:









AAILDYWGQGTLV
540)









TVSS (SEQ ID










NO: 539)






60.
FTFSD
SVIYG
CARDP
RASQG
DASNLE
CQQSY
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



HGMH
GESTY
AVAGG
ISNYL
T (SEQ
STCYT
PGGSLRLSCAASG
GDRVTITCRASQGIS



(SEQ
YA
GIFDY
A
ID NO:
F
FTFSDHGMHWVRQ
NYLAWYQQKPGKAPK



ID
(SEQ
W
(SEQ
159)
(SEQ
APGKGLEWVSVIY
LLIYDASNLETGVPS



NO:
ID
(SEQ
ID

ID
GGESTYYADSVKG
RFSGSGSGTDFTLTI



298)
NO:
ID
NO:

NO:
RFTISRDNSKNTL
SSLQPEDFATYYCQQ




299)
NO:
218)

301)
YLQMNSLRAEDTA
SYSTCYTFGQGTKLE





300)



VYYCARDPAVAGG
IK (SEQ ID NO:









GIFDYWGQGTLVT
542)









VSS (SEQ ID










NO: 541)






61.
DTFTG
GWINP
CARSG
RASQT
DASTLQ
CQQYS
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYIH
NSGGT
LWLGS
ISIWL
S (SEQ
SYPLT
PGASVKVSCKASG
GDRVTITCRASQTIS



(SEQ
NYA
YYGMD
A
ID NO:
F
DTFTGYYIHWVRQ
IWLAWYQQKPGKAPK



ID
(SEQ
VW
(SEQ
307)
(SEQ
APGQGLEWMGWIN
LLIYDASTLQSGVPS



NO:
ID
(SEQ
ID

ID
PNSGGTNYAQKFQ
RFSGSGSGTDFTLTI



303)
NO:
ID
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




304)
NO:
306)

308)
VYMELSSLRSEDT
YSSYPLTFGQGTKVE





305)



AVYYCARSGLWLG
IK (SEQ ID NO:









SYYGMDVWGQGTL
544)









VTVSS (SEQ ID










NO: 543)






62.
YTFTS
GWINP
CARSP
RASHF
AASTLQ
CQQSY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YDIN
NSGTT
YYYYG
ISRWV
S (SEQ
SGISF
PGASVKVSCKASG
GDRVTITCRASHFIS



(SEQ
GYA
MDVW
A
ID NO:
(SEQ
YTFTSYDINWVRQ
RWVAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
113)
ID
APGQGLEWMGWIN
LLIYAASTLQSGVPS



NO:
ID
ID
ID

NO:
PNSGTTGYAQKFQ
RFSGSGSGTDFTLTI



310)
NO:
NO:
NO:

314)
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




311)
312)
313)


VYMELSSLRSEDT
SYSGISFGPGTKVDI









AVYYCARSPYYYY
K (SEQ ID NO:









GMDVWGQGTTVTV
546)









SS (SEQ ID










NO: 545)






63.
FTFNN
SRINS
CARGA
RASQS
ATSSRA
CQQYY
EVQLLESGGGLVQ
EIVMTQSPATLSVSP



YGMN
DGSST
YYYYY
VSGSY
S (SEQ
SGLTF
PGGSLRLSCAASG
GERATLSCRASQSVS



(SEQ
SYA
MDVW
LA
ID NO:
(SEQ
FTFNNYGMNWVRQ
GSYLAWYQQKPGQAP



ID
(SEQ
(SEQ
(SEQ
320)
ID
APGKGLEWVSRIN
RLLIYATSSRASGIP



NO:
ID
ID
ID

NO:
SDGSSTSYADSVK
ARFSGSGSGTEFTLT



316)
NO:
NO:
NO:

321)
GRFTISRDNSKNT
ISSLQSEDFAVYYCQ




317)
318)
319)


LYLQMNSLRAEDT
QYYSGLTFGQGTKVE









AVYYCARGAYYYY
IK (SEQ ID NO:









YMDVWGQGTLVTV
548)









SS (SEQ ID










NO: 547)






64.
FTFSN
AHIWN
CARDR
RASQD
DASSLE
CQQAT
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



SDMN
DGSQK
TDPGY
IRNYL
T (SEQ
SLPLT
PGGSLRLSCAASG
GDRVTITCRASQDIR



(SEQ
YYA
SSAMD
G
ID NO:
F
FTFSNSDMNWVRQ
NYLGWYQQKPGKAPK



ID
(SEQ
VW
(SEQ
327)
(SEQ
APGKGLEWVAHIW
LLIYDASSLETGVPS



NO:
ID
(SEQ
ID

ID
NDGSQKYYADSVK
RFSGSGSGTDFTLTI



323)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




324)
NO:
326)

328)
LYLQMNSLRAEDT
ATSLPLTFGGGTKVE





325)



AVYYCARDRTDPG
IK (SEQ ID NO:









YSSAMDVWGQGTT
550)









VTVSS (SEQ ID










NO: 549)






65.
YTFTS
GWMNP
CAKDS
RASQD
QASSLE
CQQSY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YDIN
NSGNT
DYSNL
ITNDL
S (SEQ
TIPLT
PGASVKVSCKASG
GDRVTITCRASQDIT



(SEQ
GYA
LWDYW
G
ID NO:
F
YTFTSYDINWVRQ
NDLGWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
332)
(SEQ
APGQGLEWMGWMN
LLIYQASSLESGVPS



NO:
ID
ID
ID

ID
PNSGNTGYAQKFQ
RFSGSGSGTDFTLTI



310)
NO:
NO:
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




205)
330)
331)

333)
VYMELSSLRSEDT
SYTIPLTFGQGTKVE









AVYYCAKDSDYSN
IK (SEQ ID NO:









LLWDYWGQGTLVT
552)









VSS (SEQ ID










NO: 551)






66.
YTFTG
GIINP
CARDG
RASQG
SNLET
QQYYS
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



HYMH
SGGST
AWFGE
ISNWL
(SEQ
FPLYT
PGASVKVSCKASG
GDRVTITCRASQGIS



(SEQ
SYA
EYYYG
A
ID NO:
(SEQ
YTFTGHYMHWVRQ
NWLAWYQQKPGKAPK



ID
(SEQ
MDVW
(SEQ
491)
ID
APGQGLEWMGIIN
LLIYDASNLETGVPS



NO:
ID
(SEQ
ID

NO:
PSGGSTSYAQKFQ
RFSGSGSGTDFTLTI



244)
NO:
ID
NO:

555)
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




69)
NO:
554)


VYMELSSLRSEDT
YYSFPLYTFGQGTKV





553)



AVYYCARDGAWFG
EIK (SEQ ID NO:









EEYYYGMDVWGQG
557)









TTVTVSS (SEQ










ID NO: 556)






67.
YTFTG
GMIYP
CAMTG
RASQG
STLQS
QQSYS
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
RDGST
WGYGM
INNYL
SEQ
APPT
PGASVKVSCKASG
GDRVTITCRASQGIN



(SEQ
SYA
DVW
A
ID NO:
(SEQ
YTFTGYYMHWVRQ
NYLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
420)
ID
APGQGLEWMGMIY
LLIYDASTLQSGVPS



NO:
ID
ID
ID

NO:
PRDGSTSYAQKFQ
RFSGSGSGTDFTLTI



128)
NO:
NO:
NO:

561)
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




558)
559)
560)


VYMELSSLRSEDT
SYSAPPTFGQGTKLE









AVYYCAMTGWGYG
IK (SEQ ID NO:









MDVWGKGTTVTVS
563)









S (SEQ ID NO:










562)






68.
FTFGD
AVVSY
CAKDI
RASQN
DASNLE
CQQAN
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YAMS
DGTNK
CSSTS
INNYV
T (SEQ
SFPPT
PGGSLRLSCAASG
GDRVTITCRASQNIN



(SEQ
YYA
CYFDL
N
ID NO:
F
FTFGDYAMSWVRQ
NYVNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
159)
(SEQ
APGKGLEWVAVVS
LLIYDASNLETGVPS



NO:
ID
(SEQ
ID

ID
YDGTNKYYADSVK
RFSGSGSGTDFTLTI



233)
NO:
ID
NO:

NO:
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




335)
NO:
337)

338)
LYLQMNSLRAEDT
ANSFPPTFGQGTRLE





336)



AVYYCAKDICSST
IK (SEQ ID NO:









SCYFDLWGRGTLV
565)









TVSS (SEQ ID










NO: 564)






69.
YTFTS
GIIDP
CAREE
RASQG
ATSSLQ
CQQTY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
SGGST
WSSGG
ISSYL
T (SEQ
SIPIT
PGASVKVSCKASG
GDRVTITCRASQGIS



(SEQ
SYA
VGYFD
A
ID NO:
F
YTFTSYYMHWVRQ
SYLAWYQQKPGKAPK



ID
(SEQ
YW
(SEQ
343)
(SEQ
APGQGLEWMGIID
LLIYATSSLQTGVPS



NO:
ID
(SEQ
ID

ID
PSGGSTSYAQKFQ
RFSGSGSGTDFTLTI



215)
NO:
ID
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




340)
NO:
342)

344)
VYMELSSLRSEDT
TYSIPITFGQGTRLE





341)



AVYYCAREEWSSG
IK (SEQ ID NO:









GVGYFDYWGQGTL
567)









VTVSS (SEQ ID










NO: 566)






70.
YPFTD
GWIKP
CARDR
RASQS
SSLQS
QQSYD
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
NSGDT
FVGKP
ISVWL
(SEQ
TPYT
PGASVKVSCKASG
GDRVTITCRASQSIS



(SEQ
EYA
DYYYY
A
ID NO:
(SEQ
YPFTDYYMHWVRQ
VWLAWYQQKPGKAPK



ID
(SEQ
GMDVW
(SEQ
362)
ID
APGQGLEWMGWIK
LLIYAASSLQSGVPS



NO:
ID
(SEQ
ID

NO:
PNSGDTEYAQKFQ
RFSGSGSGTDFTLTI



568)
NO:
ID
NO:

572)
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




569)
NO:
571)


VYMELSSLRSEDT
SYDTPYTFGQGTKLE





570)



AVYYCARDRFVGK
IK (SEQ ID NO:









PDYYYYGMDVWGQ
574)









GTMVTVSS (SEQ










ID NO: 573)






71.
YTFTS
GIINP
CARDS
RASQG
AASSLQ
CQQSY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
SGGST
VAGTG
ISNYF
G (SEQ
SLPYT
PGASVKVSCKASG
GDRVTITCRASQGIS



(SEQ
SYA
GRYYG
A
ID NO:
F
YTFTSYYMHWVRQ
NYFAWYQQKPGKAPK



ID
(SEQ
MDVW
(SEQ
352)
(SEQ
APGQGLEWMGIIN
LLIYAASSLQGGVPS



NO:
ID
(SEQ
ID

ID
PSGGSTSYAQKFQ
RFSGSGSGTDETLTI



215)
NO:
ID
NO:

NO:
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




69)
NO:
351)

353)
VYMELSSLRSEDT
SYSLPYTFGQGTKLE





350)



AVYYCARDSVAGT
IK (SEQ ID NO:









GGRYYGMDVWGQG
576)









TLVTVSS (SEQ










ID NO: 575)






72.
YTFTS
GVINP
CASGA
RASQS
SYLAT
QQSYS
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
IGGTT
PSYYY
ISSYL
(SEQ
TPLT
PGASVKVSCKASG
GDRVTITCRASQSIS



(SEQ
TYA
YGMDV
N
ID NO:
(SEQ
YTFTSYYMHWVRQ
SYLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
579)
ID
APGQGLEWMGVIN
LLIYGTSYLATGVPS



NO:
ID
(SEQ
ID

NO:
PIGGTTTYAQKFQ
RFSGSGSGTDFTLTI



215)
NO:
ID
NO:

429)
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




577)
NO:
172)


VYMELSSLRSEDT
SYSTPLTFGQGTKVE





578)



AVYYCASGAPSYY
IK (SEQ ID NO:









YYGMDVWGQGTLV
581)









TVSS (SEQ ID










NO: 580)






73.
YTFTS
GRINP
CARAG
QASQD
TALRT
QQSYS
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



NYVH
HSGDT
QLWSD
IRNYL
(SEQ
HPLT
PGASVKVSCKASG
GDRVTITCQASQDIR



(SEQ
SYA
WYFDL
N
ID NO:
(SEQ
YTFTSNYVHWVRQ
NYLNWYQQKPGKAPK



ID
(SEQ
W
SEQ
585)
ID
APGQGLEWMGRIN
LLIYAATALRTGVPS



NO:
ID
(SEQ
ID

NO:
PHSGDTSYAQKFQ
RFSGSGSGTDFTLTI



582)
NO:
ID
NO:

586)
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




583)
NO:
280)


VYMELSSLRSEDT
SYSHPLTFGQGTKVE





584)



AVYYCARAGQLWS
IK (SEQ ID NO:









DWYFDLWGRGTLV
588)









TVSS (SEQ ID










NO: 587)






74.
YTFTG
GIINP
CTTAD
RASQG
AASSLQ
CQQYY
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



YYMH
SGGNT
YYYYM
ISNYL
S (SEQ
SNADF
PGASVKVSCKASG
GDRVTITCRASQGIS



(SEQ
KYA
DVW
A
ID NO:
(SEQ
YTFTGYYMHWVRQ
NYLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
65)
ID
APGQGLEWMGIIN
LLIYAASSLQSGVPS



NO:
ID
ID
ID

NO:
PSGGNTKYAQKFQ
RFSGSGSGTDFTLTI



128)
NO:
NO:
NO:

357)
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




355)
356)
218)


VYMELSSLRSEDT
YYSNADFGQGTKVEI









AVYYCTTADYYYY
K (SEQ ID NO:









MDVWGKGTTVTVS
590)









S (SEQ ID NO:










589)






75.
FTFSD
SYISG
CARDR
RASQS
SSLQS
QQYKS
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



FWMH
DSGYT
PYYYY
VSRSL
SEQ
YPVT
PGGSLRLSCAASG
GDRVTITCRASQSVS



(SEQ
NYA
MDVW
A
ID NO:
(SEQ
FTFSDFWMHWVRQ
RSLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
362)
ID
APGKGLEWISYIS
LLIYAASSLQSGVPS



NO:
ID
ID
ID

NO:
GDSGYTNYADSVK
RFSGSGSGTDFTLTI



359)
NO:
NO:
NO:

363)
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




170)
360)
361)


LYLQMNSLRAEDT
YKSYPVTFGQGTKVE









AVYYCARDRPYYY
IK (SEQ ID NO:









YMDVWGKGTTVTV
592)









SS (SEQ ID










NO: 591)






76.
FTFDD
SDISG
CAKDV
QASQD
SYLQS
QQAHN
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YTMH
SGGST
VVAGT
ISNYL
(SEQ
YPIT
PGGSLRLSCAASG
GDRVTITCQASQDIS



(SEQ
YYA
PLHFD
N
ID NO:
(SEQ
FTFDDYTMHWVRQ
NYLNWYQQKPGKAPK



ID
(SEQ
YW
(SEQ
368)
ID
APGKGLEWVSDIS
LLIYAASYLQSGVPS



NO:
ID
(SEQ
ID

NO:
GSGGSTYYADSVK
RFSGSGSGTDFTLTI



365)
NO:
ID
NO:

369)
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




366)
NO:
138)


LYLQMNSLRAEDT
AHNYPITFGQGTRLE





367)



AVYYCAKDVVVAG
IK (SEQ ID NO:









TPLHFDYWGQGTL
594)









VTVSS (SEQ ID










NO: 593)






77.
FTFSN
ASISS
CAREV
RASQS
SSLQS
QQANA
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



AWMS
TSAYI
VGATT
ISTWL
SEQ
FPPT
PGGSLRLSCAASE
GDRVTITCRASQSIS



(SEQ
DYA
FDYW
A
ID NO:
(SEQ
FTFSNAWMSWVRQ
TWLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
362)
ID
APGKGLEWVASIS
LLIYAASSLQSGVPS



NO:
ID
ID
ID

NO:
STSAYIDYADSVK
RFSGSGSGTDFTLTI



183)
NO:
NO:
NO:

374)
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




371)
372)
373)


LYLQMNSLRAEDT
ANAFPPTFGQGTRLE









AVYYCAREVVGAT
IK (SEQ ID NO:









TFDYWGQGTLVTV
596)









SS (SEQ ID










NO: 595)






78.
GTFSS
GWMEP
CAKGG
KSSQS
STRES
QQYYS
QVQLVQSGAEVKK
DIVMTQSPDSLAVSL



YAIS
HTGNT
FSWFD
VLYSS
(SEQ
TPPT
PGSSVKVSCKASG
GERATINCKSSQSVL



(SEQ
RYA
PW
NNKNY
ID NO:
(SEQ
GTFSSYAISWVRQ
YSSNNKNYLAWYQQK



ID
(SEQ
(SEQ
LA
378)
ID
APGQGLEWMGWME
PGQPPKLLIYWASTR



NO:
ID
ID
(SEQ

NO:
PHTGNTRYAQKFQ
ESGVPDRFSGSGSGT



77)
NO:
NO:
ID

379)
GRVTITADESTST
DFTLTISSLQAEDVA




376)
377)
NO:


AYMELSSLRSEDT
VYYCQQYYSTPPTFG






289)


AVYYCAKGGFSWF
QGTRLEIK (SEQ









DPWGQGTLVTVSS
ID NO: 598)









(SEQ ID NO:










597)






79.
FTFDD
ASITS
CARER
RASQG
STRAT
QQYYT
EVQLLESGGGLVK
EIVMTQSPATLSVSP



YAMH
SSAFI
VDWNS
ISNSY
(SEQ
YPPT
PGGSLRLSCAASG
GERATLSCRASQGIS



(SEQ
DYA
YFDLW
LA
ID NO:
(SEQ
FTFDDYAMHWVRQ
NSYLAWYQQKPGQAP



ID
(SEQ
(SEQ
(SEQ
384)
ID
APGKGLEWVASIT
RLLIYGASTRATGIP



NO:
ID
ID
ID

NO:
SSSAFIDYAASVK
ARFSGSGSGTEFTLT



135)
NO:
NO:
NO:

385)
GRFTISRDDSKNT
ISSLQSEDFAVYYCQ




381)
382)
383)


LYLQMNSLKTEDT
QYYTYPPTFGPGTKV









AVYYCARERVDWN
DIK (SEQ ID NO:









SYFDLWGRGTLVT
600)









VSS (SEQ ID










NO: 599)






80.
FTFDD
SAISG
CAKDL
QASQD
SNLEA
QQSYS
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YAMH
SGGST
GVVVP
ISNHL
(SEQ
TPLT
PGGSLRLSCAASG
GDRVTITCQASQDIS



(SEQ
YYA
AALDY
N
ID NO:
(SEQ
FTFDDYAMHWVRQ
NHLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
603)
ID
APGKGLEWVSAIS
LLIYDASNLEAGVPS



NO:
ID
(SEQ
ID

NO:
GSGGSTYYADSVK
RFSGSGSGTDFTLTI



135)
NO:
ID
NO:

429)
GRFTISRDNSKNT
SSLQPEDFATYYCQQ




103)
NO:
602)


LYLQMNSLRAEDT
SYSTPLTFGGGTKVE





601)



AVYYCAKDLGVVV
IK (SEQ ID NO:









PAALDYWGQGTTV
605)









TVSS (SEQ ID










NO: 604)






81.
FAFSS
AGTSG
CARET
RASQG
ANLEG
QQSDI
EVQLLESGGGLVK
DIQMTQSPSSLSASV



HWMH
SGESR
YYYYY
ISNYL
(SEQ
FPPT
PGGSLRLSCAASG
GDRVTITCRASQGIS



(SEQ
DYA
MDVW
A
ID NO:
(SEQ
FAFSSHWMHWVRQ
NYLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
390)
ID
APGKGLEWVAGTS
LLIYDAANLEGGVPS



NO:
ID
ID
ID

NO:
GSGESRDYADFVK
RFSGSGSGTDFTLTI



387)
NO:
NO:
NO:

391)
GRFTISRDDSKNT
SSLQPEDFATYYCQQ




388)
389)
218)


LYLQMNSLKTEDT
SDIFPPTFGQGTKVE









AVYYCARETYYYY
IK (SEQ ID NO:









YMDVWGKGTTVTV
607)









SS (SEQ ID










NO: 606)






82.
YTFTR
GWINV
CARES
RASQS
SSLQS
QQSNS
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



HWIH
KTGGA
SGWYG
ISNYL
(SEQ
FPLT
PGASVKVSCKASG
GDRATITCRASQSIS



(SEQ
GYA
TDVW
A
ID NO:
(SEQ
YTFTRHWIHWVRQ
NYLAWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
362)
ID
APGQGLEWMGWIN
LLIYAASSLQSGVPS



NO:
ID
ID
ID

NO:
VKTGGAGYAQKFQ
RFSGSGSGTDFTLTI



393)
NO:
NO:
NO:

397)
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




394)
395)
396)


VYMELSSLRSEDT
SNSFPLTFGGGTKVE









AVYYCARESSGWY
IK (SEQ ID NO:









GTDVWGQGTTVTV
609)









SS (SEQ ID










NO: 608)






83.
FTFSS
AAISY
CAREN
QASQD
NLRS
QQANS
EVQLLESGGGLVQ
DIQMTQSPSSLSASV



YWMH
DGKYK
KQWLA
ISNFV
(SEQ
FPVT
PGGSLRLSCAASG
GDRVTITCQASQDIS



(SEQ
DYE
SFDYW
N
ID NO:
(SEQ
FTFSSYWMHWVRQ
NFVNWYQQKPGKAPK



ID
(SEQ
(SEQ
(SEQ
402)
ID
APGKGLEWVAAIS
LLIYAANLRSGVPSR



NO:
ID
ID
ID

NO:
YDGKYKDYEDSVK
FSGSGSGTDFTLTIS



83)
NO:
NO:
NO:

403)
GRFTISRDNSKNT
SLQPEDFATYYCQQA




399)
400)
401)


LYLQMNSLRAEDT
NSFPVTFGPGTKVDI









AVYYCARENKQWL
(SEQ ID NO:









ASFDYWGQGTLVT
611)









VSS (SEQ ID










NO: 610)






84.
GTFSS
GWISA
CASRV
QASEH
SSLQS
QQTDS
QVQLVQSGAEVKK
DIQMTQSPSSLSASV



SAIS
YNGYT
HSGGS
IYNYL
(SEQ
IPIT
PGASVKVSCKASG
GDRVTITCQASEHIY



(SEQ
NYA
YPDDY
N
ID NO:
(SEQ
GTFSSSAISWVRQ
NYLNWYQQKPGKAPK



ID
(SEQ
W
(SEQ
362)
ID
APGQGLEWMGWIS
LLIYAASSLQSGVPS



NO:
ID
(SEQ
ID

NO:
AYNGYTNYAQKFQ
RFSGSGSGTDFTLTI



612)
NO:
ID
NO:

616)
GRVTMTRDTSTST
SSLQPEDFATYYCQQ




613)
NO:
615)


VYMELSSLRSEDT
TDSIPITFGQGTKVE





614)



AVYYCASRVHSGG
IK (SEQ ID NO:









SYPDDYWGQGTLV
618)









TVSS (SEQ ID










NO: 617)









In some embodiments, the antibody comprises the CDRs of Clone ID: 6, Clone ID: 75, or Clone ID: 79 of Table 7.


The IgG and scFv formats illustrated herein are simply non-limiting examples. The CDRs provided herein can be placed in different formats, including different VH and VL/VK formats and still be able to bind to MAdCAM.


Although the CDRs are illustrated in the tables provided herein, there are other ways to annotate or identify CDRs. For example, in some embodiments, the HCDR2 can have an extra amino acid at the N-terminus. For example, for the HCDR2 of Clone 6 the table indicates that it has a sequence of: SRINSYGTSTTYA (SEQ ID NO: 91). However, in some embodiments, the HCDR2 has a sequence of VSRINSYGTSTTYA (SEQ ID NO: 629), which is shown with an extra residue, a valine, at the N-terminus of the HCDR2. The valine is clearly illustrated in VH peptide of the tables provided herein. Therefore, in some embodiments, the HCDR2 comprises one additional amino acid immediately to the N-terminus of the HCDR2 listed in the table. The residue would be the residue that is immediately to the N-terminus of the HCDR2 found in the VH sequence provided for in the table in the same row. One of skill in the art with this information could immediately envisage the HCDR2 peptide sequence that has the additional amino acid residue immediately to the N-terminus of the HCDR2 listed in the table. These embodiments are sufficiently described and do not require application to list each of these different annotations and one of skill in the art with the guidance and description provided herein could write them out individually without any undue experimentation.


Similarly, the HCDR3 can exclude the cysteine residue. Each of the HCDR3 polypeptides provided for in Tables 6 and 7 begins with a cysteine residue. In some embodiments, the HCDR3 does not include the cysteine. Furthermore, in some embodiments, the HCDR3 does not have the last C-terminal residue illustrated in Table 6 and 7 provided for herein. Therefore, in some embodiments, the HCDR3 does not have the cysteine and/or the last C-terminal residue illustrated in the tables. One of skill in the art with this information could immediately envisage the HCDR3 peptide sequence that does not have the cysteine and/or the last C-terminal residue illustrated in the tables. These embodiments are sufficiently described and do not require application to list each of these different annotations and one of skill in the art with the guidance and description provided herein could write them out individually without any undue experimentation.


In some embodiments, the light chain CDR2 can have one or two extra amino acid residues at the N-terminus. These additional residues would be those that are immediately to the N-terminus of the light chain CDR2 (LCDR2) present in the VL/VK chain provided for herein, in the same row as the CDRs that are listed. For example, the LCDR2 of Clone 6 is provided as GASSLQS (SEQ ID NO: 87), but in some embodiments could be IYGASSLQS (SEQ ID NO: 630) or YGASSLQS (SEQ ID NO: 631). One of skill in the art with this information could immediately envisage the LCDR2 peptide sequence that has one or two extra amino acid residues at the N-terminus of the LCDR2 sequence provided for herein. These embodiments are sufficiently described and do not require application to list each of these different annotations and one of skill in the art with the guidance and description provided herein could write them out individually without any undue experimentation.


There are also alternative systems for annotating CDRs, all of which can be used. For example, CDRs can be chosen based on the Kabat systems, the IMGT system, or the CHOTHIA. Other proprietary systems can also be used, which may be based on the predicted 3-dimensional structure of the protein. Accordingly, in some embodiments, the CDRs of Clone ID: 6, Clone ID: 75, or Clone ID: 79 of Table 7 can also be characterized as shown in Table 8. These alternative CDRs can be substituted for these clone referenced in Table 7 or the equivalent clone numbering in Table 6, i.e., Clone 6, Clone 59, and Clone 63.









TABLE 8







Alterative CDRs for Certain Clones














Clone









No.









(Table
Annotation








7)
System
LCDR1
LCDR2
LCDR3
HCDR1
HCDR2
HCDR3

















6
Proprietary
RASQIIG
SSLQS
QQSYRLPFT
FTFNNYAF
SRINSYGTST
CAREGPVAGY




TNLA
(SEQ ID
(SEQ ID
H (SEQ
TYA (SEQ
WYFDLW




(SEQ ID
NO:
NO: 632)
ID NO:
ID NO: 91)
(SEQ ID




NO: 93)
362)

90)

NO: 92)



Other
RASQIIG
GASSLQS
CQQSYRLPF
FTFNNYAF
SRINSYGTST
CAREGPVAGY



Annotation
TNLA
(SEQ ID
TF (SEQ
H (SEQ
TYA (SEQ
WYFDLW




(SEQ ID
NO: 87)
ID NO:
ID NO:
ID NO: 91)
(SEQ ID




NO: 93)

94)
90

NO: 92)



Kabat
RASQIIG
GASSLQS
QQSYRLPFT
NYAFH
RINSYGTSTT
EGPVAGYWYF




TNLA
(SEQ ID
(SEQ ID
(SEQ ID
YADSVKG
DL (SEQ ID




(SEQ ID
NO: 87)
NO: 632)
NO: 633)
(SEQ ID
NO: 635)




NO: 93)



NO: 634)




IMGT
QIIGTN
GAS
QQSYRLPFT
GFTFNNYA
INSYGTST
AREGPVAGYW




(SEQ ID

(SEQ ID
(SEQ ID
(SEQ ID
YFDL (SEQ




NO:

NO: 632)
NO: 637)
NO: 638)
ID NO:




636)




639)



CHOTHIA
RASQIIG
GASSLQS
QQSYRLPFT
GFTFNNY
NSYGTS
EGPVAGYWYF




TNLA
(SEQ ID
(SEQ ID
(SEQ ID
(SEQ ID
DL (SEQ ID




(SEQ ID
NO: 87)
NO: 632)
NO: 640)
NO: 641)
NO: 635)




NO: 93)










75
Proprietary
RASQSVS
SSLQS
QQYKSYPVT
FTFSDFWM
SYISGDSGYT
CARDRPYYYY




RSLA
(SEQ ID
(SEQ ID
H (SEQ
NYA (SEQ
MDVW (SEQ




(SEQ ID
NO:
NO: 363)
ID NO:
ID NO:
ID NO:




NO:
362)

359)
170)
360)




361)








Other
RASQSVS
AASSLQS
CQQYKSYPV
FTFSDFWM
SYISGDSGYT
CARDRPYYYY



Annotation
RSLA
(SEQ ID
TF (SEQ
H (SEQ
NYA (SEQ
MDVW (SEQ




(SEQ ID
NO: 65)
ID NO:
ID NO:
ID NO:
ID NO:




NO:

642)
359)
170)
360)




361)








Kabat
RASQSVS
AASSLQS
QQYKSYPVT
DFWMH
YISGDSGYTN
DRPYYYYMDV




RSLA
(SEQ ID
(SEQ ID
(SEQ ID
YADSVKG
(SEQ ID




(SEQ ID
NO: 65)
NO: 363)
NO: 643)
(SEQ ID
NO: 645)




NO:



NO: 644)





361)








IMGT
QSVSRS
AAS
QQYKSYPVT
GFTFSDFW
ISGDSGYT
ARDRPYYYYM




(SEQ ID

(SEQ ID
(SEQ ID
(SEQ ID
DV (SEQ ID




NO:

NO: 363)
NO: 647)
NO: 648)
NO: 649)




646)








CHOTHIA
RASQSVS
AASSLQS
QQYKSYPVT
GFTFSDF
SGDSGY
DRPYYYYMDV




RSLA
(SEQ ID
(SEQ ID
(SEQ ID
(SEQ ID
(SEQ ID




(SEQ ID
NO: 65)
NO: 363)
NO: 650)
NO: 651)
NO: 645)




NO:









361)










79
Proprietary
RASQGIS
STRAT
QQYYTYPPT
FTFDDYAM
ASITSSSAFI
CARERVDWNS




NSYLA
(SEQ ID
(SEQ ID
H (SEQ
DYA (SEQ
YFDLW (SEQ




(SEQ ID
NO:
NO: 385)
ID NO:
ID NO:
ID NO:




NO:
384)

135)
381)
382)




383)








Other
RASQGIS
GASTRAT
CQQYYTYPP
FTFDDYAM
ASITSSSAFI
CARERVDWNS



Annotation
NSYLA
(SEQ ID
TF (SEQ
H (SEQ
DYA (SEQ
YFDLW (SEQ




(SEQ ID
NO:
ID NO:
ID NO:
ID NO:
ID NO:




NO:
241)
652)
135)
381)
382)




383)








Kabat
RASQGIS
GASTRAT
QQYYTYPPT
DYAMH
SITSSSAFID
ERVDWNSYFD




NSYLA
(SEQ ID
SEQ ID
(SEQ ID
YAASVKG
L (SEQ ID




(SEQ ID
NO:
NO: 385)
NO: 653)
(SEQ ID
NO: 655)




NO:
241)


NO: 654)





383)








IMGT
QGISNSY
GAS
QQYYTYPPT
GFTFDDYA
ITSSSAFI
ARERVDWNSY




(SEQ ID

(SEQ ID
(SEQ ID
(SEQ ID
FDL (SEQ




NO:

NO: 385)
NO: 657)
NO: 658)
ID NO:




656)




659)



CHOTHIA
RASQGIS
GASTRAT
QQYYTYPPT
GFTFDDY
TSSSAF
ERVDWNSYFD




NSYLA
(SEQ ID
(SEQ ID
(SEQ ID
(SEQ ID
L (SEQ ID




(SEQ ID
NO:
NO: 385)
NO: 660)
NO: 661)
NO: 655)




NO:
241)








383)









In some embodiments, the MAdCAM antibody is selected from the following table:

















TABLE 9





Clone










(Fab)
VH Seq
VL Seq
HCDR1
HCDR2
HCDR3
LCDR1
LCDR2
LCDR3







MIAB1
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CAREPV
RASQG
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
ISNSY
AT
TYPPT



FTFDDYAMHWVRQ
ASQGISNSYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYGASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


883)
NO:
241)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



383)

652)



AVYYCAREPVDWN
AVYYCQQYYTYP









SYFDLWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 662)
663)











MIAB2
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQG
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
ISNSY
AT
TYPPT



FTFDDYAMHWVRQ
ASQGISNSYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYGASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


382)
NO:
241)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



383)

652)



AVYYCARERVDWN
AVYYCQQYYTYP









SYFDLWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664)
663)











MIAB3
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQG
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
ISNSY
AT
TYPPT



FTFDDYAMHWVRQ
ASQGISNSYLAW
ID NO:
(SEQ ID
DNW
LA
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYGASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


884)
NO:
241)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



383)

652)



AVYYCARERVDWN
AVYYCQQYYTYP









SYFDNWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 665)
663)











MIAB4
EVQLLESGGGLVQ
EIVMTQSPATLS
FTLDDYA
ASITSSS
CARERV
RASQG
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
ISNSY
AT
TYPPT



FTLDDYAMHWVRQ
ASQGISNSYLAW
ID NO:
(SEQ ID
DNW
LA
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
885)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYGASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


884)
NO:
241)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



383)

652)



AVYYCARERVDWN
AVYYCQQYYTYP









SYFDNWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 666)
663)











MIAB5
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQS
DASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
VGSYL
VT
TYPPT



FTFDDYAMHWVRQ
ASQSVGSYLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDASTRVTGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


382)
NO:
887)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



886)

652)



AVYYCARERVDWN
VYYCQQYYTYPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664)
667)











MIAB6
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQG
GASTR
CQQYE



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
LWNSYF
ISNSY
AT
RWPPT



FTFDDYAMHWVRQ
ASQGISNSYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APRKGLEWVASIT
YQQKPGQAPRLL
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYGASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


888)
NO:
241)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



383)

889)



AVYYCARERVLWN
AVYYCQQYERWP









SYFDLWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 668)
669)











MIAB7
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RACQG
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
ISNSY
AT
TYPPT



FTFDDYAMHWVRQ
ACQGISNSYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYGASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


382)
NO:
241)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



890)

652)



AVYYCARERVDWN
AVYYCQQYYTYP









SYFDLWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664)
670)











MIAB8
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQS
DASAR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
VGSYL
AT
TYPPT



FTFDDYAMHWVRQ
ASQSVGSYLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDASARATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


382)
NO:
891)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



886)

652)



AVYYCARERVDWN
VYYCQQYYTYPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664)
671)











MIAB9
EVQLLESGGGLVQ
EIVMTQSPATLS
FTLDDYA
ASITSSS
CARERV
RASQG
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
ISNSY
AT
TYPPT



FTLDDYAMHWVRQ
ASQGISNSYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
885
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYGASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


382)
NO:
241)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



383)

652)



AVYYCARERVDWN
AVYYCQQYYTYP









SYFDLWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 672)
663)











MIAB10
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQG
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
ISNSY
AT
KYPPT



FTFDDYAMHWVRQ
ASQGISNSYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYGASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


382
NO:
241)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



383)

892)



AVYYCARERVDWN
AVYYCQQYYKYP









SYFDLWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664)
673)











MIAB11
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQG
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
ISNNY
AT
TYPPT



FTFDDYAMHWVRQ
ASQGISNNYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYGASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


382)
NO:
241)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



893)

652)



AVYYCARERVDWN
AVYYCQQYYTYP









SYFDLWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664)
674)











MIAB12
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RACPG
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
ISNSY
AT
TYPPT



FTFDDYAMHWVRQ
ACPGISNSYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYGASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


382)
NO:
241)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



894)

652)



AVYYCARERVDWN
AVYYCQQYYTYP









SYFDLWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664)
675)











MIAB13
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQN
DATTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
LWNSYF
VNNNL
AT
HWPQT



FTFDDYAMHWVRQ
ASQNVNNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDATTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


888)
NO:
896)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



895)

897)



AVYYCARERVLWN
VYYCQQYYHWPQ









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 676)
677)











MIAB14
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQN
DATTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
VNNNL
AT
HWPQT



FTFDDYAMHWVRQ
ASQNVNNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDATTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


382)
NO:
896)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



895)

897)



AVYYCARERVDWN
VYYCQQYYHWPQ









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664)
677)











MIAB15
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQN
DATTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
LWNSYF
VNNNY
AT
HWPQT



FTFDDYAMHWVRQ
ASQNVNNNYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYDATTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


888)
NO:
896)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



898)

897)



AVYYCARERVLWN
AVYYCQQYYHWP









SYFDLWGQGTLVT
QTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 676)
678)











MIAB16
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQG
DATTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
LWNSYF
VNNNL
AT
HWPQT



FTFDDYAMHWVRQ
ASQGVNNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDATTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


888)
NO:
896)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



899)

897)



AVYYCARERVLWN
VYYCQQYYHWPQ









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 676)
679)











MIAB17
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQN
DATTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
LWNSYF
INNNL
AT
HWPQT



FTFDDYAMHWVRQ
ASQNINNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDATTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


888)
NO:
896)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



900)

897)



AVYYCARERVLWN
VYYCQQYYHWPQ









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 676)
680)











MIAB18
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQN
DATTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
LWNSYF
VSNNL
AT
HWPQT



FTFDDYAMHWVRQ
ASQNVSNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
SEQ



SSSAFIDYADSVK
YDATTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


888)
NO:
896)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



901)

897)



AVYYCARERVLWN
VYYCQQYYHWPQ









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 676)
681)











MIAB19
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQN
DATTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
LWNSYF
VNNSL
AT
HWPQT



FTFDDYAMHWVRQ
ASQNVNNSLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDATTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


888)
NO:
896)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



902)

897)



AVYYCARERVLWN
VYYCQQYYHWPQ









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 676)
682)











MIAB20
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQN
GATTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
LWNSYF
VNNNL
AT
HWPQT



FTFDDYAMHWVRQ
ASQNVNNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YGATTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


888)
NO:
903)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



895)

897)



AVYYCARERVLWN
VYYCQQYYHWPQ









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 676)
683)











MIAB21
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQN
DASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
LWNSYF
VNNNL
AT
HWPQT



FTFDDYAMHWVRQ
ASQNVNNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDASTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


888)
NO:
904)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



895)

897)



AVYYCARERVLWN
VYYCQQYYHWPQ









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 676)
684)











MIAB22
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQN
DATTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
LWNSYF
VNNNL
AT
TWPQT



FTFDDYAMHWVRQ
ASQNVNNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDATTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


888)
NO:
896)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



895)

905)



AVYYCARERVLWN
VYYCQQYYTWPQ









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 676)
685)











MIAB23
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQN
DATTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
LWNSYF
VNNNL
AT
HYPQT



FTFDDYAMHWVRQ
ASQNVNNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDATTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


888)
NO:
896)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



895)

906)



AVYYCARERVLWN
VYYCQQYYHYPQ









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 676)
686)











MIAB24
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQN
DATTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
LWNSYF
VNNNL
AT
HWPPT



FTFDDYAMHWVRQ
ASQNVNNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDATTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


888)
NO:
896)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



895)

907)



AVYYCARERVLWN
VYYCQQYYHWPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 676)
687)











MIAB25
EVQLLESGGGLVQ
EIVMTQSPATLS
FIFDDYA
ASITSSS
CARERV
RASQS
DASTR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWFSYF
VSNNL
AT
HWPPT



FIFDDYAMHWVRQ
ASQSVSNNLVWY
ID NO:
(SEQ ID
DLW
V
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
908)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDASTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


909)
NO:
904)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



910)

911)



AVYYCARERVDWF
VYYCQQYSHWPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 688)
689)











MIAB26
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQS
RASTR
CQQYH



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
VYSNL
AT
IWPPT



FTFDDYAMHWVRQ
ASQSVYSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YRASTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


382)
NO:
913)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



912)

914)



AVYYCARERVDWN
VYYCQQYHIWPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664)
690)











MIAB27
EVQLLESGGGLVQ
EIVMTQSPATLS
FAFSNFA
TITSSGG
KARERV
RASQS
DASSR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STDYA
DWNSYF
VTSDL
AM
TWPPT



FAFSNFAMSWVRQ
ASQSVTSDLAWY
ID NO:
(SEQ ID
NLW
A
(SEQ
F



APGKGLEWSTITS
QQKPGQAPRLLI
915)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTDYADSVKG
YDASSRAMGIPA

916)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


917)
NO:
919)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



918)

920)



VYYKARERVDWNS
VYYCQQYSTWPP









YFNLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 691)
692)











MIAB28
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSSFA
SISSSGS
CIRERV
RASQS
GESTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
LS (SEQ
GGSTNYA
DWNSYF
VTRNL
AT
NWPPS



FTFSSFALSWVRQ
ASQSVTRNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSSISS
QQKPGQAPRLLI
921)
NO:
(SEQ
(SEQ
ID
(SEQ



SGSGGSTNYADSV
YGESTRATGIPA

922)
ID NO:
ID
NO:
ID



KGRFTISRDNSKN
RFSGSGSGTEFT


923)
NO:
925)
NO:



TLYLQMNSLRAED
LTISSLQSEDFA



924)

926)



TAVYYCIRERVDW
VYYCQQYYNWPP









NSYFDLWGQGTLV
SFGQGTKVEIK









TVSS (SEQ ID
(SEQ ID NO:









NO: 693)
694











MIAB29
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFNDYA
SISSSGG
CAREKV
RASQS
GTSNR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
SIDYA
DWNSYF
VSNTL
AA
TTPLT



FTFNDYAMTWVRQ
ASQSVSNTLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWASISS
QQKPGQAPRLLI
927)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSIDYADSVKG
YGTSNRAAGIPA

928
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


929)
NO:
931)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



930)

932)



VYYCAREKVDWNS
VYYCQQYYTTPL









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 695)
696)











MIAB30
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSDYA
AISTSGG
CARERV
RASQS
GASTG
CQQYN



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
STYYV
DWNSYF
VISNL
AT
NRPPT



FTFSDYAMTWVRQ
ASQSVISNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAIST
QQKPGQAPRLLI
933)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYYVDSVKG
YGASTGATGIPA

934)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


382)
NO:
936)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



935)

937)



VYYCARERVDWNS
VYYCQQYNNRPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 697)
698)











MIAB31
EVQLLESGGGLVQ
EIVMTQSPATLS
LTFSSHA
AITGSGG
CARERS
RASQS
GASTR
CQQYN



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
NTYYA
DWNSYF
VDNNL
DT
YWPPT



LTFSSHAMSWVRQ
ASQSVDNNLAWY
ID NO:
(SEQ ID
DLH
A
(SEQ
F



APGKGLEWAAITG
QQKPGQAPRLLI
938)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGNTYYADSVKG
YGASTRDTGIPA

939)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


940)
NO:
942)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



941)

943)



VYYCARERSDWNS
VYYCQQYNYWPP









YFDLHGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 699)
700)











MIAB32
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQS
DVSTR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWWSYF
ISNNL
AT
LWPPT



FTFDDYAMHWVRQ
ASQSISNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDVSTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


944)
NO:
946)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



945)

947)



AVYYCARERVDWW
VYYCQQYSLWPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 701)
702)











MIAB33
EVQLLESGGGLVQ
EIVMTQSPATLS
FTLSSYG
SITGSGD
CARERV
RASRS
DAFTR
CQQYD



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
TSYYA
DWNSYF
ISSNL
AT
TWPET



FTLSSYGMSWVRQ
ASRSISSNLAWY
ID NO:
(SEQ ID
DRW
A
(SEQ
F



APGKGLEWASITG
QQKPGQAPRLLI
948)
NO:
(SEQ
(SEQ
ID
(SEQ



SGDTSYYADSVKG
YDAFTRATGIPA

949)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


950)
NO:
952)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



951)

953)



VYYCARERVDWNS
VYYCQQYDTWPE









YFDRWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 703)
704)











MIAB34
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSTYV
SISYSGG
CARERV
RASQS
DVSIR
CQQYT



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
FIYYA
MWNSYF
VSVNL
AT
TWPPT



FTFSTYVMTWVRQ
ASQSVSVNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWASISY
QQKPGQAPRLLI
954)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGFIYYADSVKG
YDVSIRATGIPA

955)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


956)
NO:
958)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



957)

959)



VYYCARERVMWNS
VYYCQQYTTWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 705)
706)











MIAB35
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CNRERV
RASQS
DTSSR
CQQYH



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
VNNYL
AT
SWPPT



FTFDDYAMHWVRQ
ASQSVNNYLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDTSSRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


960)
NO:
962)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



961)

963)



AVYYCNRERVDWN
VYYCQQYHSWPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 707)
708)











MIAB36
EVQLLESGGGLVQ
EIVMTQSPATLS
FIFSDYA
AISGSGG
CAREMV
RASQS
SASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STYYT
DWNSYF
ITTNL
AT
DWPFT



FIFSDYAMSWVRQ
ASQSITTNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
964)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYYTDSVKG
YSASTRATGIPA

965)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


966)
NO:
968)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



967)

969)



VYYCAREMVDWNS
VYYCQQYYDWPF









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 709)
710)











MIAB37
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CAQERV
RASQG
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
ISNSY
AT
TYPPT



FTFDDYAMHWVRQ
ASQGISNSYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYGASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


970)
NO:
241)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



383)

652)



AVYYCAQERVDWN
AVYYCQQYYTYP









SYFDLWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 711)
663)











MIAB38
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFRNYA
SISSSGG
CARERV
RASQS
DVSTR
CQQYK



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
STYYA
DYNSYF
IGNNL
AT
HWPPT



FTFRNYAMTWVRQ
ASQSIGNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSSISS
QQKPGQAPRLLI
971)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYYADSVKG
YDVSTRATGIPA

972)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


973)
NO:
946)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



974)

975)



VYYCARERVDYNS
VYYCQQYKHWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 712)
713)











MIAB39
EVQLLESGGGLVQ
EIVMTQSPATLS
FTLRNYA
AISGSGG
CDRERV
RASQS
ASSTR
CQQYN



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STSYA
DWNSYF
VSNNV
AT
TWPFT



FTLRNYAMSWVRQ
ASQSVSNNVAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
976)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTSYADSVKG
YASSTRATGIPA

978)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


979)
NO:
981)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



980)

982)



VYYCDRERVDWNS
VYYCQQYNTWPF









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 714)
715)











MIAB40
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDTYA
GISGSGG
CARERV
RASQS
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MN (SEQ
SPYYA
LWNSYF
FSSNL
ST
DWPIT



FTFDTYAMNWVRQ
ASQSFSSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWFGISG
QQKPGQAPRLLI
983)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSPYYADSVKG
YGASTRSTGIPA

984)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


888)
NO:
986)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



985)

987)



VYYCARERVLWNS
VYYCQQYYDWPI









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 716)
717)











MIAB41
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSDYA
TISGSGG
CERERV
RASQS
DASSR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
LS (SEQ
NTYYA
DWNSYF
IRNNL
AT
IWPLT



FTFSDYALSWVRQ
ASQSIRNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSTISG
QQKPGQAPRLLI
988)
NO:
(SEQ
SEQ
ID
(SEQ



SGGNTYYADSVKG
YDASSRATGIPA

989)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


990)
NO:
992)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



991)

993)



VYYCERERVDWNS
VYYCQQYYIWPL









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 718)
719)











MIAB42
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSSSA
AISGSGG
CAREVV
RASQS
GASTT
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STYYT
DWNSYF
ISSDL
AT
TWPLT



FTFSSSAMSWVRQ
ASQSISSDLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
994)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYYTDSVKG
YGASTTATGIPA

965)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


995)
NO:
997)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



996)

998)



VYYCAREVVDWNS
VYYCQQYSTWPL









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 720)
721)











MIAB43
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSTHA
TISGSGA
CARETV
RASQS
DASTR
CQQYN



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
TTEYA
DWNSYF
VSNDL
VT
HWPPT



FTFSTHAMTWVRQ
ASQSVSNDLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSTISG
QQKPGQAPRLLI
999)
NO:
(SEQ
(SEQ
ID
(SEQ



SGATTEYADSVKG
YDASTRVTGIPA

1000)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1001)
NO:
887)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1002)

1003)



VYYCARETVDWNS
VYYCQQYNHWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 722)
723)











MIAB44
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSNYP
SISWSGG
CAREHV
RASQN
DASTT
CQQYD



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
SIDYD
DWNSYF
VRSNL
AT
TWPLT



FTFSNYPMTWVRQ
ASQNVRSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSSISW
QQKPGQAPRLLI
1004)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSIDYDDSVKG
YDASTTATGIPA

1005)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1006)
NO:
1008)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1007)

1009)



VYYCAREHVDWNS
VYYCQQYDTWPL









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 724)
725











MIAB45
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFRDYA
SISGSGG
CARERV
RASQS
AASTR
CQQYG



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
SIDYA
DWNSYF
VSSLL
AT
TWPQT



FTFRDYAMSWVRQ
ASQSVSSLLAWY
ID NO:
(SEQ ID
DAW
A
(SEQ
F



APGKGLEWSSISG
QQKPGQAPRLLI
1010)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSIDYADSVKG
YAASTRATGIPA

1011)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1012)
NO:
1014)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1013)

1015)



VYYCARERVDWNS
VYYCQQYGTWPQ









YFDAWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 726)
727)











MIAB46
EVQLLESGGGLVQ
EIVMTQSPATLS
FTLSSYA
GISGSGG
CARIRV
RASQS
DVSTR
CQQYN



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
RTYYA
DWNSYF
FSSNL
AT
HWPPT



FTLSSYAMSWVRQ
ASQSFSSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWAGISG
QQKPGQAPRLLI
1016)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGRTYYADSVKG
YDVSTRATGIPA

1017)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1018)
NO:
946)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



985)

1003)



VYYCARIRVDWNS
VYYCQQYNHWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 728)
729)











MIAB47
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFNNYA
AISGSGG
CARERL
RASQT
DAFTR
CQQYG



PGGSLRLSCAASG
VSPGERATLSCR
MN (SEQ
RTHYA
DINSYF
VSSNL
AT
TWPLT



FTFNNYAMNWVRQ
ASQTVSSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
1019)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGRTHYADSVKG
YDAFTRATGIPA

1020)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1021)
NO:
952)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1022)

1023)



VYYCARERLDINS
VYYCQQYGTWPL









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 730)
731)











MIAB48
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQS
GASTT
CQQYH



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWLSYF
VYSNL
AT
NWPPT



FTFDDYAMHWVRQ
ASQSVYSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YGASTTATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


1024)
NO:
997)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



912)

1025)



AVYYCARERVDWL
VYYCQQYHNWPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 732)
733)











MIAB49
EVQLLESGGGLVQ
EIVMTQSPATLS
LTFSSYA
AISGTGG
CARERV
RASQG
YASTR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MN (SEQ
STYYA
DWNNYF
ISNSY
AT
DWPPT



LTFSSYAMNWVRQ
ASQGISNSYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APGKGLEWSAISG
YQQKPGQAPRLL
1026)
NO:
(SEQ
(SEQ
ID
(SEQ



TGGSTYYADSVKG
IYYASTRATGIP

1027)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
ARFSGSGSGTEF


1028)
NO:
1029)
NO:



YLQMNSLRAEDTA
TLTISSLQSEDF



383)

1030)



VYYCARERVDWNN
AVYYCQQYSDWP









YFDLWGQGTLVTV
PTFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 734)
735)











MIAB50
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFTTYA
AISGSGS
CARERV
RASQS
GASIR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
LS (SEQ
NTYYA
DWNVYF
VGTDL
AI
KWPET



FTFTTYALSWVRQ
ASQSVGTDLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWAAISG
QQKPGQAPRLLI
1031)
NO:
(SEQ
(SEQ
ID
(SEQ



SGSNTYYADSVKG
YGASIRAIGIPA

1032)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1033)
NO:
1035)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1034)

1036)



VYYCARERVDWNV
VYYCQQYYKWPE









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 736)
737)











MIAB51
EVQLLESGGGLVQ
EIVMTQSPATLS
LTFSNYA
AISSSSG
CAREHV
RASQS
DVSIR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MA (SEQ
GTFYA
DWNSYF
VSSNL
AT
VWPDT



LTFSNYAMAWVRQ
ASQSVSSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWAAISS
QQKPGQAPRLLI
1037)
NO:
(SEQ
(SEQ
ID
(SEQ



SSGGTFYADSVKG
YDVSIRATGIPA

1038)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1006)
NO:
958)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1039)

1040)



VYYCAREHVDWNS
VYYCQQYYVWPD









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 738)
739)











MIAB52
EVQLLESGGGLVQ
EIVMTQSPATLS
FAFSNHA
AISSSGG
CARERV
RASQS
GASSR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MN (SEQ
SIDYA
IWNSYF
VSTNF
AT
KWPPL



FAFSNHAMNWVRQ
ASQSVSTNFAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISS
QQKPGQAPRLLI
1041)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSIDYADSVKG
YGASSRATGIPA

1042)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1043)
NO:
1045)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1044)

1046)



VYYCARERVIWNS
VYYCQQYYKWPP









YFDLWGQGTLVTV
LFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 740)
741)











MIAB53
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFTNYA
SITGSGG
CARERD
RASQS
GASSR
CQQYK



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
NTDYA
DWNSYF
VSRNL
VT
TLPHT



FTFTNYAMTWVKQ
ASQSVSRNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSSITG
QQKPGQAPRLLI
1047)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGNTDYADSVKG
YGASSRVTGIPA

1048)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1049)
NO:
1051)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1050)

1052)



VYYCARERDDWNS
VYYCQQYKTLPH









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 742)
743)











MIAB54
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFTSYA
AISGSGG
FARERV
RASQS
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MN (SEQ
STDYA
DWNSYF
VGTNL
AT
DIPET



FTFTSYAMNWVRQ
ASQSVGTNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
1053)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTDYADSVKG
YGASTRATGIPA

1054)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1055)
NO:
241)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1056)

1057)



VYYFARERVDWNS
VYYCQQYYDIPE









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 744)
745)











MIAB55
EVQLLESGGGLVQ
EIVMTQSPATLS
FAFSTYA
AISGSGG
CARERV
RASQS
GASTW
CQQYT



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STYHA
DWNSYN
VSSYL
AT
TWPRT



FAFSTYAMSWVRQ
ASQSVSSYLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
1058)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYHADSVKG
YGASTWATGIPA

1059)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1060)
NO:
1062)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1061)

1063)



VYYCARERVDWNS
VYYCQQYTTWPR









YNDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 746)
747)











MIAB56
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSNYA
GIGGSGG
CARERV
RASQT
AASNR
CQQYK



PGGSLRLSCAASG
VSPGERATLSCR
MD (SEQ
STYYA
DWNSYF
VGSNL
AT
IWPPT



FTFSNYAMDWVRQ
ASQTVGSNLAWY
ID NO:
(SEQ ID
YLW
A
(SEQ
F



APGKGLEWSGIGG
QQKPGQAPRLLI
1064)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYYADSVKG
YAASNRATGIPA

1065)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1066)
NO:
1068)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1067)

1069)



VYYCARERVDWNS
VYYCQQYKIWPP









YFYLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 748)
749)











MIAB57
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSNFA
VITGSGG
CAREMV
RASQS
SASTR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MN (SEQ
STYYA
DWNSYF
VTSKL
AA
HWPPT



FTFSNFAMNWVRQ
ASQSVTSKLAWY
ID NO:
(SEQ ID
DLW
A
SEQ
F



APGKGLEWSVITG
QQKPGQAPRLLI
1070)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYYADSVKG
YSASTRAAGIPA

1071)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


966)
NO:
1073)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1072)

911)



VYYCAREMVDWNS
VYYCQQYSHWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 750)
751)











MIAB58
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSNYA
AISTSGG
CALERA
RASQS
AASSR
CQQYD



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
STYYA
DWNSYF
VKSNL
AT
TWPLT



FTFSNYAMHWVRQ
ASQSVKSNLAWY
ID NO:
(SEQ ID
DLW
A
SEQ
F



APGKGLEWSAIST
QQKPGQAPRLLI
1074)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYYADSVKG
YAASSRATGIPA

1075)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1076)
NO:
1078)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1077)

1009)



VYYCALERADWNS
VYYCQQYDTWPL









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 752)
753)











MIAB59
EVQLLESGGGLVQ
EIVMTQSPATLS
FSFSIYA
AISGSGT
CWRERV
RASQS
DTSIR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STYYA
DWNSYF
IGSSL
AT
HWPPT



FSFSIYAMSWVRQ
ASQSIGSSLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
1079)
NO:
(SEQ
(SEQ
ID
(SEQ



SGTSTYYADSVKG
YDTSIRATGIPA

1080)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1081)
NO:
1083)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1082)

911)



VYYCWRERVDWNS
VYYCQQYSHWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 754)
755)











MIAB60
EVQLLESGGGLVQ
EIVMTQSPATLS
FSFSGYA
SITSSGG
CARERV
RASQS
GTSSR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STYYA
DWNSYF
ITSNL
AT
IWPLT



FSFSGYAMSWVRQ
ASQSITSNLAWY
ID NO:
(SEQ ID
DRW
A
(SEQ
F



APGKGLEWSSITS
QQKPGQAPRLLI
1084)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYYADSVKG
YGTSSRATGIPA

1085)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


950)
NO:
1087)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1086)

993)



VYYCARERVDWNS
VYYCQQYYIWPL









YFDRWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 756)
757)











MIAB61
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSRYG
AISGTGG
HARERV
RASQS
DASTR
CQQYD



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STYYA
DWNSYF
ISDNL
AP
IWPPT



FTFSRYGMSWVRQ
ASQSISDNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
1088)
NO:
SEQ
(SEQ
ID
(SEQ



TGGSTYYADSVKG
YDASTRAPGIPA

1027)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1089)
NO:
1091)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1090)

1092)



VYYHARERVDWNS
VYYCQQYDIWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 758)
759)











MIAB62
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSSFA
TISGSGV
CARERV
RASQS
RASIR
CQQYD



PGGSLRLSCAASG
VSPGERATLSCR
LS (SEQ
NTYYA
DWNSYF
LSTNL
AT
TWPLT



FTFSSFALSWVRQ
ASQSLSTNLAWY
ID NO:
(SEQ ID
DLL
A
(SEQ
F



APGKGLEWSTISG
QQKPGQAPRLLI
921)
NO:
(SEQ
(SEQ
ID
(SEQ



SGVNTYYADSVKG
YRASIRATGIPA

1093)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1094)
NO:
1096)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1095)

1009)



VYYCARERVDWNS
VYYCQQYDTWPL









YFDLLGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 760)
761)











MIAB63
EVQLLESGGGLVQ
EIVMTQSPATLS
FAFSNYA
SISSSGG
TARERV
RASQS
GASTT
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STDYA
DWNSYF
VSSDL
AT
SWPKT



FAFSNYAMSWVRQ
ASQSVSSDLVWY
ID NO:
(SEQ ID
DLW
V
(SEQ
F



APGKGLEWSSISS
QQKPGQAPRLLI
1097)
NO:
SEQ
(SEQ
ID
(SEQ



SGGSTDYADSVKG
YGASTTATGIPA

1098)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1099)
NO:
997)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1100)

1101)



VYYTARERVDWNS
VYYCQQYYSWPK









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 762)
763











MIAB64
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSNYA
AISSSSA
CAREHV
RASQS
SASIR
CQQYI



PGGSLRLSCAASG
VSPGERATLSCR
MG (SEQ
TTNYA
DWNSYF
VRSNL

RWPPT



FTFSNYAMGWVRQ
ASQSVRSNLVWY
ID NO:
(SEQ ID
VLW
V
AT
F



APGKGLEWCAISS
QQKPGQAPRLLI
1102)
NO:
(SEQ
(SEQ
(SEQ
(SEQ



SSATTNYADSVKG
YSASIRATGIPA

1103)
ID NO:
ID
ID
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1104)
NO:
NO:
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1105)
1106)
1107)



VYYCAREHVDWNS
VYYCQQYIRWPP









YFVLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 764)
765)











MIAB65
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFTSYT
SITSSGG
CARERV
RASQS
EASTR
CQQFY



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
GTSYA
DWNKYF
VSDKL
AT
TWPWT



FTFTSYTMSWVRQ
ASQSVSDKLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSSITS
QQKPGQAPRLLI
1108)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGGTSYADSVKG
YEASTRATGIPA

1109)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1110)
NO:
1112)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1111)

1113)



VYYCARERVDWNK
VYYCQQFYTWPW









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 767)
768)











MIAB66
EVQLLESGGGLVQ
EIVMTQSPATLS
LTFSSYA
GISGSGG
CARERV
RASQS
DGSTR
CQQYN



PGGSLRLSCAASG
VSPGERATLSCR
MN (SEQ
NTHYA
DWNSYF
GAGNL
AT
HWPPT



LTFSSYAMNWVRQ
ASQSGAGNLAWY
ID NO:
(SEQ ID
DLE
A
(SEQ
F



APGKGLEWSGISG
QQKPGQAPRLLI
1026)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGNTHYADSVKG
YDGSTRATGIPA

1114)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1115)
NO:
1117)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1116)

1003)



VYYCARERVDWNS
VYYCQQYNHWPP









YFDLEGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 769)
770)











MIAB67
EVQLLESGGGLVQ
EIVMTQSPATLS
FTLSSYG
GISGSGV
CARERV
RASQS
SASTR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
NTYYA
DWNSYD
VFSNL
AT
TWPQT



FTLSSYGMSWVRQ
ASQSVFSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSGISG
QQKPGQAPRLLI
948)
NO:
(SEQ
(SEQ
ID
(SEQ



SGVNTYYADSVKG
YSASTRATGIPA

1118)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1119)
NO:
968)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1120)

1121)



VYYCARERVDWNS
VYYCQQYSTWPQ









YDDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 771)
772)











MIAB68
EVQLLESGGGLVQ
EIVMTQSPATLS
FSFSTYA
SITGSGG
CARERD
RASQS
ASSTR
CQQYT



PGGSLRLSCAASG
VSPGERATLSCR
MA (SEQ
LISYA
DWNSYF
VSNTL
AT
TWPYT



FSFSTYAMAWVRQ
ASQSVSNTLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWASITG
QQKPGQAPRLLI
1122)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGLISYADSVKG
YASSTRATGIPA

1123)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1049)
NO:
981)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



930)

1124)



VYYCARERDDWNS
VYYCQQYTTWPY









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 773)
774)











MIAB69
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSTYV
GISSSGG
CAREHV
RASQS
GASFR
CQQYT



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
STYYA
DWNSYF
VSTYL
AT
TWPQT



FTFSTYVMTWVRQ
ASQSVSTYLAWY
ID NO:
(SEQ ID
DLW
A
SEQ
F



APGKGLEWSGISS
QQKPGQAPRLLI
954)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYYADSVKG
YGASFRATGIPA

1125)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1006)
NO:
1127)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1126)

1128)



VYYCAREHVDWNS
VYYCQQYTTWPQ









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 775)
776)











MIAB70
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSIYA
AISSSSG
CARERV
RTSQS
ASSTR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
RTYYA
DWNSWF
ISSNL
AT
EWPPT



FTFSIYAMSWVRQ
TSQSISSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWAAISS
QQKPGQAPRLLI
1129)
NO:
(SEQ
(SEQ
ID
(SEQ



SSGRTYYADSVKG
YASSTRATGIPA

1130)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1131)
NO:
981)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1132)

1133)



VYYCARERVDWNS
VYYCQQYSEWPP









WFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 777)
778)











MIAB71
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSTYA
AISGSGG
CASERV
TASQS
TASIR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCT
MS (SEQ
STSYA
DWNSYF
VSSNL
AT
SWPKT



FTFSTYAMSWVRQ
ASQSVSSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
1134)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTSYADSVKG
YTASIRATGIPA

978)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1135)
NO:
1137)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1136)

1101)



VYYCASERVDWNS
VYYCQQYYSWPK









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 779)
780)











MIAB72
EVQLLESGGGLVQ
EIVMTQSPATLS
FIFSNYG
SISGGGG
CARERV
RASQS
GASRR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STYYA
TWNSYF
VRGNL
AT
RWPLT



FIFSNYGMSWVRQ
ASQSVRGNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSSISG
QQKPGQAPRLLI
1138)
NO:
(SEQ
(SEQ
ID
(SEQ



GGGSTYYADSVKG
YGASRRATGIPA

1139)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1140)
NO:
1142)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1141)

1143)



VYYCARERVTWNS
VYYCQQYYRWPL









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 781)
782)











MIAB73
EVQLLESGGGLVQ
EIVMTQSPATLS
FAFNNYA
GISGSGG
NARERV
RASQS
TASIR
CQQYK



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
TTYYA
DWNSYF
VRSSL
AT
NYPLT



FAFNNYAMSWVRQ
ASQSVRSSLSWY
ID NO:
(SEQ ID
DLW
S
(SEQ
F



APGKGLEWSGISG
QQKPGQAPRLLI
1144)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGTTYYADSVKG
YTASIRATGIPA

1145)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1146)
NO:
1137)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1147)

1148)



VYYNARERVDWNS
VYYCQQYKNYPL









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 783)
784)











MIAB74
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFNNYA
AVSGSGA
CHRERV
RASQS
GSFTR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MN (SEQ
STYYA
DWNSYF
VSSNL
AT
NWPPL



FTFNNYAMNWVRQ
ASQSVSSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAVSG
QQKPGQAPRLLI
1019)
NO:
(SEQ
(SEQ
ID
(SEQ



SGASTYYADSVKG
YGSFTRATGIPA

1149)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1150)
NO:
1151)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1039)

1152)



VYYCHRERVDWNS
VYYCQQYSNWPP









YFDLWGQGTLVTV
LFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 785)
786)











MIAB75
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFGDYA
TVSSASA
CKRERV
RASQS
DATTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
LIYYA
DWNSYF
VSNTL
AT
DWPIT



FTFGDYAMSWVRQ
ASQSVSNTLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWATVSS
QQKPGQAPRLLI
1153)
NO:
(SEQ
(SEQ
ID
(SEQ



ASALIYYADSVKG
YDATTRATGIPA

1154)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1155)
NO:
896)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



930)

987)



VYYCKRERVDWNS
VYYCQQYYDWPI









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 787)
788)











MIAB76
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSNYV
GISGSGT
CARERV
RASQS
AASTR
CQQYE



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
NTYYA
DWNSQF
VNDNL
VT
RWPPT



FTFSNYVMTWVRQ
ASQSVNDNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSGISG
QQKPGQAPRLLI
1156)
NO:
(SEQ
(SEQ
ID
(SEQ



SGTNTYYADSVKG
YAASTRVTGIPA

1157)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1158)
NO:
1160)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1159)

889)



VYYCARERVDWNS
VYYCQQYERWPP









QFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 789)
790)











MIAB77
EVQLLESGGGLVQ
EIVMTQSPATLS
LTFSSYA
SITGSGS
CARERV
RASQS
GGSTR
CQQYH



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
GTFYA
DWNSYF
VSSNV
AT
LWPPT



LTFSSYAMSWVRQ
ASQSVSSNVAWY
ID NO:
(SEQ ID
DDW
A
(SEQ
F



APGKGLEWASITG
QQKPGQAPRLLI
1161)
NO:
(SEQ
(SEQ
ID
(SEQ



SGSGTFYADSVKG
YGGSTRATGIPA

1162)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1163)
NO:
1165)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1164)

1166)



VYYCARERVDWNS
VYYCQQYHLWPP









YFDDWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 791)
792)











MIAB78
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSTYA
AVSGSGA
CRRERV
RASRS
GTSSR
CQQYE



PGGSLRLSCAASG
VSPGERATLSCR
TS (SEQ
STYYA
DWNSYF
VSTNL
AT
RWPPT



FTFSTYATSWVRQ
ASRSVSTNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAVSG
QQKPGQAPRLLI
1167)
NO:
(SEQ
(SEQ
ID
(SEQ



SGASTYYADSVKG
YGTSSRATGIPA

1149)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1168)
NO:
1087)
NO:



YLQMNS LRAEDTA
LTISSLQSEDFA



1169)

889)



VYYCRRERVDWNS
VYYCQQYERWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 793)
794)











MIAB79
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSSYG
GISGSGG
CAEERV
RASHS
EASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MN (SEQ
NTFYA
DWNSYF
VSSKL
AT
HWPRT



FTFSSYGMNWVRQ
ASHSVSSKLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSGISG
QQKPGQAPRLLI
1170)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGNTFYADSVKG
YEASTRATGIPA

1171)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1172)
NO:
1112)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1173)

1174)



VYYCAEERVDWNS
VYYCQQYYHWPR









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 795)
796)











MIAB80
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSNYV
AISGSGR
CARERV
RASQS
DASTR
CQQYN



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STYYA
DNNSYF
VRDNL
VT
HWPPT



FTFSNYVMSWVRQ
ASQSVRDNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
1175)
NO:
(SEQ
(SEQ
ID
(SEQ



SGRSTYYADSVKG
YDASTRVTGIPA

1176)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1177)
NO:

NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1178)
887)
1003)



VYYCARERVDNNS
VYYCQQYNHWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 797)
798)











MIAB81
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFTTYA
AISGSGG
WARERV
RASQS
RASTR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
LS (SEQ
STYSA
DWNSYF
VSSYL
AA
DWPPT



FTFTTYALSWVRQ
ASQSVSSYLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
1031)
NO:
SEQ
(SEQ
ID
(SEQ



SGGSTYSADSVKG
YRASTRAAGIPA

1179)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1180)
NO:
1181)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1061)

1030)



VYYWARERVDWNS
VYYCQQYSDWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 799)
800)











MIAB82
EVQLLESGGGLVQ
EIVMTQSPATLS
FAFSSSA
ALSGSGG
CARERV
RASQS
AASTR
CHQYY



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STYSA
DWNSYF
ISTKL
AT
TWPYT



FAFSSSAMSWVRQ
ASQSISTKLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSALSG
QQKPGQAPRLLI
1182)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYSADSVKG
YAASTRATGIPA

1183)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


382)
NO:
1014)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1184)

1185)



VYYCARERVDWNS
VYYCHQYYTWPY









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 801)
802)











MIAB83
EVQLLESGGGLVQ
EIVMTQSPATLS
FIFTDYA
AITGSGG
CAREGV
RASES
DASTR
CQQYK



PGGSLRLSCAASG
VSPGERATLSCR
MS SEQ
TTYYA
DWNSYF
VRSNL
TT
TLPHT



FIFTDYAMSWVRQ
ASESVRSNLAWY
ID NO:
(SEQ ID
DLW
A
SEQ
F



APGKGLEWSAITG
QQKPGQAPRLLI
1186)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGTTYYADSVKG
YDASTRTTGIPA

1187)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1188)
NO:
1190)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1189)

1052)



VYYCAREGVDWNS
VYYCQQYKTLPH









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 803)
804)











MIAB84
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSSYA
TISGSGR
CTRERV
RASQS
GASTS
CQHYY



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
STYYA
DWNSYF
VSSRL
AT
NWPPT



FTFSSYAMTWVRQ
ASQSVSSRLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSTISG
QQKPGQAPRLLI
1191)
NO:
(SEQ
SEQ
ID
(SEQ



SGRSTYYADSVKG
YGASTSATGIPA

1192)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1193)
NO:
1195)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1194)

1196)



VYYCTRERVDWNS
VYYCQHYYNWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 805)
806)











MIAB85
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERR
RASQS
DASTT
CQQYH



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
ISSNL
AT
LWPPT



FTFDDYAMHWVRQ
ASQSISSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDASTTATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


1197)
NO:
1008)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



1198)

1166)



AVYYCARERRDWN
VYYCQQYHLWPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 807)
808)











MIAB86
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFNNYA
TITSSGA
CARERV
RASQS
AASTR
CQQYK



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STFYA
DKNSYF
VNDNL
VT
TWPLT



FTFNNYAMSWVRQ
ASQSVNDNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSTITS
QQKPGQAPRLLI
1199)
NO:
(SEQ
(SEQ
ID
(SEQ



SGASTFYADSVKG
YAASTRVTGIPA

1200)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1201)
NO:
1160)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1159)

1202)



VYYCARERVDKNS
VYYCQQYKTWPL









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 809)
810)











MIAB87
EVQLLESGGGLVQ
EIVMTQSPATLS
LTFSSSA
AIRGSGG
CTRERV
RTSQS
GISTR
CQQYK



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STYYA
DWNSYF
VSSNL
AT
TWPWT



LTFSSSAMSWVRQ
TSQSVSSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAIRG
QQKPGQAPRLLI
1203)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYYADSVKG
YGISTRATGIPA

1204)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1193)
NO:
1206)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1205)

1207)



VYYCTRERVDWNS
VYYCQQYKTWPW









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 811)
812)











MIAB88
EVQLLESGGGLVQ
EIVMTQSPATLS
FIFSNYG
TISSSGA
NARERV
RASQS
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
FTYYA
DWNSYF
VRGNL
AN
RWPPT



FIFSNYGMSWVRQ
ASQSVRGNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSTISS
QQKPGQAPRLLI
1138)
NO:
(SEQ
(SEQ
ID
(SEQ



SGAFTYYADSVKG
YGASTRANGIPA

1208)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1146)
NO:
1209)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1141)

1210)



VYYNARERVDWNS
VYYCQQYYRWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID









NO: 813)
NO: 814)











MIAB89
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSSYA
SISGSSG
CARERV
RASQS
AASNR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
SIFYA
DWNSYF
ISSYL
AT
TWPQT



FTFSSYAMSWVRQ
ASQSISSYLAWY
ID NO:
(SEQ ID
DEW
A
(SEQ
F



APGKGLEWSSISG
QQKPGQAPRLLI
1211)
NO:
(SEQ
(SEQ
ID
(SEQ



SSGSIFYADSVKG
YAASNRATGIPA

1212)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1213)
NO:
1068)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1214)

1121)



VYYCARERVDWNS
VYYCQQYSTWPQ









YFDEWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 815)
816)











MIAB90
EVQLLESGGGLVQ
EIVMTQSPATLS
FSFSTYA
GISGSGG
CARERV
RASQS
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
NTHYA
DWNSNF
VSSNV
AT
DYPRT



FSFSTYAMSWVRQ
ASQSVSSNVAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSGISG
QQKPGQAPRLLI
1215)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGNTHYADSVKG
YGASTRATGIPA

1114)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1216)
NO:
241)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1164)

1217)



VYYCARERVDWNS
VYYCQQYYDYPR









NFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 817)
818)











MIAB91
EVQLLESGGGLVQ
EIVMTQSPATLS
FTSSSYA
SISYSGG
CARERV
RASQS
GASSR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MG (SEQ
STDYA
DWNSYF
VSDKL
AA
DWPPT



FTSSSYAMGWVRQ
ASQSVSDKLAWY
ID NO:
(SEQ ID
GLW
A
(SEQ
F



APGKGLEWASISY
QQKPGQAPRLLI
1218)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTDYADSVKG
YGASSRAAGIPA

1219)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1220)
NO:
1221)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1111)

1222)



VYYCARERVDWNS
VYYCQQYYDWPP









YFGLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 819)
820)











MIAB92
EVQLLESGGGLVQ
EIVMTQSPATLS
FIFRNYA
AITGSGG
CARERV
RASHS
GAATR
CQQYN



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
TTDYA
DWYSYF
VSSNL
AT
NRPPT



FIFRNYAMSWVRQ
ASHSVSSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAITG
QQKPGQAPRLLI
1223)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGTTDYADSVKG
YGAATRATGIPA

1224)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1225)
NO:
1227)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1226)

937)



VYYCARERVDWYS
VYYCQQYNNRPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 821)
822)











MIAB93
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFNFYA
AISSSSG
CAREDV
TASQS
DATTR
CQQYT



PGGSLRLSCAASG
VSPGERATLSCT
MS (SEQ
RTYYA
DWNSYF
VSSNL
AT
TWPPT



FTFNFYAMSWVRQ
ASQSVSSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWAAISS
QQKPGQAPRLLI
1228)
NO:
(SEQ
(SEQ

(SEQ



SSGRTYYADSVKG
YDATTRATGIPA

1130)
ID NO:
ID
ID
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1229)
NO:
NO:
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1136)
896)
959)



VYYCAREDVDWNS
VYYCQQYTTWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 823)
824)











MIAB94
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFGNYA
TITSSGG
CARERV
RASQS
GASTR
CQQYD



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
STDYA
DENSYF
ISTSL
AG
DWPPT



FTFGNYAMTWVRQ
ASQSISTSLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSTITS
QQKPGQAPRLLI
1230)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTDYADSVKG
YGASTRAGGIPA

916)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1231)
NO:
1233)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1232)

1234)



VYYCARERVDENS
VYYCQQYDDWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 825)
826)











MIAB95
EVQLLESGGGLVQ
EIVMTQSPATLS
FTLSNYA
AISGSGG
CARERV
RASQS
DASSR
CQQYK



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
RTYYA
DWNSYN
VSSNV
AT
TLPHT



FTLSNYAMSWVRQ
ASQSVSSNVAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
1235)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGRTYYADSVKG
YDASSRATGIPA

1236)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1060)
NO:
992)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1164)

1052)



VYYCARERVDWNS
VYYCQQYKTLPH









YNDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 827)
828)











MIAB96
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSTYA
AISSSGG
CARERV
RASQS
DASTR
CQQYH



PGGSLRLSCAASG
VSPGERATLSCR
MI (SEQ
SIDYA
DANSYF
ISGNL
AA
NWPPT



FTFSTYAMIWVRQ
ASQSISGNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISS
QQKPGQAPRLLI
1237)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSIDYADSVKG
YDASTRAAGIPA

1042)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1238)
NO:
1240)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1239)

1025)



VYYCARERVDANS
VYYCQQYHNWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 829)
830)











MIAB97
EVQLLESGGGLVQ
EIVMTQSPATLS
FSFSNYA
TITSSGG
CARERV
RASQS
SASAR
CQQYK



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
STDYA
DWNSYF
VSRNL
AT
TLPHT



FSFSNYAMTWVRQ
ASQSVSRNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSTITS
QQKPGQAPRLLI
1241)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTDYADSVKG
YSASARATGIPA

916)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


382)
NO:
1242)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1050)

1052)



VYYCARERVDWNS
VYYCQQYKTLPH









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 831)
832)











MIAB98
EVQLLESGGGLVQ
EIVMTQSPATLS
FTLRNYA
GISGSGG
CARSRV
RASQS
DASNR
CQQYD



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
SPYYA
DWNSYF
VGNNL
AT
DWPPT



FTLRNYAMSWVRQ
ASQSVGNNLAWY
ID NO:
(SEQ ID
QLW
A
(SEQ
F



APGKGLEWSGISG
QQKPGQAPRLLI
976)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSPYYADSVKG
YDASNRATGIPA

984)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1243)
NO:
1245)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1244)

1234)



VYYCARSRVDWNS
VYYCQQYDDWPP









YFQLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 833)
834)











MIAB99
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSSFG
AISGGGG
CARERV
RASQS
DTSSR
CQQYK



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
TTYYA
DWKSYF
VGSNL
AT
TWPFT



FTFSSFGMSWVRQ
ASQSVGSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
1246)
NO:
(SEQ
(SEQ
ID
(SEQ



GGGTTYYADSVKG
YDTSSRATGIPA

1247)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1248)
NO:
962)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1249)

1250)



VYYCARERVDWKS
VYYCQQYKTWPF









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 835)
836)











MIAB100
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFTTYA
TISGSGG
CARVRV
RASQS
SASSR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
STYYV
DWNSYF
IGTNL
AT
HWPQT



FTFTTYAMTWVRQ
ASQSIGTNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSTISG
QQKPGQAPRLLI
1251)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYYVDSVKG
YSASSRATGIPA

1252)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1253)
NO:
1255)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1254)

897)



VYYCARVRVDWNS
VYYCQQYYHWPQ









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 837)
838)











MIAB101
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFGSFA
VISGSGG
CARERV
RASQS
GASNR
CQQYD



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STHYA
DWNSYF
VSTYL
AT
TWPYT



FTFGSFAMSWVRQ
ASQSVSTYLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSVISG
QQKPGQAPRLLI
1256)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTHYADSVKG
YGASNRATGIPA

1257)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


382)
NO:
1258)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1126)

1259)



VYYCARERVDWNS
VYYCQQYDTWPY









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 839)
840)











MIAB102
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFTDYA
TISGSGA
CAREDV
RTSQS
GPSTR
CQQYK



PGGSLRLSCAASG
VSPGERATLSCR
MN (SEQ
TTYYA
DWNSYF
VSSDL
AT
TWPQT



FTFTDYAMNWVRQ
TSQSVSSDLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSTISG
QQKPGQAPRLLI
1260)
NO:
(SEQ
(SEQ
ID
(SEQ



SGATTYYADSVKG
YGPSTRATGIPA

1261)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1229)
NO:
1263)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1262)

1264)



VYYCAREDVDWNS
VYYCQQYKTWPQ









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 841)
626)











MIAB103
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSSYA
SISGSGG
CARERM
RASQS
AASTR
CQQYN



PGGSLRLSCAASG
VSPGERATLSCR
MN (SEQ
GTYYA
DWNSYF
VSTDL
VT
TAPLT



FTFSSYAMNWVRQ
ASQSVSTDLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSSISG
QQKPGQAPRLLI
1265)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGGTYYADSVKG
YAASTRVTGIPA

1266)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1267)
NO:
1160)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1268)

1269)



VYYCARERMDWNS
VYYCQQYNTAPL









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 842)
843)











MIAB104
EVQLLESGGGLVQ
EIVMTQSPATLS
FSFGSYA
TISGSGA
CARERV
RASQS
GAATR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
GTYYA
DWNSYI
ISGNL
AT
KWPIT



FSFGSYAMSWVRQ
ASQSISGNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSTISG
QQKPGQAPRLLI
1270)
NO:
(SEQ
(SEQ
ID
(SEQ



SGAGTYYADSVKG
YGAATRATGIPA

1271)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1272)
NO:
1227)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1239)

1273)



VYYCARERVDWNS
VYYCQQYYKWPI









YIDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 844)
845)











MIAB105
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSSFP
SISGSGA
CAREEV
RASQS
DASTR
CQQYD



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
SIYYA
DWNSYF
VNNNL
AI
TWPPT



FTFSSFPMSWVRQ
ASQSVNNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKDLEWSSISG
QQKPGQAPRLLI
1274)
NO:
(SEQ
(SEQ
ID
(SEQ



SGASIYYADSVKG
YDASTRAIGIPA

1275)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1276)
NO:
1278)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1277)

1279)



VYYCAREEVDWNS
VYYCQQYDTWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 846)
847)











MIAB106
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQS
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
VGTDL
AA
TYPPT



FTFDDYAMHWVRQ
ASQSVGTDLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YGASTRAAGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


382)
NO:
1280)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



1034)

652)



AVYYCARERVDWN
VYYCQQYYTYPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664)
848)











MIAB107
EVQLLESGGGLVQ
EIVMTQSPATLS
FIFSDYA
GISGSSG
CAYERV
RASQS
AASIR
CQQYK



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
TIYYA
DWNSYF
VDTNL
AT
TLPHT



FIFSDYAMSWVRQ
ASQSVDTNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSGISG
QQKPGQAPRLLI
964)
NO:
(SEQ
(SEQ
ID
(SEQ



SSGTIYYADSVKG
YAASIRATGIPA

1281)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1282)
NO:
1284)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1283)

1052)



VYYCAYERVDWNS
VYYCQQYKTLPH









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 849)
850)











MIAB108
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFGSYA
TISGSGG
CARERV
RASQS
GVSTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STHYA
DWGSYF
VGSDL
AA
KWPPT



FTFGSYAMSWVRQ
ASQSVGSDLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSTISG
QQKPGQAPRLLI
1285)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTHYADSVKG
YGVSTRAAGIPA

1286)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1287)
NO:
1289)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1288)

1290)



VYYCARERVDWGS
VYYCQQYYKWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 851)
852)











MIAB109
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RACQG
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
ISNSY
GT
TYPPT



FTFDDYAMHWVRQ
ACQGISNSYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYGASTRGTGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


382)
NO:
1291)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



890)

652)



AVYYCARERVDWN
AVYYCQQYYTYP









SYFDLWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664)
853)











MIAB110
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSSYA
AISGSSG
CARERM
RASQS
VASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STYYA
DWNSYF
IDTNL
AT
SWPKT



FTFSSYAMSWVRQ
ASQSIDTNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
1211)
NO:
(SEQ
(SEQ
ID
(SEQ



SSGSTYYADSVKG
YVASTRATGIPA

1292)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1267)
NO:
1294)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1293)

1101)



VYYCARERMDWNS
VYYCQQYYSWPK









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 854)
855)











MIAB111
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDTYA
SITGSGV
CARESV
RASQS
DASIR
CQQYN



PGGSLRLSCAASG
VSPGERATLSCR
MN (SEQ
STDYA
DWNSYF
VSSNI
AT
KWPPT



FTFDTYAMNWVRQ
ASQSVSSNIAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSSITG
QQKPGQAPRLLI
983)
NO:
(SEQ
(SEQ
ID
(SEQ



SGVSTDYADSVKG
YDASIRATGIPA

1295)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1296)
NO:
1298)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1297)

1299)



VYYCARESVDWNS
VYYCQQYNKWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 856)
857)











MIAB112
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFRTYA
IITGSGG
CAMERV
RASQS
AASIR
CQQYD



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STYYA
DWNSYF
VSYKL
DT
TWPLT



FTFRTYAMSWVRQ
ASQSVSYKLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSIITG
QQKPGQAPRLLI
1300)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYYADSVKG
YAASIRDTGIPA

1301)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1302)
NO:
1304)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1303)

1009)



VYYCAMERVDWNS
VYYCQQYDTWPL









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 858)
859)











MIAB113
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSSYS
AISSSGG
CAREMV
RASES
DASTR
CQQYT



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
SIDYA
DWNSYF
VSSNL
AT
TWPYT



FTFSSYSMTWVRQ
ASESVSSNLAWY
ID NO:
(SEQ ID
WLW
A
(SEQ
F



APGKGLEWSAISS
QQKPGQAPRLLI
1305)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSIDYADSVKG
YDASTRATGIPA

1042)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1306)
NO:
904)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1307)

1124)



VYYCAREMVDWNS
VYYCQQYTTWPY









YFWLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 860)
861)











MIAB114
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFRSYA
VISGSGG
CARERV
RASQS
DASTT
CQQYD



PGGSLRLSCAASG
VSPGERATLSCR
MN (SEQ
STYYA
DWNSYF
VSTYL
AT
TWPFT



FTFRSYAMNWVRQ
ASQSVSTYLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSVISG
QQKPGQAPRLLI
1308)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYYADSVKG
YDASTTATGIPA

1309)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


382)
NO:
1008)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1126)

1310)



VYYCARERVDWNS
VYYCQQYDTWPF









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 862)
863)











MIAB115
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQS
GASSR
CQQYN



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
ISSHL
AS
IWPPT



FTFDDYAMHWVRQ
ASQSISSHLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YGASSRASGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


382)
NO:
1312)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



1311)

1313)



AVYYCARERVDWN
VYYCQQYNIWPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664)
864)











MIAB116
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSDYA
AISGTGG
CARERV
RASRS
GGSTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MN (SEQ
TTYYA
DWNSWF
VSSNL
AT
VWPPT



FTFSDYAMNWVRQ
ASRSVSSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
1314)
NO:
(SEQ
(SEQ
ID
(SEQ



TGGTTYYADSVKG
YGGSTRATGIPA

1315)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1131)
NO:
1165)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1316)

1317)



VYYCARERVDWNS
VYYCQQYYVWPP









WFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID









NO: 865)
NO: 866)











MIAB117
EVQLLESGGGLVQ
EIVMTQSPATLS
FSFSTYA
TISGSGV
CARERV
RAGQS
GASPR
CQQYD



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
NTYYA
DWNSEF
VSNNL
AT
TSPLT



FSFSTYAMTWVRQ
AGQSVSNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSTISG
QQKPGQAPRLLI
1318)
NO:
(SEQ
(SEQ
ID
(SEQ



SGVNTYYADSVKG
YGASPRATGIPA

1093)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1319)
NO:
1321)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1320)

1322)



VYYCARERVDWNS
VYYCQQYDTSPL









EFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NQ









NO: 867)
868)











MIAB118
EVQLLESGGGLVQ
EIVMTQSPATLS
FSFGSYA
IISSSGA
CARERL
RASQS
GASSR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MG (SEQ
FTYYA
DWNSYF
VTRNL
AA
NWPPT



FSFGSYAMGWVRQ
ASQSVTRNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSIISS
QQKPGQAPRLLI
1323)
NO:
(SEQ
(SEQ
ID
(SEQ



SGAFTYYADSVKG
YGASSRAAGIPA

1324)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1325)
NO:
1221)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



924)

1326)



VYYCARERLDWNS
VYYCQQYYNWPP









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 869)
870)











MIAB119
EVQLLESGGGLVQ
EIVMTQSPATLS
FSFSTYA
AISGGGG
CARERV
RASQS
GASTR
CQQYH



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
STFYA
DWNSTF
VTTNL
AN
KWPPT



FSFSTYAMHWVRQ
ASQSVTTNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
1327)
NO:
(SEQ
(SEQ
ID
(SEQ



GGGSTFYADSVKG
YGASTRANGIPA

1328)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1329)
NO:
1209)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1330)

1331)



VYYCARERVDWNS
VYYCQQYHKWPP









TFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 871)
872)











MIAB120
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CAREPV
RASQN
DATTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
LWNSYF
VNNNL
AT
HWPQT



FTFDDYAMHWVRQ
ASQNVNNNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDATTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


1332)
NO:
896)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



895)

897)



AVYYCAREPVLWN
VYYCQQYYHWPQ









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 873)
677)











MIAB121
EVQLLESGGGLVQ
EIVMTQSPATLS
FIFDDYA
ASITSSS
CARERV
RACPS
DASTR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWFSYF
VSNNL
AT
HWPPT



FIFDDYAMHWVRQ
ACPSVSNNLVWY
ID NO:
(SEQ ID
DLW
V
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
908)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDASTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


909)
NO:
904)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



1333)

911)



AVYYCARERVDWF
VYYCQQYSHWPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 688)
874)











MIAB122
EVQLLESGGGLVQ
EIVMTQSPATLS
FIFDDYA
ASITSSS
CARERV
RACPS
DASTR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWFSYF
VSNNY
AT
HWPPT



FIFDDYAMHWVRQ
ACPSVSNNYLVW
ID NO:
(SEQ ID
DLW
LV
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
908)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYDASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


909)
NO:
904)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



1334)

911)



AVYYCARERVDWF
AVYYCQQYSHWP









SYFDLWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 688
875)











MIAB123
EVQLLESGGGLVQ
EIVMTQSPATLS
FIFDDYA
ASITSSS
CARERV
RASQS
DASTR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWFSYF
VSNNY
AT
HWPPT



FIFDDYAMHWVRQ
ASQSVSNNYLVW
ID NO:
(SEQ ID
DLW
LV
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
908)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYDASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


909)
NO:
904)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



1335)

911)



AVYYCARERVDWF
AVYYCQQYSHWP









SYFDLWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 688)
876)











MIAB124
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSTDA
AISGSGG
CARARV
RASQS
AASTR
CQQYS



PGGSLRLSCAASG
VSPGERATLSCR
MS (SEQ
STYSA
DWNSYN
VNNKL
AT
TWPIT



FTFSTDAMSWVRQ
ASQSVNNKLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSAISG
QQKPGQAPRLLI
1336)
NO:
(SEQ
SEQ
ID
(SEQ



SGGSTYSADSVKG
YAASTRATGIPA

1179)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1337)
NO:
1014)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1338)

1339)



VYYCARARVDWNS
VYYCQQYSTWPI









YNDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 877)
878)











MIAB125
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSNYA
DISGSGG
CARERV
RASQG
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
IS (SEQ
TTYYA
DWNSYF
ISNSY
AT
TYPPT



FTFSNYAISWVRQ
ASQGISNSYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APGKGLEWSDISG
YQQKPGQAPRLL
1340)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGTTYYADSVKG
IYGASTRATGIP

1341)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
ARFSGSGSGTEF


382)
NO:
241)
NO:



YLQMNSLRAEDTA
TLTISSLQSEDF



383)

652)



VYYCARERVDWNS
AVYYCQQYYTYP









YFDLWGQGTLVTV
PTFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 879)
663











MIAB126
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQG
GASTR
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWMSYF
ISNSY
AT
TYPPT



FTFDDYAMHWVRQ
ASQGISNSYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYGASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


1342)
NO:
241)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



383)

652)



AVYYCARERVDWM
AVYYCQQYYTYP









SYFDLWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 880)
663)











MIAB127
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFSNYG
SIGGSGG
CARKRV
RASQS
DASTG
CQQYY



PGGSLRLSCAASG
VSPGERATLSCR
MT (SEQ
STYYA
DWISYF
VTSKL
AT
DIPET



FTFSNYGMTWVRQ
ASQSVTSKLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWSSIGG
QQKPGQAPRLLI
1343)
NO:
(SEQ
(SEQ
ID
(SEQ



SGGSTYYADSVKG
YDASTGATGIPA

1344)
ID NO:
ID
NO:
ID



RFTISRDNSKNTL
RFSGSGSGTEFT


1345)
NO:
627)
NO:



YLQMNSLRAEDTA
LTISSLQSEDFA



1072)

1057)



VYYCARKRVDWIS
VYYCQQYYDIPE









YFDLWGQGTLVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 881)
882)











MIAB128
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
NYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1399)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPNYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1346)
592)











MIAB128
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS


A
PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
QYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1400)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPQYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1348)
592)











MIAB129
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
GYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1401)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPGYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1349)
592)











MIAB130
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYQMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1402)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









QMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1350)
592)











MIAB131
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYGMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1403)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









GMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1351)
592)











MIAB132
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSNFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSNFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
1404)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1352)
592)











MIAB133
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSSFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
1405)
NO:
SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1353)
592)











MIAB134
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSAFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSAFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
1406)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1354)
592)








MIAB135
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSNNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1355)
592)











MIAB136
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYA
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MS (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSSYAMSWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
473)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1356)
592)











MIAB137
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1357)
592)











MIAB138
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYA
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MS (SEQ
GSTYYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSSYAMSWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
473)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1358)
592)











MIAB139
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQSYS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
ISSYL
(SEQ
TPRT



FTFSDFWMHWVRQ
ASQSISSYLNWY
ID NO:
(SEQ ID
VW
N
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

1407)



LYLQMNSLRAEDT
LTISSLQPEDFA



172)





AVYYCARDRPYYY
TYYCQQSYSTPR









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1360)











MIAB140
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYA
SAISGSG
CARDRP
RASQS
SSLQS
QQSYS



PGGSLRLSCAASG
ASVGDRVTITCR
MS (SEQ
GSTYYA
YYYYMD
ISSYL
(SEQ
TPRT



FTFSSYAMSWVRQ
ASQSISSYLNWY
ID NO:
(SEQ ID
VW
N
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
473)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

1407)



LYLQMNSLRAEDT
LTISSLQPEDFA



172)





AVYYCARDRPYYY
TYYCQQSYSTPR









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1358)
1360)











MIAB141
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
ISSYL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSISSYLNWY
ID NO:
(SEQ ID
VW
N
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



172)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1361)











MIAB142
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQSYS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
TPRT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

1407)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQSYSTPR









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1362)











MIAB143
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
592)











MIAB144
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
592)











MIAB145
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
ISRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSISRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1408)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1363)











MIAB146
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSSSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSSSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1409)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1364)











MIAB147
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRYL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRYLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1410)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1365)











MIAB148
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLNWY
ID NO:
(SEQ ID
VW
N
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1411)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1366)











MIAB149
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
ISSSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSISSSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1412)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1367)











MIAB150
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
ISRYL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSISRYLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1413)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1368)











MIAB151
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
ISRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSISRSLNWY
ID NO:
(SEQ ID
VW
N
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNS KNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1414)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591
1369)











MIAB152
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSSYL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSSYLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS


ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT

170)
360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1415)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1370)











MIAB153
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSSSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSSSLNWY
ID NO:
(SEQ ID
VW
N
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1416)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SSV (SEQ ID
(SEQ ID NO:









NO: 1548)
1371)











MIAB154
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRYL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRYLNWY
ID NO:
(SEQ ID
VW
N
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1417)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1372)











MIAB155
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
ISSSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSISSSLNWY
ID NO:
(SEQ ID
VW
N
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1418)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1373)











MIAB156
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
ISRYL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSISRYLNWY
ID NO:
(SEQ ID
VW
N
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1419)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1374)











MIAB157
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
ISSYL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSISSYLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1420)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1375)











MIAB158
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSSYL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSSYLNWY
ID NO:
(SEQ ID
VW
N
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1421)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1376)











MIAB159
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGES
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GESGYTNYADSVK
YAASSLQSGVPS

1422)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1377)
592)











MIAB160
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTQYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTQYADSVK
YAASSLQSGVPS

1423)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1378)
592)











MIAB161
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDQSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1379)
592)











MIAB162
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLGWY
ID NO:
(SEQ ID
VW
G
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1424)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1380)











MIAB163
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL

YPVT



FTFSDFWMHWVRQ
ASQSVSRSLDWY
ID NO:
(SEQ ID
VW
D
(SEQ
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
ID
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
NO:
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:
362)
363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1425)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1381)











MIAB164
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLTWY
ID NO:
(SEQ ID
VW
T
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1426)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1382)











MIAB165
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLSWY
ID NO:
(SEQ ID
VW
S
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1427)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1383)











MIAB166
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLEWY
ID NO:
(SEQ ID
VW
E
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1428)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1384)











MIAB167
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLKWY
ID NO:
(SEQ ID
VW
K
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1429)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NQ









NO: 591)
1385)











MIAB168
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLLWY
ID NO:
(SEQ ID
VW
L
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1430)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
1386)











MIAB169
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYIMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1387)
592)











MIAB170
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYWMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1432)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









WMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1388)
592)











MIAB171
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
SYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1433)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPSYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1389)
592)











MIAB172
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
TYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1434)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPTYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1390)
592)











MIAB173
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 591)
592)











MIAB174
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDYW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDYWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
1435)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1391)
592)











MIAB175
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSSYWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
83)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1392)
592)











MIAB176
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SAISGSS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISAIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GSSGSTYYADSVK
YAASSLQSGVPS

1436)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1393)
592)











MIAB177
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRETISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1357)
592)











MIAB178
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYW
SAISGSS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSSYWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISAIS
QQKPGKAPKLLI
83)
NO:
(SEQ
(SEQ
NO:
ID



GSSGSTYYADSVK
YAASSLQSGVPS

1436)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1394)
592)











MIAB179
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYW
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYYMD
ISRYL
(SEQ
YPVT



FTFSSYWMHWVRQ
ASQSISRYLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
83)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1413)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1395)
1368)











MIAB180
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYW
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYYMD
VSRSL
(SEQ
YPVT



FTFSSYWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
83)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1395)
592)











MIAB181
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYW
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYYMD
ISRYL
(SEQ
YPVT



FTFSSYWMHWVRQ
ASQSISRYLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
83)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1413)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1395)
1368)











MIAB182
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYW
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYYMD
ISRSL
(SEQ
YPVT



FTFSSYWMHWVRQ
ASQSISRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
83)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1408)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1395)
1363)











MIAB183
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYW
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH SEQ
GSTYYA
YYYYMD
VSSSL
(SEQ
YPVT



FTFSSYWMHWVRQ
ASQSVSSSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
83)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1409)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1395)
1364)











MIAB184
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYW
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYYMD
ISSSL
(SEQ
YPVT



FTFSSYWMHWVRQ
ASQSISSSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
83)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


360)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1412)





AVYYCARDRPYYY
TYYCQQYKSYPV









YMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1395)
1367)











MIAB185
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYIMD
ISRSL
(SEQ
YPVT



FTFSSYWMHWVRQ
ASQSISRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
83)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1408)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1396)
1363)











MIAB186
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYIMD
VSSSL
(SEQ
YPVT



FTFSSYWMHWVRQ
ASQSVSSSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
83)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1409)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1396)
1364)











MIAB187
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYIMD
ISSSL
(SEQ
YPVT



FTFSSYWMHWVRQ
ASQSISSSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
83)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1412)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1396)
1367)











MIAB188
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYIMD
ISRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSISRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1408)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1397)
1363)











MIAB189
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYIMD
VSSSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSSSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1409)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1397)
1364)











MIAB190
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYIMD
ISSSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSISSSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1412)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1397)
1367)











MIAB191
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYW
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYIMD
ISRSL
(SEQ
YPVT



FTFSSYWMHWVRQ
ASQSISRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
83)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1408)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1398)
1363)











MIAB192
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYW
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYIMD
VSSSL
(SEQ
YPVT



FTFSSYWMHWVRQ
ASQSVSSSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
83)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1409)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1398)
1364)











MIAB193
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSSYW
SAISGSG
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GSTYYA
YYYIMD
ISSSL
(SEQ
YPVT



FTFSSYWMHWVRQ
ASQSISSSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWVSAIS
QQKPGKAPKLLI
83)
NO:
(SEQ
(SEQ
NO:
ID



GSGGSTYYADSVK
YAASSLQSGVPS

103)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1412)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1398)
1367)











MIAB194
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYIMD
ISRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSISRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1408)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1387)
1363)











MIAB195
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYIMD
VSSSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSSSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1409)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1387)
1364)











MIAB196
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYIMD
ISSSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSISSSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1412)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1387)
1367)











MIAB197
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYIMD
ISRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSISRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



1408)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1387)
1363)











MIAB198
EVQLLESGGGLVQ
DIQMTQSPSSLS
FTFSDFW
SYISGDS
CARDRP
RASQS
SSLQS
QQYKS



PGGSLRLSCAASG
ASVGDRVTITCR
MH (SEQ
GYTNYA
YYYIMD
VSRSL
(SEQ
YPVT



FTFSDFWMHWVRQ
ASQSVSRSLAWY
ID NO:
(SEQ ID
VW
A
ID
(SEQ



APGKGLEWISYIS
QQKPGKAPKLLI
359)
NO:
(SEQ
(SEQ
NO:
ID



GDSGYTNYADSVK
YAASSLQSGVPS

170)
ID NO:
ID
362)
NO:



GRFTISRDNSKNT
RFSGSGSGTDFT


1431)
NO:

363)



LYLQMNSLRAEDT
LTISSLQPEDFA



361)





AVYYCARDRPYYY
TYYCQQYKSYPV









IMDVWGKGTTVTV
TFGQGTKVEIK









SS (SEQ ID
(SEQ ID NO:









NO: 1387)
592)











MIAB205
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQS
RASTR
CQQYH



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWFSYF
VYSNL
AT
IWPPT



FTFDDYAMHWVRQ
ASQSVYSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YRASTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


909)
NO:
913)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



912)

914)



AVYYCARERVDWF
VYYCQQYHIWPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 1533)
690)











MIAB206
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQS
RASTR
CQQYH



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWYSYF
VYSNL
AT
IWPPT



FTFDDYAMHWVRQ
ASQSVYSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YRASTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


1225)
NO:
913)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



912)

914)



AVYYCARERVDWY
VYYCQQYHIWPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 1534)
690)











MIAB207
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQS
RASTR
CQQYH



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
VYSNL
AT
IWPPT



FTFDDYAMHWVRQ
ASQSVYSNLVWY
ID NO:
(SEQ ID
DLW
V
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YRASTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


382)
NO:
913)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



1540)

914)



AVYYCARERVDWN
VYYCQQYHIWPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664
1535)











MIAB208
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQS
DASTR
CQQYH



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
VYSNL
AT
IWPPT



FTFDDYAMHWVRQ
ASQSVYSNLAWY
ID NO:
(SEQ ID
DLW
A
(SEQ
F



APGKGLEWVASIT
QQKPGQAPRLLI
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
YDASTRATGIPA

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
RFSGSGSGTEFT


382)
NO:
904)
NO:



LYLQMNSLRAEDT
LTISSLQSEDFA



912)

914)



AVYYCARERVDWN
VYYCQQYHIWPP









SYFDLWGQGTLVT
TFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664)
1536)











MIAB209
EVQLLESGGGLVQ
EIVMTQSPATLS
FTFDDYA
ASITSSS
CARERV
RASQS
RASTR
CQQYH



PGGSLRLSCAASG
VSPGERATLSCR
MH (SEQ
AFIDYA
DWNSYF
VYSNY
AT
IWPPT



FTFDDYAMHWVRQ
ASQSVYSNYLAW
ID NO:
(SEQ ID
DLW
LA
(SEQ
F



APGKGLEWVASIT
YQQKPGQAPRLL
135)
NO:
(SEQ
(SEQ
ID
(SEQ



SSSAFIDYADSVK
IYRASTRATGIP

381)
ID NO:
ID
NO:
ID



GRFTISRDNSKNT
ARFSGSGSGTEF


382)
NO:
913)
NO:



LYLQMNSLRAEDT
TLTISSLQSEDF



1541)

914)



AVYYCARERVDWN
AVYYCQQYSHWP









SYFDLWGQGTLVT
PTFGQGTKVEIK









VSS (SEQ ID
(SEQ ID NO:









NO: 664)
1537)









In some embodiments, the MAdCAM antibody comprises one or more sequences, or a combination thereof, of the sequences presented in Table 9.


In some embodiments, the antibody is linked to another antibody or therapeutic. In some embodiments, the MAdCAM antibody is linked to a PD-1 antibody or an IL-2 mutein as provided herein or that is incorporated by reference.


In some embodiments, the variable light chain MAdCAM antibody comprises a mutation selected from the group comprising V29I; R31S; S32Y; A34N; Y91S; K92Y; Y94T; and V99R.


In some embodiments, the variable heavy chain MAdCAM antibody comprises a mutation selected from the group comprising D31S, F32Y, I48V, Y50A, D54S, Y57S, N59Y, Y103G, V29I, R31S; D31S, F32Y, I48V, Y50A, D54S, Y57S, N59Y, V29I, R31S; D31S, F32Y, I48V, Y50A, D54S, Y57S, N59Y, Y103G, V29I; D31S, F32Y, I48V, Y50A, D54S, Y57S, N59Y, V29I; D31S, F32Y, Y50A, D54S, S55G, Y57S, N59Y, Y103G, V29I, R31S; D31S, F32Y, Y50A, D54S, S55G, Y57S, N59Y, V29I, R31S; D31S, F32Y, Y50A, D54S, S55G, Y57S, N59Y, Y103G, V29I; D31S, F32Y, Y50A, D54S, S55G, Y57S, N59Y, V29I; D31S, F32Y, I48V, Y50A, D54S, S55G, Y57S, N59Y, Y103G, V29I, R31S; D31S, F32Y, I48V, Y50A, D54S, S55G, Y57S, N59Y, V29I, R31S; D31S, F32Y, I48V, Y50A, D54S, S55G, Y57S, N59Y, Y103G, V29I; D31S, F32Y, I48V, Y50A, D54S, S55G, Y57S, N59Y, V29I; D31S, F32Y, I48V, D54S, S55G, Y103G, V29I, R31S; D31S, F32Y, I48V, Y50A, D54S, S55G, Y57S, N59Y, Y105D, V29I, R31S; D31S, F32Y, I48V, D54S, S55G, Y105D, V29I, R31S; D31S, F32Y, I48V, Y50A, D54S, S55G, Y57S, N59Y, Y103G, V29I, R31S; D31S, F32Y, I48V, D54S, S55G, Y105D, V29I, R31S; D31S; F32Y; W33A; H35S; I48V; Y50A; D54S; 555G; Y57S; N59Y; D60A; D60Q; N72A; N72Q; N82A; N82G; and N82Q.


In some embodiments, the MAdCAM antibody comprises one or more sequences as shown in Table 6 or Table 9. In some embodiments, the MAdCAM antibody comprises a combination of one or more sequence as shown in Table 6, or Table 9. In some embodiments, the MAdCAM antibody is in a scFv format as illustrated in Table 6. In some embodiments, the antibody comprises a CDR1 from any one of clones 1-66 of Table 6, a CDR2 from any one of clones 1-84, and a CDR3 from any one of clones 1-66 of Table 6. In some embodiments, the antibody comprises a LCDR1 from any one of clones 1-66 of Table 6, a LCDR2 from any one of clones 1-66 of Table 6, and a LCDR3 from any one of clones 1-66 of Table 6. In some embodiments, the MAdCAM antibody is in a Fab format as illustrated in Table 9. In some embodiments, the antibody comprises a HCDR1 from any one of clones MIAB1-198 or MIAB205-209 of Table 9, a HCDR2 from any one of clones MIAB1-198 or MIAB205-209 of Table 9, and a HCDR3 from any one of clones MIAB1-198 or MIAB205-209 of Table 9. In some embodiments, the antibody comprises a LCDR1 from any one of clones MIAB1-198 or MIAB205-209 of Table 9, a LCDR2 from any one of clones MIAB1-198 or MIAB205-209 of Table 9, and a LCDR3 from any one of clones MIAB1-198 or MIAB205-209 of Table 9. In some embodiments, the amino acid residues of the CDRs shown above contain mutations. In some embodiments, the CDRs contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions or mutations. In some embodiments, the substitution is a conservative substitution.


In some embodiments, the MAdCAM antibody has a VH region selected from any one of clones 1-84 of Table 7 and a VL region selected from any one of clones 1-84 as set forth in of Table 7. In some embodiments, the antibody comprises a CDR1 from any one of clones 1-84 of Table 7, a CDR2 from any one of clones 1-84, and a CDR3 from any one of clones 1-84 of Table 7. In some embodiments, the antibody comprises a LCDR1 from any one of clones 1-84 of Table 7, a LCDR2 from any one of clones 1-84 of Table 7, and a LCDR3 from any one of clones 1-84 of Table 7. In some embodiments, the MAdCAM antibody has a VH region selected from any one of clones MIAB1-198 or MIAB205-209 of Table 9 and a VL region selected from any one of clones MIAB1-198 or MIAB205-209 as set forth in of Table 9. In some embodiments, the antibody comprises a CDR1 from any one of clones MIAB1-198 or MIAB205-209 of Table 9, a CDR2 from any one of clones MIAB1-198 or MIAB205-209, and a CDR3 from any one of clones MIAB1-198 or MIAB205-209 of Table 9. In some embodiments, the antibody comprises a LCDR1 from any one of clones MIAB1-198 or MIAB205-209 of Table 9, a LCDR2 from any one of clones MIAB1-198 or MIAB205-209 of Table 9, and a LCDR3 from any one of clones MIAB1-198 or MIAB205-209 of Table 9.


In some embodiments, the amino acid residues of the CDRs shown above contain mutations. In some embodiments, the CDRs contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions or mutations. In some embodiments, the substitution is a conservative substitution.


In some embodiments, the molecule comprises an antibody that binds to MAdCAM. In some embodiments, the antibody comprises (i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of any of the CDR1 sequences set forth in Table 6, Table 7, or Table 9; the heavy chain CDR2 has the amino acid sequence of any of the CDR2 sequences set forth in Table 6, Table 7, or Table 9, and the heavy chain CDR3 has the amino acid sequence of any of the CDR3 sequences set forth in Table 6, Table 7, or Table 9; or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of any of the LCDR1 sequences set forth in Table 6, Table 7, or Table 9; the light chain LCDR2 has the amino acid sequence of any of the LCDR2 sequences set forth in Table 6, Table 7, or Table 9, and the light chain CDR3 has the amino acid sequence of any of the LCDR3 sequences set forth in Table 6, Table 7, or Table 9, or variants of any of the foregoing.


In some embodiments, the antibody comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1, CDR2, and CDR3 sequences have the amino acid sequence as set forth in Antibody 6 of Table 6 or Antibody 6 of Table 7, or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1, CDR2, and CDR3 sequences have the amino acid sequence as set forth sequence as set forth in Antibody 6 of Table 6 or Antibody 6 of Table 7, or variants of any of the foregoing.


In some embodiments, the antibody comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1, CDR2, and CDR3 sequences have the amino acid sequence as set forth in Antibody 59 of Table 6 or Antibody 75 of Table 7, or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1, CDR2, and CDR3 sequences have the amino acid sequence as set forth sequence as set forth in Antibody 59 of Table 6 or Antibody 75 of Table 7, or variants of any of the foregoing.


In some embodiments, the antibody comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1, CDR2, and CDR3 sequences have the amino acid sequence as set forth in Antibody 63 of Table 6 or Antibody 79 of Table 7, or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1, CDR2, and CDR3 sequences have the amino acid sequence as set forth sequence as set forth in Antibody 63 of or Antibody 79 of Table 7, or variants of any of the foregoing.


In some embodiments, the antibody comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1, CDR2, and CDR3 sequences have the amino acid sequence as set forth in MIAB197 of Table 9, or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1, CDR2, and CDR3 sequences have the amino acid sequence as set forth sequence as set forth in MIAB197 of Table 9, or variants of any of the foregoing.


In some embodiments, the antibody comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1, CDR2, and CDR3 sequences have the amino acid sequence as set forth in MIAB126 of Table 9, or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1, CDR2, and CDR3 sequences have the amino acid sequence as set forth sequence as set forth in MIAB126 of Table 9, or variants of any of the foregoing.


These are non-limiting illustrative examples and the antibodies can have the CDRs as set forth in the tables provided herein and are explicitly referenced without writing out the previous paragraphs for each CDR set.


In some embodiments, the MAdCAM antibody comprises a VH and VL(VK) chain as provided herein, such as those listed in the Table 7, MAdCAM Antibody CDR Table 1, and Table 9. In some embodiments, the VH peptide comprises a sequence of SEQ ID NO: 414, 591, 599, 880, or 1387. In some embodiments, the VL chain comprises a sequence of 415, 592, 600, 663, or 1363. In some embodiments, the antibody comprises a VH of SEQ ID NO: 414 and a VL of SEQ ID NO: 415. In some embodiments, the antibody comprises a VH of SEQ ID NO: 591 and a VL of SEQ ID NO: 592. In some embodiments, the antibody comprises a VH of SEQ ID NO: 599 and a VL of SEQ ID NO: 600. In some embodiments, the antibody comprises a VH of SEQ ID NO: 880 and a VL of SEQ ID NO: 663. In some embodiments, the antibody comprises a VH of SEQ ID NO: 1387 and a VL of SEQ ID NO: 1363. The VH and VL can also be in a scFv format as illustrated in the Table 6, Table 11, Table 12, and Table 14. The VH and VL can also be in a Fab format as illustrated in the Table 9.


In some embodiments, a therapeutic is provided comprising one or more of the following polypeptides:













SEQ ID NO:
Sequence
















620
EVQLLESGGGLVQPGGSLRLSCAASGFTFNNYAFHWVRQAPGKGLEWVSRINSYGTSTTYADSVKGRF



TISRDNSKNTLYLQMNSLRAEDTAVYYCAREGPVAGYWYFDLWGQGTLVTVSSASTKGPSVFPLAPSS



KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH



EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI



SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF



FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSAPTSSSTKKTQLQLEHLLLDL



QMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISDI



NVIVLELKGSETTFMCEYADETATIVEFINRWITFSQSIISTLT





621
DIQMTQSPSSLSASVGDRVTITCRASQIIGTNLAWYQQKPGKAPKLLIYGASSLQSGVPSRFSGSGSG



TDFTLTISSLQPEDFATYYCQQSYRLPFTFGQGTKVEIKRRTVAAPSVFIFPPSDEQLKSGTASVVCL



LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS



PVTKSFNRGEC





622
EVQLLESGGGLVQPGGSLRLSCAASGFTFSDFWMHWVRQAPGKGLEWISYISGDSGYTNYADSVKGRF



TISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPYYYYMDVWGKGTTVTVSSASTKGPSVFPLAPSSKS



TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV



NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED



PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK



AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL



YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSAPTSSSTKKTQLQLEHLLLDLQM



ILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISDINV



IVLELKGSETTFMCEYADETATIVEFINRWITFSQSIISTLT





623
DIQMTQSPSSLSASVGDRVTITCRASQSVSRSLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG



TDFTLTISSLQPEDFATYYCQQYKSYPVTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL



NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP



VTKSFNRGEC





624
EVQLLESGGGLVKPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVASITSSSAFIDYAASVKGRF



TISRDDSKNTLYLQMNSLKTEDTAVYYCARERVDWNSYFDLWGRGTLVTVSSASTKGPSVFPLAPSSK



STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN



VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE



DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS



KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF



LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSAPTSSSTKKTQLQLEHLLLDLQ



MILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISDIN



VIVLELKGSETTFMCEYADETATIVEFINRWITFSQSIISTLT





625
EIVMTQSPATLSVSPGERATLSCRASQGISNSYLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGS



GTEFTLTISSLQSEDFAVYYCQQYYTYPPTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCL



LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS



PVTKSFNRGEC









In some embodiments, the polypeptide comprises one peptide of SEQ ID NO: 620, 622, or 624 and a second peptide of SEQ ID NO: 621, 623, or 625. In some embodiments, a polypeptide is provided comprising a first peptide of SEQ ID NO: 620 and a second peptide comprising a sequence of SEQ ID NO: 621. In some embodiments, a polypeptide is provided comprising a first peptide of SEQ ID NO: 620 and a second peptide comprising a sequence of SEQ ID NO: 623. In some embodiments, a polypeptide is provided comprising a first peptide of SEQ ID NO: 620 and a second peptide comprising a sequence of SEQ ID NO: 625. In some embodiments, a polypeptide is provided comprising a first peptide of SEQ ID NO: 622 and a second peptide comprising a sequence of SEQ ID NO: 621. In some embodiments, a polypeptide is provided comprising a first peptide of SEQ ID NO: 622 and a second peptide comprising a sequence of SEQ ID NO: 623. In some embodiments, a polypeptide is provided comprising a first peptide of SEQ ID NO: 622 and a second peptide comprising a sequence of SEQ ID NO: 625. In some embodiments, a polypeptide is provided comprising a first peptide of SEQ ID NO: 624 and a second peptide comprising a sequence of SEQ ID NO: 621. In some embodiments, a polypeptide is provided comprising a first peptide of SEQ ID NO: 624 and a second peptide comprising a sequence of SEQ ID NO: 623. In some embodiments, a polypeptide is provided comprising a first peptide of SEQ ID NO: 624 and a second peptide comprising a sequence of SEQ ID NO: 625.


In some embodiments, the therapeutic comprises a MAdCAM IgG wherein the IL-2 mutein is fused to the C-terminus of the IgG heavy chain, and is selected from one or more of the following sequences:















TABLE 10








Fc-IL-








2M







IgG1 Constant
Linker





Ab
VH Seq
Domains Seq
Seq
IL-2M Seq
VL Seq
CK Seq







MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


1
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



AREPVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYTYPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 662)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







663)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


2
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYTYPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







663)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


3
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDNWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYTYPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 665)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







663)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


4
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTLDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDNWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYTYPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 666)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







663)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


5
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VGSYLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTRVT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YTYPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


667)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


6
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PRKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVLWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YERWPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 668)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







669)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


7
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRACQG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYTYPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







670)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


8
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VGSYLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASARAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YTYPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


671)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


9
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTLDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYTYPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 672)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







663)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


10
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYKYPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







673)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


11
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNNYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYTYPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







674)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


12
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRACPG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYTYPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







675)



MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


13
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQN
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNNNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DATTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVLWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YHWPQTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 676)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


677)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


14
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQN
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNNNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DATTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YHWPQTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


677)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


15
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQN
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNNNYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YDATTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVLWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYHWPQT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 676)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







678)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


16
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNNNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DATTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVLWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YHWPQTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 676)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


679)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


17
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQN
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
INNNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DATTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVLWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YHWPQTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 676)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


680)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


18
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQN
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSNNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DATTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVLWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YHWPQTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 676)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


681)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


19
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQN
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNNSLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DATTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVLWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YHWPQTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 676)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


682)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


20
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQN
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNNNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GATTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVLWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YHWPQTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 676)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


683)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


21
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQN
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNNNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVLWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YHWPQTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 676)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


684)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


22
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQN
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNNNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DATTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVLWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YTWPQTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 676)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


685)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


23
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQN
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNNNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DATTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVLWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YHYPQTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 676)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


686)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


24
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQN
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNNNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DATTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVLWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YHWPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 676)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


687)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


25
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFIFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSNNLVW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVDWF
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
SHWPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 688)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


689)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


26
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VYSNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
RASTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
HIWPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


690)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


27
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFAFSNF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VTSDLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TITSSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TDYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASSRAM
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYKA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFNLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
STWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 691)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


692)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


28
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSSF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



ALSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VTRNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SISSSGSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



GSTNYADS
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GESTRAT
GNSQESV



VKGRFTIS
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



RDNSKNTL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



YLQMNSLR
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



AEDTAVYY
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



CIRERVDW
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



NSYFDLWG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YNWPPSF
QGLSSPV



QGTLVTVS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



S (SEQ
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



ID NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



693)
NO: 44)


694)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


29
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFNDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSNTLAW
LNNFYPR



PGKGLEWA
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SISSSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



IDYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GTSNRAA
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



REKVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YTTPLTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 695)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


696)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


30
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VISNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISTSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYVDSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASTGAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
NNRPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 697)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


698)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


31
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGLTFSSH
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VDNNLAW
LNNFYPR



PGKGLEWA
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AITGSGGN
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASTRDT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERSDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLHGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
NYWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 699)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


700)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


32
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DVSTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVDWW
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
SLWPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 701)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


702)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


33
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTLSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASRS
TASVVCL



GMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSNLAW
LNNFYPR



PGKGLEWA
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SITGSGDT
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



SYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DAFTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDRWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
DTWPETF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 703)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


704)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


34
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



VMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSVNLAW
LNNFYPR



PGKGLEWA
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SISYSGGF
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



IYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DVSIRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVMWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
TTWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 705)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


706)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


35
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNNYLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DTSSRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



NRERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
HSWPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 707)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


708)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


36
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFIFSDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ITTNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYTDSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
SASTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



REMVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YDWPFTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 709)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


710)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


37
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



AQERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYTYPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 711)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







663)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


38
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFRNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
IGNNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SISSSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DVSTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDYNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KHWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 712)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


713)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


39
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTLRNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSNNVAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TSYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
ASSTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCD
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
NTWPFTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 714)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


715)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


40
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMNWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
FSSNLAW
LNNFYPR



PGKGLEWF
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



GISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



PYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASTRST
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVLWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YDWPITF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 716)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


717)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


41
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



ALSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
IRNNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TISGSGGN
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASSRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCE
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YIWPLTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 718)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


719)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


42
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSSS
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSDLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYTDSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASTTAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



REVVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
STWPLTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 720)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


721)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


43
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSTH
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSNDLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TISGSGAT
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TEYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTRVT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RETVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
NHWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 722)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


723)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


44
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQN
TASVVCL



PMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VRSNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SISWSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



IDYDDSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTTAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



REHVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
DTWPLTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 724)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


725
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


45
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFRDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSLLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



IDYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDAWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
GTWPQTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 726)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


727)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


46
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTLSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
FSSNLAW
LNNFYPR



PGKGLEWA
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



GISGSGGR
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DVSTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RIRVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
NHWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 728)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


729)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


47
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFNNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQT
TASVVCL



AMNWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGSGGR
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



THYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DAFTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERLDINS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
GTWPLTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 730)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


731)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


48
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VYSNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASTTAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVDWL
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
HNWPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 732)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


733)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


49
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGLTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQG
TASVVCL



AMNWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



AISGTGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YYASTRA
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



RERVDWNN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YSDWPPT
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 734)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







735)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


50
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFTTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



ALSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VGTDLAW
LNNFYPR



PGKGLEWA
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGSGSN
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASIRAI
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNV
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YKWPETF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 736)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


737)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


51
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGLTFSNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMAWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSNLAW
LNNFYPR



PGKGLEWA
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISSSSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TFYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DVSIRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



REHVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YVWPDTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 738)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


739)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


52
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFAFSNH
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMNWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSTNFAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISSSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



IDYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASSRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVIWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YKWPPLF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 740)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


741)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


53
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFTNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMTWVKQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SITGSGGN
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TDYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASSRVT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERDDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KTLPHTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 742)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


743)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


54
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFTSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMNWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VGTNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TDYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYFA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YDIPETF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 744)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


745)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


55
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFAFSTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSYLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYHADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASTWAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YNDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
TTWPRTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 746)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


747)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


56
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQT
TASVVCL



AMDWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VGSNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



GIGGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASNRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFYLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KIWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 748)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


749)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


57
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSNF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMNWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VTSKLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



VITGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
SASTRAA
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



REMVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
SHWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 750)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


751)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


58
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VKSNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISTSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



LERADWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
DTWPLTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 752)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


753)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


59
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFSFSIY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
IGSSLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGSGTS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DTSIRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCW
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
SHWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 754)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


755)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


60
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFSFSGY
GLYSLSSVVTVPSSSLGTQT
23
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ITSNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SITSSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GTSSRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDRWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YIWPLTE
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 756)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


757)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


61
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSRY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



GMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISDNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGTGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTRAP
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYHA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
DIWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 758)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


759)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


62
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSSF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



ALSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
LSTNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TISGSGVN
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
RASIRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLLGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
DTWPLTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 760)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


761)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


63
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFAFSNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSDLVW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SISSSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TDYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASTTAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYTA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YSWPKTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 762)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


763)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


64
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMGWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VRSNLVW
LNNFYPR



PGKGLEWC
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISSSSAT
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TNYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
SASIRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



REHVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFVLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
IRWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 764)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


765)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


65
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFTSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



TMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSDKLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SITSSGGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TSYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
EASTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNK
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQF
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YTWPWTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 767)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


768)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


66
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGLTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMNWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
GAGNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



GISGSGGN
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



THYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DGSTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYI
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLEGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
NHWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 769)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


770)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


67
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTLSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



GMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VFSNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



GISGSGVN
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
SASTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YDDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
STWPQTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 771)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


772)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


68
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFSFSTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMAWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSNTLAW
LNNFYPR



PGKGLEWA
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SITGSGGL
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



ISYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
ASSTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERDDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
TTWPYTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 773)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


774)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


69
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



VMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSTYLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



GISSSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASFRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



REHVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
TTWPQTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 775)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


776)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


70
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSIY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRTSQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSNLAW
LNNFYPR



PGKGLEWA
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISSSSGR
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
ASSTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



WFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
SEWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 777)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


778)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


71
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCTASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TSYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
TASIRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



SERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YSWPKTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 779)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


780)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


72
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFIFSNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



GMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VRGNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SISGGGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASRRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVTWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YRWPLTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 781)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


782)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


73
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFAFNNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VRSSLSW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



GISGSGGT
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
TASIRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYNA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KNYPLTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 783)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


784)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


74
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFNNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMNWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AVSGSGAS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GSFTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCH
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
SNWPPLF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 785)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


786)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


75
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFGDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSNTLAW
LNNFYPR



PGKGLEWA
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TVSSASAL
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



IYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DATTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCK
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YDWPITF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 787)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


788)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


76
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



VMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNDNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



GISGSGTN
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASTRVT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



QFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
ERWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 789)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


790)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


77
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGLTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSNVAW
LNNFYPR



PGKGLEWA
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SITGSGSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TFYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GGSTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDDWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
HLWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 791)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


792)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


78
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASRS
TASVVCL



ATSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSTNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AVSGSGAS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GTSSRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCR
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
ERWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 793)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


794)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


79
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASHS
TASVVCL



GMNWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSKLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



GISGSGGN
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TFYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
EASTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



EERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YHWPRTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 795)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


796)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


80
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



VMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VRDNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGSGRS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTRVT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDNNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
NHWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 797)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


798)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


81
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFTTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



ALSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSYLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYSADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
RASTRAA
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYWA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
SDWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 799)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


800)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


82
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFAFSSS
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISTKLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ALSGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYSADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCHQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YTWPYTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 801)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


802)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


83
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFIFTDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASES
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VRSNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AITGSGGT
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTRTT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



REGVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KTLPHTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 803)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


804)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


84
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSRLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TISGSGRS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASTSAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCT
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQHY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YNWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 805)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


806)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


85
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTTAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERRDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
HLWPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 807)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


808)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


86
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFNNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNDNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TITSSGAS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TFYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASTRVT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDKNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KTWPLTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 809)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


810)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


87
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGLTFSSS
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRTSQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AIRGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GISTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCT
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KTWPWTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 811)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


812)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


88
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFIFSNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



GMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VRGNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TISSSGAF
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASTRAN
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYNA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YRWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 813)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


814)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


89
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSYLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SISGSSGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



IFYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASNRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDEWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
STWPQTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 815)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


816)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


90
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFSFSTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSNVAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



GISGSGGN
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



THYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



NFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YDYPRTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 817)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


818)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


91
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTSSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMGWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSDKLAW
LNNFYPR



PGKGLEWA
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SISYSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TDYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASSRAA
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYI
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFGLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YDWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 819)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


820)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


92
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFIFRNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASHS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AITGSGGT
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TDYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GAATRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWYS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
NNRPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 821)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


822)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


93
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFNFY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCTASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSNLAW
LNNFYPR



PGKGLEWA
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISSSSGR
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DATTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



REDVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
TTWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 823)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


824)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


94
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFGNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISTSLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TITSSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TDYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASTRAG
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDENS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
DDWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 825)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


826)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


95
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTLSNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSNVAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGSGGR
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASSRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YNDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KTLPHTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 827)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


828)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


96
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMIWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISGNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISSSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



IDYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTRAA
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDANS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
HNWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 829)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


830)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


97
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFSFSNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TITSSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TDYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
SASARAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KTLPHTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 831)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


832)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


98
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTLRNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VGNNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



GISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



PYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASNRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RSRVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFQLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
DDWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 833)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


834)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


99
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSSF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



GMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VGSNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGGGGT
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DTSSRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWKS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KTWPFTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 835)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


836)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


100
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFTTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
IGTNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYVDSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
SASSRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RVRVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YHWPQTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 837)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


838)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


101
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFGSF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSTYLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



VISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



THYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASNRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
DTWPYTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 839)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


840)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


102
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFTDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRTSQS
TASVVCL



AMNWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSDLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TISGSGAT
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GPSTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



REDVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KTWPQTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 841)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


626)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


103
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMNWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSTDLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SISGSGGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASTRVT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERMDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
NTAPLTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 842)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


843)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


104
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFSFGSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISGNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TISGSGAG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GAATRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YIDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YKWPITF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 844)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


845)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


105
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSSF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



PMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNNNLAW
LNNFYPR



PGKDLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SISGSGAS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



IYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTRAI
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



REEVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
DTWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 846)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


847)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


106
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VGTDLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASTRAA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YTYPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


848)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


107
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFIFSDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VDTNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



GISGSSGT
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



IYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASIRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



YERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KTLPHTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 849)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


850)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


108
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFGSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VGSDLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



THYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GVSTRAA
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWGS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YKWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 851)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


852)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


109
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRACQG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRG
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYTYPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







853)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


110
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
IDTNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGSSGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
VASTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERMDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YSWPKTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 854)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


855)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


111
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMNWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSNIAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SITGSGVS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TDYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASIRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RESVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
NKWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 856)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


857)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


112
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFRTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSYKLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



IITGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASIRDT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



MERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
DTWPLTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 858)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


859)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


113
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASES
TASVVCL



SMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISSSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



IDYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



REMVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFWLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
TTWPYTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 860)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


861)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


114
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFRSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMNWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSTYLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



VISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTTAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
DTWPFTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 862)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


863)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


115
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSHLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASSRAS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
NIWPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


864)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


116
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASRS
TASVVCL



AMNWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGTGGT
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GGSTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



WFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YVWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 865)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


866)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


117
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFSFSTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRAGQS
TASVVCL



AMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSNNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



TISGSGVN
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASPRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



EFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
DTSPLTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 867)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44


868)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


118
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFSFGSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMGWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VTRNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



IISSSGAF
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASSRAA
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERLDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YNWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 869)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


870)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


119
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFSFSTY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VTTNLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGGGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TFYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
GASTRAN
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



TFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
HKWPPTF
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 871)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


872)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


120
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQN
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNNNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DATTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



AREPVLWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YHWPQTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 873)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


677)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


121
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFIFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRACPS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSNNLVW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVDWF
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
SHWPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 688)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


874)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


122
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFIFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRACPS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSNNYLV
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YDASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVDWE
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YSHWPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 688)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







875)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


123
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFIFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSNNYLV
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YDASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVDWF
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YSHWPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 688)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







876)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


124
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSTD
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VNNKLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



AISGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYSADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASTRAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RARVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YNDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
STWPITE
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 877)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


878)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


125
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQG
TASVVCL



AISWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



DISGSGGT
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRA
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



RERVDWNS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYTYPPT
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 879)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







663)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


126
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVDWM
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYTYPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 880)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







663)






MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


127
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFSNY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



GMTWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VTSKLAW
LNNFYPR



PGKGLEWS
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



SIGGSGGS
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



TYYADSVK
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTGAT
GNSQESV



GRFTISRD
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



NSKNTLYL
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



QMNSLRAE
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



DTAVYYCA
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



RKRVDWIS
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



YFDLWGQG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YDIPETE
QGLSSPV



TLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 881)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


882)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


128
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPNYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1346)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


128A
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPQYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1348)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


129
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPGYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1349)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


130
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



QMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1350)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


131
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



GMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1351)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


132
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSNF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1352)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


133
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1353)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


134
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSAF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1354)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


135
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSNNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1355)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


136
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1356)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


137
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1357)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


138
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1358)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


139
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSYLNW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQS
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YSTPRTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1360)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


140
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



AMSWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSYLNW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQS
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YSTPRTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1358)
NO: 44)


1360)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


141
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSYLNW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1361)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


142
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQS
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YSTPRTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1362)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


143
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


144
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


145
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1363)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


146
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
2KSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1364)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


147
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRYLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1365)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


148
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLNW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1366)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


149
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1367)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


150
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISRYLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1368)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


151
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISRSLNW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1369)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


152
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSYLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1370)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


153
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSSLNW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1371)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


154
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRYLNW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1372)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


155
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSSLNW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1373)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


156
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDE
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISRYLNW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1374)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


157
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSYLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1375)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


158
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSYLNW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1376)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


159
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGESG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1377)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


160
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTQYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1378)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


161
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DQSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1379)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


162
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLGW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1380)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


163
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLDW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1381)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


164
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLTW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1382)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


165
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLSW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1383)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


166
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLEW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1384)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


167
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLKW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1385)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


168
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLLW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1386)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


169
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1387)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


170
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



WMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1388)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


171
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPSYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1389)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


172
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPTYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1390)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


173
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


174
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1391)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


175
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1392)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


176
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1393)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


177
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1357)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


178
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1394)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


179
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISRYLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1395)
NO: 44)


1368)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


180
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1395)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


181
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEç
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISRYLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1395)
NO: 44)


1368)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


182
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISRSLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1395)
NO: 44)


1363)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


183
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSSLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1395)
NO: 44)


1364)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


184
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSSLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1395)
NO: 44)


1367)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


185
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1396)
NO: 44)


1363)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


186
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1396)
NO: 44)


1364)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


187
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1396)
NO: 44)


1367)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


188
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISRSLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1397)
NO: 44)


1363)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


189
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSSLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1397)
NO: 44)


1364)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


190
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSSLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1397)
NO: 44)


1367)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


191
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISRSLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1398)
NO: 44)


1363)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


192
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSSLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1398)
NO: 44)


1364)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


193
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSSY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSSLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SAISGSGG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



STYYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1398)
NO: 44)


1367)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


194
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1387)
NO: 44)


1363)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


195
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSSSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1387)
NO: 44)


1364)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


196
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISSSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1387)
NO: 44)


1367)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


197
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1387)
NO: 44)


1363)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


198
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



IMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1387)
NO: 44)


592)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


205
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VYSNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
RASTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVDWF
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
HIWPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1533)
NO: 44)


690)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


206
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VYSNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
RASTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVDWY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
HIWPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO:
QKSLSLSPG (SEQ ID


ID NO:
ID NO:



1534)
NO: 44)


690)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


207
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VYSNLVW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
RASTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
HIWPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1535)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


208
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VYSNLAW
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGQ
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APRLLIY
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
DASTRAT
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GIPARFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTE
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQSEDFA
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
VYYCQQY
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
HIWPPTF
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


1536)
45)





MIAB
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


209
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQS
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VYSNYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YRASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGQ
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YSHWPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGQGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


EIK
EC (SEQ



NO: 664)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







1537)






PRNT
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
EIVMTQS
RTVAAPS


2
GGLVKPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PATLSVS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
PGERATL
DEQLKSG



SGFTFDDY
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
SCRASQG
TASVVCL



AMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
ISNSYLA
LNNFYPR



PGKGLEWV
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
WYQQKPG
EAKVQWK



ASITSSSA
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
QAPRLLI
VDNALQS



FIDYAASV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
YGASTRA
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
TGIPARF
TEQDSKD



DDSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
SGSGSGT
STYSLSS



LQMNSLKT
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
EFTLTIS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
SLQSEDF
DYEKHKV



ARERVDWN
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
AVYYCQQ
YACEVTH



SYFDLWGR
AVEWESNGQPENNYKTTPPV

TLT (SEQ
YYTYPPT
QGLSSPV



GTLVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
FGPGTKV
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


DIK
EC (SEQ



NO: 599)
QKSLSLSPG (SEQ ID


(SEQ ID
ID NO:




NO: 44)


NO:
45)







600)






PRNT
EVQLLESG
ASTKGPSVFPLAPSSKSTSG
GGGGS
APTSSSTKKT
DIQMTQS
RTVAAPS


1
GGLVQPGG
GTAALGCLVKDYFPEPVTVS
(SEQ
QLQLEHLLLD
PSSLSAS
VFIFPPS



SLRLSCAA
WNSGALTSGVHTFPAVLQSS
ID NO:
LQMILNGINN
VGDRVTI
DEQLKSG



SGFTFSDF
GLYSLSSVVTVPSSSLGTQT
23)
YKNPKLTRML
TCRASQS
TASVVCL



WMHWVRQA
YICNVNHKPSNTKVDKKVEP

TFKFYMPKKA
VSRSLAW
LNNFYPR



PGKGLEWI
KSCDKTHTCPPCPAPEAAGA

TELKHLQCLE
YQQKPGK
EAKVQWK



SYISGDSG
PSVFLFPPKPKDTLMISRTP

EELKPLEEAL
APKLLIY
VDNALQS



YTNYADSV
EVTCVVVDVSHEDPEVKFNW

NLAPSKNFHL
AASSLQS
GNSQESV



KGRFTISR
YVDGVEVHNAKTKPREEQYN

RPRDLISDIN
GVPSRFS
TEQDSKD



DNSKNTLY
STYRVVSVLTVLHQDWLNGK

VIVLELKGSE
GSGSGTD
STYSLSS



LQMNSLRA
EYKCKVSNKALPAPIEKTIS

TTFMCEYADE
FTLTISS
TLTLSKA



EDTAVYYC
KAKGQPREPQVYTLPPSREE

TATIVEFINR
LQPEDFA
DYEKHKV



ARDRPYYY
MTKNQVSLTCLVKGFYPSDI

WITFSQSIIS
TYYCQQY
YACEVTH



YMDVWGKG
AVEWESNGQPENNYKTTPPV

TLT (SEQ
KSYPVTF
QGLSSPV



TTVTVSS
LDSDGSFFLYSKLTVDKSRW

ID NO: 41)
GQGTKVE
TKSFNRG



(SEQ ID
QQGNVFSCSVMHEALHNHYT


IK (SEQ
EC (SEQ



NO: 591)
QKSLSLSPG (SEQ ID


ID NO:
ID NO:




NO: 44)


592)
45)









In some embodiments, the therapeutic comprises one or more sequences, or a combination thereof, selected from the Table 10. In some embodiments, the therapeutic comprises the peptides of SEQ ID NOs: 1387, 44, 23, 41, 1363, and 45.


In additional embodiments, the MAdCAM antibody comprises an IL-2 mutein fused to the N-terminus of an Fc heavy chain, wherein the Fc is further fused at its C-terminus to a MAdCAM scFv, and has one or more of the sequences as set forth in the following table
















TABLE 11







IL-2M-









Fc



Intra





Linker

Fc-scFv
scFv VH
scFv
scFv VK


Ab
IL-2M Seq
Seq
Fc Domain Seq
Linker
Seq
Linker
Seq







MIAB199
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGS
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
(SEQ ID
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
NO: 23)
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKFNWYVDGVEV

DFWMHWVRQA
GS
SVSRSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY

PGKGLEWISY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWLNG

ISGDSGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYYMDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 591)

NO: 592)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB200
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGS
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
(SEQ ID
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKFNWYVDGVEV
NO:
DFWMHWVRQA
GS
SVSRSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY
619)
PGKGLEWISY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWLNG

ISGDSGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYYMDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 591)

NO: 592)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB201
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGSGGGG
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
S (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKFNWYVDGVEV
ID NO:
DFWMHWVRQA
GS
SVSRSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY
30)
PGKGLEWISY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWLNG

ISGDSGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYYMDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 591)

NO: 592)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB202
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGS
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
(SEQ ID
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
NO: 23)
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV

DFWMHWVRQA
GS
SVSRSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY

PGKGLEWISY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWLNG

ISGDSGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYYMDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 591)

NO: 592)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB203
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGS
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
(SEQ ID
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV
NO:
DFWMHWVRQA
GS
SVSRSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY
619)
PGKGLEWISY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWLNG

ISGDSGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYYMDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 591)

NO: 592)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB204
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGSGGGG
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
S (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV
ID NO:
DFWMHWVRQA
GS
SVSRSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY
30)
PGKGLEWISY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWLNG

ISGDSGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI

QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY
22)
GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYYMDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 591)

NO: 592)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB212
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGSGGGG
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
00 (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY
30)
PGKGLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWING

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDMDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1445)

NO: 1367)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB213
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGSGGGG
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
S (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY
30)
PGKGLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWING

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDIDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1477)

NO: 1367)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB214
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGSGGGG
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
S (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY
30)
PGKGLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDLDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1480)

NO: 1367)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB215
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGSGGGG
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
S (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY
30)
PGKCLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDMDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

CGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1542)

NO: 1543)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB216
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGSGGGG
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
S (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY
30)
PGKCLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDIDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

CGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1544)

NO: 1543)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB217
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGSGGGG
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
S (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY
30)
PGKCLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWING

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDLDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

CGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1545)

NO: 1543)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB218
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGSEGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GSEGGGS
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
E (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY
1546)
PGKGLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWING

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDMDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1445)

NO: 1367)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB219
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGSEGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GSEGGGS
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
E (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY
1546)
PGKGLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDIDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1477)

NO: 1367)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB220
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGSEGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GSEGGGS
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
E (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY
1546)
PGKGLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDLDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1480)

NO: 1367)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB221
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGSEGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GSEGGGS
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
E (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKENWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY
1546)
PGKCLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDMDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

CGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1542)

NO: 1543)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB222
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGSEGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GSEGGGS
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
E (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY
1546)
PGKCLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWING

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDIDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

CGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1544)

NO: 1543)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB223
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGSEGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GSEGGGS
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGS
ISRTPEVTCVVVDVSH
E (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
(SEQ
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
ID NO:
HNAKTKPREEQYNSTY
1546)
PGKCLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
30)
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL

KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDLDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

CGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1545)

NO: 1543)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB224
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGSGGGG
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
S (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY
30)
PGKGLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDMDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1445)

NO: 1367)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB225
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGSGGGG
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
S (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY
30)
PGKGLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDIDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1477)

NO: 1367)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB226
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGSGGGG
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
S (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY
30)
PGKGLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDLDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1480)

NO: 1367)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB227
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGSGGGG
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
S (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY
30)
PGKCLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI

QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDMDVWG
22)
YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

CGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1542)

NO: 1543)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB228
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGSGGGG
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
S (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY
30)
PGKCLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDIDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

CGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1544)

NO: 1543)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB229
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGGSGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GGSGGGG
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
S (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY
30)
PGKCLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDLDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

CGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1545)

NO: 1543)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB230
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGSEGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GSEGGGS
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
E (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY
1546)
PGKGLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWING

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDMDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1445)

NO: 1367)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB231
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGSEGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GSEGGGS
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
E (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY
1546)
PGKGLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDIDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1477)

NO: 1367)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB232
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGSEGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GSEGGGS
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
E (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY
1546)
PGKGLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDLDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

QGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1480)

NO: 1367)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB233
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGSEGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GSEGGGS
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
E (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY
1546)
PGKCLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWING

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDMDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

CGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1542)

NO: 1543)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB234
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGSEGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GSEGGGS
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
E (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY
1546)
PGKCLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWING

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDIDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

CGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1544)

NO: 1543)



ID NO: 41)

PG (SEQ ID NO:









21)









MIAB235
APTSSSTKKT
GGGGSG
DKTHTCPPCPAPEAAG
GGGSEGG
EVQLLESGGG
GGGGSG
DIQMTQSPS



QLQLEHLLLD
GGGSGG
APSVFLFPPKPKDTLM
GSEGGGS
LVQPGGSLRL
GGGSGG
SLSASVGDR



LQMILNGINN
GGSGGG
ISRTPEVTCVVVDVSH
E (SEQ
SCAASGFTFS
GGSGGG
VTITCRASQ



YKNPKLTRML
GS
EDPEVKFNWYVDGVEV
ID NO:
SYWMHWVRQA
GS
SISSSLAWY



TFKFYMPKKA
(SEQ
HNAKTKPREEQYNSTY
1546)
PGKCLEWVSY
(SEQ
QQKPGKAPK



TELKHLQCLE
ID NO:
RVVSVLTVLHQDWLNG

ISGSGGYTNY
ID NO:
LLIYAASSL



EELKPLEEAL
22)
KEYKCKVSNKALPAPI

ADSVKGRFTI
22)
QSGVPSRFS



NLAPSKNFHL

EKTISKAKGQPREPQV

SRDNSKNTLY

GSGSGTDFT



RPRDLISDIN

YTLPPSREEMTKNQVS

LQMNSLRAED

LTISSLQPE



VIVLELKGSE

LTCLVKGFYPSDIAVE

TAVYYCARDR

DFATYYCQQ



TTFMCEYADE

WESNGQPENNYKTTPP

PYYYDLDVWG

YKSYPVTFG



TATIVEFINR

VLDSDGSFFLYSKLTV

KGTTVTVSS

CGTKVEIK



WITFSQSIIS

DKSRWQQGNVFSCSVM

(SEQ ID

(SEQ ID



TLT (SEQ

HEALHNHYTQKSLSLS

NO: 1545)

NO: 1543)



ID NO: 41)

PG (SEQ ID NO:









21)









In some embodiments, the therapeutic comprises one or more sequences, or a combination thereof, selected from Table 11.


In some embodiments, the polypeptide is referred to as an antibody or antigen binding protein.


In some embodiments, as provided for herein, the MAdCAM antibody, or binding fragment thereof, is linked directly or indirectly to a PD-1 antibody or binding fragment thereof.


In some embodiments, as provided for herein, the MAdCAM antibody, or binding fragment thereof, is linked directly or indirectly to a IL-2 mutein or binding fragment thereof. The IL-2 mutein can be any mutein as provided for herein or other IL-2 muteins known to one of skill in the art.


In some embodiments, if the therapeutic compound comprises a Fc portion, the Fc domain, (portion) bears mutations to render the Fc region “effectorless,” that is unable to bind FcRs. The mutations that render Fc regions effectorless are known. In some embodiments, the mutations in the Fc region, which is according to the known numbering system, are selected from the group consisting of: K322A, L234A, L235A, G237A, L234F, L235 E, N297, P331S, or any combination thereof. In some embodiments, the Fc mutations comprises a mutation at L234 and/or L235 and/or G237. In some embodiments, the Fc mutations comprise L234A and/or L235A mutations, which can be referred to as LALA mutations. In some embodiments, the Fc mutations comprise L234A, L235A, and G237A mutations.


Disclosed herein are Linker Region polypeptides, therapeutic peptides, and nucleic acids encoding the polypeptides (e.g. therapeutic compounds), vectors comprising the nucleic acid sequences, and cells comprising the nucleic acids or vectors


Therapeutic compounds can comprise a plurality of specific targeting moieties. In some embodiments, the therapeutic compound comprises a plurality one specific targeting moiety, a plurality of copies of a donor specific targeting moiety or a plurality of tissue specific targeting moieties. In some embodiments, a therapeutic compound comprises a first and a second donor specific targeting moiety, e.g., a first donor specific targeting moiety specific for a first donor target and a second donor specific targeting moiety specific for a second donor target, e.g., wherein the first and second target are found on the same donor tissue. In some embodiments, the therapeutic compound comprises e.g., a first specific targeting moiety for a tissue specific target and a second specific targeting moiety for a second target, e.g., wherein the first and second target are found on the same or different target tissue.


In some embodiments, a therapeutic compound comprises a plurality of effector binding/modulating moieties each comprising an ICIM binding/modulating moiety, the number of ICIM binding/modulating moieties is sufficiently low that clustering of the ICIM binding/modulating moiety's ligand on immune cells (in the absence of target binding) is minimized, e.g., to avoid systemic agonizing of immune cells in the absence of binding of the therapeutic compound to target.


In some embodiments, the therapeutic compound has the formula from N-terminus to C-terminus:

    • A1—Linker A—A2—Linker B—A3
    • A3—Linker A—A2—Linker B—A1,


      wherein,
    • A1 and A3, each independently comprises an effector binding/modulating moiety, e.g., an WWI binding/modulating moiety, an IIC binding/modulating moiety, ICSM binding/modulating moiety, or an SM binding/modulating moiety; or a specific targeting moiety,
    • A2 comprises an Fc region or is absent; and
    • Linker A and Linker B, each are independent linkers.


In Some Embodiments:

    • A1 comprises an IL-2 mutein molecule,
    • A3 comprises a specific targeting moiety, e.g. anti-human MAdCAM Ab, such as a scFv,
    • A2 comprises an Fc region, and
    • Linker A and Linker B, each are independent linkers further comprising glycine/serine linkers.


In some embodiments, a polypeptide is provided, wherein the polypeptide comprises a peptide of the formula:


Ab-ConstantDomain-LinkerA-IL2 Mutein-LinkerB-FcRegion, wherein the Ab is a variable heavy chain domain that binds to MAdCAM, the Constant domain is an Ig constant domain such as IgG1, IgG2, IgG3, or IgG4, Linker A is a linker, such as those provided herein, and the IL2 Mutein is an IL-2 mutein, such as those provided for herein. In some embodiments, the variable heavy domain is a variable heavy chain domain as illustrated in Table 7. In some embodiments, the variable heavy chain domain comprises the variable heavy chain domain of Clone ID: 6, 75, or 79 of Table 7; MIAB126, MIAB197 of Table 9, or MIAB204 of Table 11. In some embodiments, the variable heavy chain domain comprises the CDRs of the heavy domain of 6, 75, or 79 of Table 7; MIAB126, or MIAB197 of Table 9. In some embodiments, the VH comprises a sequence of SEQ ID NO: 414, SEQ ID NO: 591, SEQ ID NO: 599, SEQ ID NO: 880, and SEQ ID NO: 1387.


In some embodiments, the ConstantDomain comprises a IgG1 constant domain, such as those provided for herein. In some embodiments, the constant domain comprises mutations to render the constant region “effectorless,” that is unable to bind FcRs. The mutations that render constant regions effectorless are known. In some embodiments, the mutations in the constant region, which is according to the known numbering system, are selected from the group consisting of: K322A, L234A, L235A, G237A, L234F, L235 E, N297, P331S, or any combination thereof. In some embodiments, the constant region mutations comprises a mutation at L234 and/or L235 and/or G237. In some embodiments, the constant region mutations comprise L234A and/or L235A mutations, which can be referred to as LALA mutations. In some embodiments, the constant region mutations comprise L234A, L235A, and G237A mutations. In some embodiments, the ConstantDomain comprises SEQ ID NO: 44.


In some embodiments, the MAdCAM antibody is selected from the following table:

















TABLE 15





Clone
scFv VH
scFV VK








(scFv)
Seq
Seq
HCDR1
HCDR2
HCDR3
LCDRI
LCDR2
LCDR3







MIAB212
EVQLLESGGG
DIQMTQSPSS
FTFSS
SYISG
CARDR
RASQS
SSLQS
QQYKS



LVQPGGSLRL
LSASVGDRVT
YWMH
SGGYT
PYYYD
ISSSL
(SEQ
YPVT



SCAASGFTFS
ITCRASQSIS
(SEQ
NYA
MDVW
A
ID
(SEQ



SYWMHWVRQA
SSLAWYQQKP
ID
(SEQ
(SEQ
(SEQ
NO:
ID



PGKGLEWVSY
GKAPKLLIYA
NO:
ID
ID
ID
1497)
NO:



ISGSGGYTNY
ASSLQSGVPS
1499)
NO:
NO:
NO:

1498)



ADSVKGRFTI
RFSGSGSGTD

1506)
1507)
1502)





SRDNSKNTLY
FTLTISSLQP









LQMNSLRAED
EDFATYYCQQ









TAVYYCARDR
YKSYPVTFGQ









PYYYDMDVWG
GTKVEIK









KGTTVTVSS
(SEQ ID









(SEQ ID
NO: 1367)









NO: 1445)












MIAB213
EVQLLESGGG
DIQMTQSPSS
FTFSS
SYISG
CARDR
RASQS
SSLQS
QQYKS



LVQPGGSLRL
LSASVGDRVT
YWMH
SGGYT
PYYYD
ISSSL
(SEQ
YPVT



SCAASGFTFS
ITCRASQSIS
(SEQ
NYA
IDVW
A
ID
(SEQ



SYWMHWVRQA
SSLAWYQQKP
ID
(SEQ
(SEQ
(SEQ
NO:
ID



PGKGLEWVSY
GKAPKLLIYA
NO:
ID
ID
ID
1497)
NO:



ISGSGGYTNY
ASSLQSGVPS
1499)
NO:
NO:
NO:

1498)



ADSVKGRFTI
RFSGSGSGTD

1506)
1531)
1502)





SRDNSKNTLY
FTLTISSLQP









LQMNSLRAED
EDFATYYCQQ









TAVYYCARDR
YKSYPVTFGQ









PYYYDIDVWG
GTKVEIK









KGTTVTVSS
(SEQ ID









(SEQ ID
NO: 1367)









NO: 1477)












MIAB214
EVQLLESGGG
DIQMTQSPSS
FTFSS
SYISG
CARDR
RASQS
SSLQS
QQYKS



LVQPGGSLRL
LSASVGDRVT
YWMH
SGGYT
PYYYD
ISSSL
(SEQ
YPVT



SCAASGFTFS
ITCRASQSIS
(SEQ
NYA
LDVW
A
ID
(SEQ



SYWMHWVRQA
SSLAWYQQKP
ID
(SEQ
(SEQ
(SEQ
NO:
ID



PGKGLEWVSY
GKAPKLLIYA
NO:
ID
ID
ID
1497)
NO:



ISGSGGYTNY
ASSLQSGVPS
1499)
NO:
NO:
NO:

1498)



ADSVKGRFTI
RFSGSGSGTD

1506)
1532)
1502)





SRDNSKNTLY
FTLTISSLQP









LQMNSLRAED
EDFATYYCQQ









TAVYYCARDR
YKSYPVTFGQ









PYYYDLDVWG
GTKVEIK









KGTTVTVSS
(SEQ ID









(SEQ ID
NO: 1367)









NO: 1480)









Although the antibodies described in Table 15 or throughout the present application may be referenced in a scFv format, the antibodies can also be made in other formats as provided for herein.


In some embodiments, the variable heavy chain domain comprises a first CDR of SEQ ID NO: 90, a second CDR of SEQ ID NO: 91, and a third CDR of SEQ ID NO: 92. In some embodiments, the variable heavy chain domain comprises a first CDR of SEQ ID NO: 359, a second CDR of SEQ ID NO: 170, and a third CDR of SEQ ID NO: 360. In some embodiments, the variable heavy chain domain comprises a first CDR of SEQ ID NO: 135, a second CDR of SEQ ID NO: 381, and a third CDR of SEQ ID NO: 382. In some embodiments, the variable heavy chain domain comprises a first CDR of SEQ ID NO: 135, a second CDR of SEQ ID NO: 381, and a third CDR of SEQ ID NO: 1342. In some embodiments, the variable heavy chain domain comprises a first CDR of SEQ ID NO: 359, a second CDR of SEQ ID NO: 170, and a third CDR of SEQ ID NO: 1431. These are illustrative only and the CDR sets as set forth herein and in the tables are also provided.


In some embodiments, the LinkerA is a glycine/serine linker, which can be any glycine/serine linker provided for herein. In some embodiments, the linker comprises a sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22), or GGGGSGGGGSGGGGS (SEQ ID NO: 30). These are non-limiting examples and the linker can have varying number of GGGGS (SEQ ID NO: 23) or GGGGA repeats (SEQ ID NO: 29), or a mixture of the two. In some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the GGGGS (SEQ ID NO: 23) and/or GGGGA repeats (SEQ ID NO: 29) (repeats disclosed as SEQ ID NOS 1550-1551, respectively). In some embodiments, the linker is 10 amino acids in length. In some embodiments, the linker is 5 amino acids in length. In some embodiments, the linker is 15 amino acids in length. In some embodiments, the linker is 20 amino acids in length. In some embodiments, the linker is 25 amino acids in length. In some embodiments, the linker is 30 amino acids in length. In some embodiments, the linker is 35 amino acids in length. In some embodiments, the linker is from 5-50 amino acids in length.


In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 31. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 32. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 33. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 34. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 35. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 36. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 37. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 38. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 39. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 40. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 41. In some embodiments, the IL-2 mutein further comprises a T3A substitution (mutation). In some embodiments, the Fc Region comprises a peptide having a sequence of SEQ ID NO: 21. In some embodiments, the Fc Region comprises a peptide having a sequence of SEQ ID NO: 28. In some embodiments, the C-terminus of the Fc Region is linked to the N-terminus or the C-terminus of the variable heavy chain or IL-2 mutein. In some embodiments, the linker linking the Fc Region to the variable heavy chain or the IL-2 mutein is a glycine/serine or a glycine/alanine linker. In some embodiments, the linker linking the Fc region to the C- or N-terminus of the variable heavy chain or IL-2 mutein is a glycine/serine linker, which can be a sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22) or GGGGSGGGGSGGGGS (SEQ ID NO: These are non-limiting examples and the linker can have varying number of GGGGS (SEQ ID NO: 23) or GGGGA repeats (SEQ ID NO: 29), or a mixture of the two. In some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the GGGGS (SEQ ID NO: 23) and/or GGGGA repeats (SEQ ID NO: 29) (repeats disclosed as SEQ ID NOS 1550-1551, respectively). In some embodiments, the linker is 10 amino acids in length. In some embodiments, the linker is 5 amino acids in length. In some embodiments, the linker is 15 amino acids in length. In some embodiments, the linker is 20 amino acids in length. In some embodiments, the linker is 25 amino acids in length. In some embodiments, the linker is 30 amino acids in length. In some embodiments, the linker is 35 amino acids in length. In some embodiments, the linker is from 5-50 amino acids in length.


In some embodiments, the polypeptide further comprises a polypeptide of formula VL-ConstantDomainLight, wherein VL is a variable light chain and ConstantDomainLight is a IgG light chain constant domain, wherein the polypeptide can be or is associated with the polypeptide having the formula of Ab-ConstantDomain-LinkerA-IL2 Mutein-LinkerB-FcRegion. In some embodiments, the VL comprises a sequence of SEQ ID NO: 415, SEQ ID NO: 592, SEQ ID NO: 600 or SEQ ID NO: 1363. These are illustrative only and the VL domain can be VL/VK sequence provided for herein, such as in Table 7, or Table 9. In some embodiments, the variable light chain domain comprises a first CDR of SEQ ID NO: 93, a second CDR of SEQ ID NO: 87, and a third CDR of SEQ ID NO: 94. In some embodiments, the variable light chain domain comprises a first CDR of SEQ ID NO: 361, a second CDR of SEQ ID NO: 362, and a third CDR of SEQ ID NO: 363. In some embodiments, the variable heavy chain domain comprises a first CDR of SEQ ID NO: 383, a second CDR of SEQ ID NO: 384, and a third CDR of SEQ ID NO: 385. In some embodiments, the variable heavy chain domain comprises a first CDR of SEQ ID NO: 383, a second CDR of SEQ ID NO: 241, and a third CDR of SEQ ID NO: 652. In some embodiments, the variable heavy chain domain comprises a first CDR of SEQ ID NO: 1408, a second CDR of SEQ ID NO: 362, and a third CDR of SEQ ID NO: 363. These are illustrative only and the CDR sets as set forth herein and in the tables are also provided.


In some embodiments, the constant domain also comprises mutations to negate the effector function, such as those provided for herein. In some embodiments, the ConstantDomainLight comprises a sequence of:









(SEQ ID NO: 45)


RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG





NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK





SFNRGEC






The different polypeptides of formula IL2 Mutein-LinkerA-FcRegion-LinkerB-Ab and VL-ConstantDomainLight can be interchanged with one another. In some embodiments, the polypeptide comprises a variable heavy chain comprising a first CDR of SEQ ID NO: 90, a second CDR of SEQ ID NO: 91, and a third CDR of SEQ ID NO: 92 and a variable light chain comprising a first CDR of SEQ ID NO: 93, a second CDR of SEQ ID NO: 87, and a third CDR of SEQ ID NO: 94. In some embodiments, the polypeptide comprises a variable heavy chain comprising a first CDR of SEQ ID NO: 359, a second CDR of SEQ ID NO: 170, and a third CDR of SEQ ID NO: 360 and a variable light chain comprising a first CDR of SEQ ID NO: 361, a second CDR of SEQ ID NO: 362, and a third CDR of SEQ ID NO: 363. In some embodiments, the polypeptide comprises a variable heavy chain comprising a first CDR of SEQ ID NO: 135, a second CDR of SEQ ID NO: 381, and a third CDR of SEQ ID NO: 382 and a variable light chain comprising a first CDR of SEQ ID NO: 383, a second CDR of SEQ ID NO: 384, and a third CDR of SEQ ID NO: 385. In some embodiments, the polypeptide comprises a variable heavy chain comprising a first CDR of SEQ ID NO: 135, a second CDR of SEQ ID NO: 381, and a third CDR of SEQ ID NO: 1342; and a variable light chain comprising a first CDR of SEQ ID NO: 383, a second CDR of SEQ ID NO: 241, and a third CDR of SEQ ID NO: 652. In some embodiments, the polypeptide comprises a variable heavy chain comprising a first CDR of SEQ ID NO: 359, a second CDR of SEQ ID NO: 170, and a third CDR of SEQ ID NO: 1431; and a variable light chain comprising a first CDR of SEQ ID NO: 1408, a second CDR of SEQ ID NO: 362, and a third CDR of SEQ ID NO: 363. These are non-limiting examples and the CDR combinations as illustrated in the Table 9 and Table 14 can be also be used and are provided for herein.


In some embodiments, compounds are provided comprising the following formula, from N-terminus to C-terminus:


IL2 Mutein-LinkerA-FcRegion-LinkerB-Ab, wherein the IL2 Mutein is any IL-2 mutein that can, for example, preferentially activate Tregs; the LinkerA and Linker B are, each, independently, a linker as provided herein, the Fc Region can any one of such as provided herein, and the Ab is a tissue targeting moiety, such as those provided herein. In some embodiments, the Ab is an antibody that binds to MAdCAM or another cell surface target as provided herein. In some embodiments, the antibody is in a scFv format. In some embodiments, the antibody is in a Fab format. In some embodiments, the antibody in a Fab format is an antibody as provided in Table 9. In some embodiments, the antibody in a Fab format is an antibody that comprises the CDRs as set forth in Table 9. In some embodiments, the antibody in scFV format is an antibody as provided in the Table 6 or Table 14. In some embodiments, the antibody in scFV format is an antibody that comprises the CDRs as set forth in Table 6, Table 7, Table 11, or Table 14.


In some embodiments, the C-terminus of the IL-2 mutein is linked to the N-terminus of the Fc region. In some embodiments, the linkage is direct or through a linker, such as those described herein. In some embodiments, the linker is a glycine/serine linker. In some embodiments, the linker linking the IL-2 mutein to the Fc region is a glycine/serine linker, which can be a sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22), or GGGGSGGGGSGGGGS (SEQ ID NO: 30). These are non-limiting examples and the linker can have varying number of GGGGS (SEQ ID NO: 23), or GGGGA repeats (SEQ ID NO: 29), or a mixture of the two. In some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the GGGGS (SEQ ID NO: 23) and/or GGGGA repeats (SEQ ID NO: 29) (repeats disclosed as SEQ ID NOS 1550-1551, respectively). In some embodiments, the linker is 10 amino acids in length. In some embodiments, the linker is 5 amino acids in length. In some embodiments, the linker is 15 amino acids in length. In some embodiments, the linker is 20 amino acids in length. In some embodiments, the linker is 25 amino acids in length. In some embodiments, the linker is 30 amino acids in length. In some embodiments, the linker is 35 amino acids in length. In some embodiments, the linker is from 5-50 amino acids in length.


In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 31. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 32. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 33. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 34. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 35. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 36. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 37. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 38. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 39. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 40. In some embodiments, the IL-2 mutein comprises a sequence of SEQ ID NO: 41. In some embodiments, the IL-2 mutein further comprises a T3A substitution (mutation). In some embodiments, the Fc Region comprises a peptide having a sequence of SEQ ID NO: 21. In some embodiments, the Fc Region comprises a peptide having a sequence of SEQ ID NO: 28. In some embodiments, the C-terminus of the Fc Region is linked to the N-terminus of the variable heavy chain. In some embodiments, the linker linking the Fc Region to the variable heavy chain is a glycine/serine or a glycine/alanine linker. In some embodiments, the linker linking the Fc region to the N-terminus of the variable heavy chain is a glycine/serine linker, which can be a sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22) or GGGGSGGGGSGGGGS (SEQ ID NO: 30). These are non-limiting examples and the linker can have varying number of GGGGS (SEQ ID NO: 23) or GGGGA repeats (SEQ ID NO: 29), or a mixture of the two. In some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the GGGGS (SEQ ID NO: 23) and/or GGGGA repeats (SEQ ID NO: 29) (repeats disclosed as SEQ ID NOS 1550-1551, respectively). In some embodiments, the linker is 10 amino acids in length. In some embodiments, the linker is 5 amino acids in length. In some embodiments, the linker is 15 amino acids in length. In some embodiments, the linker is 20 amino acids in length. In some embodiments, the linker is 25 amino acids in length. In some embodiments, the linker is 30 amino acids in length. In some embodiments, the linker is 35 amino acids in length. In some embodiments, the linker is from 5-50 amino acids in length.


In some embodiments, the variable heavy chain comprises the CDRs as set forth in Table 6, Table 7, Table 9, or Table 14. In some embodiments, the variable heavy chain comprises a HCDR1, HCDR2, and a HCDR3, wherein the HCDR1, HCDR2, and a HCDR3 are as set forth in Table 6, Table 7, Table 9, or Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 1 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 2 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 3 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 4 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 5 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 6 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 7 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 8 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 9 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 10 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 11 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 12 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 13 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 14 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 15 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 16 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 17 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 1 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 18 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 19 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 20 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 21 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 22 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 23 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 24 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 25 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 26 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 27 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 28 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 29 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 30 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 31 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 32 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 33 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 34 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 35 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 36 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 37 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 38 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 39 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 40 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 41 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 42 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 43 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 44 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 45 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 46 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 47 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 48 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 49 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 50 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 51 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 52 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 53 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 54 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 55 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 56 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 57 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 58 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 59 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 60 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 61 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 62 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 63 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 64 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 65 in Table 6. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 66 in Table 6.


In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 1 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 2 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 3 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 4 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 5 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 6 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 7 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 8 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 9 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 10 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 11 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 12 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 13 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 14 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 15 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 16 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 17 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 1 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 18 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 19 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 20 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 21 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 22 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 23 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 24 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 25 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 26 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 27 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 28 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 29 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 30 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 31 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 32 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 33 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 34 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 35 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 36 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 37 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 38 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 39 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 40 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 41 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 42 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 43 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 44 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 45 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 46 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 47 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 48 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 49 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 50 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 51 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 52 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 53 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 54 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 55 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 56 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 57 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 58 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 59 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 60 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 61 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 62 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 63 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 64 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 65 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 66 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 67 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 68 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 69 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 70 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 71 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 72 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 73 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 74 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 75 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 76 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 77 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 78 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 79 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 80 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 81 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 82 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 83 in Table 7. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for Clone 84 in Table 7.


In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB1 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB2 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB3 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB4 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR5 as set forth for MIAB1 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB6 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB7 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB8 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB9 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB10 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB11 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB12 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB13 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB14 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB15 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB16 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB17 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB18 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB19 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB20 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB21 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB22 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB23 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB24 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB25 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB26 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB27 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB28 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB29 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB30 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB31 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB32 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB33 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB34 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB35 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB36 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB37 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB38 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB39 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB40 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB41 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB42 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB43 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB44 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB45 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB46 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB47 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB48 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB49 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB50 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB51 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB52 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB53 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB54 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB55 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB56 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB57 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB58 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB59 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB60 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB61 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB62 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB63 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB64 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB65 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB66 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB67 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB68 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB69 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB70 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB71 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB72 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB73 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB74 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB75 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB76 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB77 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB78 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB79 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB80 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB81 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB82 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB83 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB84 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB85 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB86 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB87 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB88 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB89 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB90 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB91 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB92 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB93 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB94 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB95 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB96 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB97 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB98 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB99 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB100 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB101 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB102 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB103 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB104 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB105 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB106 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB107 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB108 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB109 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB110 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB111 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB112 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB113 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB114 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB115 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB116 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB117 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB118 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB119 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB120 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB121 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB122 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB123 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB124 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB125 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB126 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB127 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB128 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB128A in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB129 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB130 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB131 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB132 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB133 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB134 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB135 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB136 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB137 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB138 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB139 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB140 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB141 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB142 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB143 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB144 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB145 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB146 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB147 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB148 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB149 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB150 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB151 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB152 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB153 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB154 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB155 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB156 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB157 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB158 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB159 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB160 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB161 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB162 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB163 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB164 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB165 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB166 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB167 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB168 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB169 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB170 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB171 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB172 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB173 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB174 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB175 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB176 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB177 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB178 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB179 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB180 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB181 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB182 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB183 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB184 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB185 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB186 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB187 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB188 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB189 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB190 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB191 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB192 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB193 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB194 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB195 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB196 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB197 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB198 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB205 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB206 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB207 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB208 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB209 in Table 9.


In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB1 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB3 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB4 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB5 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB6 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB7 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB8 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB9 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB1 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB10 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB11 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB12 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB13 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB14 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB15 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB16 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB1 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB19 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB20 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB21 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB22 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB23 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB24 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB25 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB26 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB27 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB28 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB29 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB30 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB31 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB32 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR33 as set forth for PMAB33 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB34 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB35 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB36 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB37 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB38 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB39 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB40 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB41 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB42 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB43 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB44 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB45 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB46 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB47 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB48 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB49 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB50 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB51 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB52 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB53 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for PMAB55 in Table 14.


In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB212 in Table 15. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB213 in Table 15. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR3 as set forth for MIAB214 in Table 15.


In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 1 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 2 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 3 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 4 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 5 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 6 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 7 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 8 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 9 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 10 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 11 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 12 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 13 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 14 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 15 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 16 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 17 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 1 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 18 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 19 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 20 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 21 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 22 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 23 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 24 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 25 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 26 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 27 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 28 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 29 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 30 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 31 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 32 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 33 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 34 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 35 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 36 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 37 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 38 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 39 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 40 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 41 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 42 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 43 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 44 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 45 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 46 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 47 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 48 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 49 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 50 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 51 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 52 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 53 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 54 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 55 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 56 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 57 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 58 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 59 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 60 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 61 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 62 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 63 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 64 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 65 in Table 6. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 66 in Table 6.


In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 1 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 2 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 3 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 4 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 5 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 6 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 7 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 8 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 9 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 10 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 11 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 12 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 13 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 14 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 15 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 16 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 17 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 1 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 18 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 19 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 20 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 21 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 22 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 23 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 24 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 25 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 26 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 27 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 28 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 29 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 30 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 31 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 32 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 33 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 34 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 35 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 36 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 37 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 38 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 39 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 40 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 41 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 42 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 43 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 44 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 45 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 46 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 47 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 48 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 49 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 50 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 51 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 52 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 53 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 54 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 55 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 56 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 57 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 58 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 59 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 60 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 61 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 62 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 63 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 64 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 65 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 66 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 67 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 68 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 69 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 70 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 71 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 72 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 73 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 74 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 75 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 76 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 77 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 78 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 79 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 80 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 81 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 82 in Table 7. In some embodiments, the variable heavy chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 83 in Table 7. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for Clone 84 in Table 7.


In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB1 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB2 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB3 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB4 in Table 9. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR5 as set forth for MIAB1 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB6 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB7 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB8 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB9 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB10 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB11 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB12 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB13 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB14 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB15 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB16 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB17 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB18 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB19 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB20 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB21 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB22 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB23 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB24 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB25 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB26 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB27 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB28 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB29 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB30 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB31 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB32 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB33 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB34 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB35 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB36 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB37 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB38 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB39 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB40 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB41 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB42 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB43 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB44 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB45 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB46 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB47 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB48 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB49 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB50 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB51 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB52 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB53 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB54 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB55 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB56 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB57 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB58 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB59 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB60 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB61 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB62 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB63 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB64 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB65 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB66 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB67 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB68 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB69 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB70 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB71 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB72 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB73 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB74 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB75 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB76 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB77 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB78 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB79 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB80 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB81 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB82 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB83 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB84 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB85 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB86 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB87 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB88 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB89 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB90 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB91 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB92 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB93 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB94 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB95 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB96 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB97 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB98 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB99 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB100 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB101 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB102 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB103 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB104 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB105 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB106 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB107 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB108 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB109 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB110 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB111 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB112 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB113 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB114 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB115 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB116 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB117 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB118 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB119 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB120 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB121 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB122 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB123 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB124 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB125 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB126 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB127 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB128 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB128A in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB129 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB130 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB131 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB132 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB133 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB134 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB135 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB136 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB137 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB138 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB139 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB140 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB141 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB142 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB143 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB144 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB145 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB146 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB147 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB148 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB149 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB150 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB151 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB152 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB153 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB154 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB155 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB156 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB157 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB158 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB159 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB160 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB161 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB162 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB163 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB164 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB165 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB166 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB167 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB168 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB169 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB170 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB171 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB172 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB173 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB174 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB175 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB176 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB177 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB178 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB179 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB180 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB181 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB182 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB183 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB184 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB185 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB186 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB187 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB188 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB189 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB190 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB191 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB192 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB193 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB194 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB195 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB196 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB197 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB198 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB205 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB206 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB207 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB208 in Table 9. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB209 in Table 9.


In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB1 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB3 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB4 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB5 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB6 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB7 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB8 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB9 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB1 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB10 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB11 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB12 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB13 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB14 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB15 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB16 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB1 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB19 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB20 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB21 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB22 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB23 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB24 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB25 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB26 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB27 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB28 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB29 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB30 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB31 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB32 in Table 14. In some embodiments, the variable heavy chain has a HCDR1, HCDR2, and a HCDR33 as set forth for PMAB33 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB34 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB35 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB36 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB37 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB38 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB39 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB40 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB41 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB42 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB43 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB44 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB45 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB46 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB47 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB48 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB49 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB50 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB51 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB52 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB53 in Table 14. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for PMAB55 in Table 14.


In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB212 in Table 15. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB213 in Table 15. In some embodiments, the variable light chain has a LCDR1, LCDR2, and a LCDR3 as set forth for MIAB214 in Table 15. In some embodiments, the CDRS are swapped for one another. For example, the HCDR1 of clone 1 can be substituted for the HCDR1 of clone 10, or vice versa. This CDR swapping can be done for any of the HCDRs of the clones provided herein (e.g., HCDR1 for HCDR1; HCDR2 for HCDR2; or HCDR3 for HCDR3) or the LCDRs (e.g., LCDR1 for LCDR1; LCDR2 for LCDR2; or LCDR3 for LCDR3). Therefore, in some embodiments, the antibody comprises a HCDR1 as set forth in any of Clones 1-66 of Table 6, Clones 1-84 of Table 7, MIAB1-198 or MIAB205-209 of Table 9, PMAB1-55 of Table 14, or PMAB212-214 of Table a HCDR2 as set forth in any of Clones 1-66 of Table 6, Clones 1-84 of Table 7, MIAB1-198 or MIAB205-209 of Table 9, PMAB1-55 of Table 14, or PMAB212-214 of Table 15; a HCDR3 as set forth in any of Clones 1-66 of Table 6, Clones 1-84 of Table 7, MIAB1-198 or MIAB205-209 of Table 9, PMAB1-55 of Table 14, or PMAB212-214 of Table 15; a LCDR1 as set forth in any of Clones 1-66 of Table 6, Clones 1-84 of Table 7, MIAB1-198 or MIAB205-209 of Table 9, PMAB1-55 of Table 14, or PMAB212-214 of Table 15; a LCDR2 as set forth in any of Clones 1-66 of Table 6, Clones 1-84 of Table 7, MIAB1-198 or MIAB205-209 of Table 9, PMAB1-55 of Table 14, or PMAB212-214 of Table 15; a LCDR3 as set forth in any of Clones 1-66 of Table 6, Clones 1-84 of Table 7, MIAB1-198 or MIAB205-209 of Table 9, PMAB1-55 of Table 14, or PMAB212-214 of Table 15, or a variant of any of the foregoing.


In some embodiments, the MAdCAM Antibody is a scFv format as shown in clones 6, 59, 63, MIAB199, MIAB200, MIAB201, MIAB202, MIAB203, MIAB204, or PMAB1-55. The linker as shown in those sequences is 20 amino acid residues in length, but could also be 5, 10, or 15 amino acid residues in length. In some embodiments, the linker the links the VH and VL (or VK) sequences of the antibody is a glycine/serine linker, which can be a sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22), or GGGGSGGGGSGGGGS (SEQ ID NO: This is simply a non-limiting example and the linker can have varying number of GGGGS (SEQ ID NO: 23), or GGGGA repeats (SEQ ID NO: 29). In some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the GGGGS (SEQ ID NO: 23), or GGGGA repeats (SEQ ID NO: 29) (repeats disclosed as SEQ ID NOS 1550-1551, respectively). Thus, the linkers shown in Table 6 are non-limiting examples and can be substituted with any other linkers, such as those provided for herein.


In some embodiments, the polypeptide comprises the formula of:









(SEQ ID NOS 1552-1553, respectively)


APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA





TELKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISDINVIVLELKGSE





TTFMCEYADETATIVEFINRWITFSQSIISTLT-Linker1-





DKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED





PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK





CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK





GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG





NVFSCSVMHEALHNHYTQKSLSLSPG-Linker2-Ab,







wherein Linker 1, Linker2, and Ab are as provided herein. In some embodiments, Linker 1 is GGGGSGGGGSGGGGS (SEQ ID NO: 30) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22). In some embodiments, Linker 1 is GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22). In some embodiments, Linker 1 is GGGGS (SEQ ID NO: 23). In some embodiments, Linker 1 is GGGGSGGGGS (SEQ ID NO: 619). In some embodiments, Linker 1 is GGGGSGGGGSGGGGS (SEQ ID NO: 30). In some embodiments, Linker 2 is GGGGS (SEQ ID NO: 23). In some embodiments, Linker 2 is GGGGSGGGGS (SEQ ID NO: 619). In some embodiments, Linker 2 is GGGGSGGGGSGGGGS (SEQ ID NO: 30). In some embodiments, Linker 2 is GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22). In some embodiments, Ab is the scFV as set forth in Table 6, Table 12, or Table 14. In some embodiments, the Ab comprises a sequence of SEQ ID NO: 95. In some embodiments, the Ab comprises a sequence of SEQ ID NO: 364. In some embodiments, the Ab comprises a sequence of SEQ ID NO: 386. In some embodiments, the Ab comprises a sequences of SEQ ID NOs: 41, 22, 1437, 30, 591, 22, and 592. In some embodiments, the Ab comprises a VH and a VK or VL segment. In some embodiments, the VH comprises a sequence as set forth in Table 7, Table 9, Table 10, Table 12, or Table 14. In some embodiments, the VL comprises a sequence as set forth in Table 7, Table 9, Table 10, Table 12, or Table 14. In some embodiments, the Ab comprises a VH and a VL as set forth for the clones in Table 7, Table 9, Table 10, Table 12, or Table 14. In some embodiments, the VH and VL are linked by a linker. In some embodiments, the VH and VL are linked by a peptide linker comprising a peptide of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22). In some embodiments, the VH and VL are linked by a peptide linker comprising a peptide of GGGGS (SEQ ID NO: 23). In some embodiments, the VH and VL are linked by a peptide linker comprising a peptide of GGGGSGGGGS (SEQ ID NO: 619). In some embodiments, the VH and VL are linked by a peptide linker comprising a peptide of GGGGSGGGGSGGGGS (SEQ ID NO: 30).


In some embodiments, the Ab comprises a VH of SEQ ID NO: 414 and a VL of SEQ ID NO: 415. In some embodiments, the Ab comprises a VH of SEQ ID NO: 591 and a VL of SEQ ID NO: 592. In some embodiments, the Ab comprises a VH of SEQ ID NO: 599 and a VL of SEQ ID NO: 600. In some embodiments, the Ab comprises a VH of SEQ ID NO: 880 and a VL of SEQ ID NO: 663. In some embodiments, the Ab comprises a VH of SEQ ID NO: 1387 and a VL of SEQ ID NO: 1363.


In some embodiments, the peptide comprises:









(SEQ ID NO: 1554)


APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKA





TELKHLQCLEEELKPLEEALNLAPSKNFHLRPRDLISDINVIVLELKGSE





TTFMCEYADETATIVEFINRWITFSQSIISTLT-(GGGGGGGGSGGGGS





or GGGGSGGGGSGGGGSGGGGS)-DKTHTCPPCPAPEAAGAPSVFLFPP





KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ





YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE





PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP





PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP





G-(GGGGS or GGGGSGGGGS or GGGGSGGGGSGGGGS)-Ab,







wherein Ab is set forth as herein. In some embodiments, the Ab comprises a sequence of SEQ ID NO: 95. In some embodiments, the Ab comprises a sequence of SEQ ID NO: 364. In some embodiments, the Ab comprises a sequence of SEQ ID NO: 386. In some embodiments, the Ab comprises a VH and a VK or VL segment. In some embodiments, the VH comprises a sequence as set forth in Table 7, Table 9, Table 10, Table 12, or Table 14. In some embodiments, the VL comprises a sequence as set forth in Table 7, Table 9, Table 10, Table 12, or Table 14. In some embodiments, the Ab comprises a VH and a VL as set forth for the clones in Table 7, Table 9, Table 10, Table 12, or Table 14. In some embodiments, the VH and VL are linked by a linker. In some embodiments, the VH and VL are linked by a peptide linker comprising a peptide of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22). In some embodiments, the VH and VK are linked by a peptide linker comprising a peptide of GGGGS (SEQ ID NO: 23). In some embodiments, the VH and VL are linked by a peptide linker comprising a peptide of GGGGSGGGGS (SEQ ID NO: 619).


In some embodiments, the Ab comprises a VH of SEQ ID NO: 414 and a VL of SEQ ID NO: 415. In some embodiments, the Ab comprises a VH of SEQ ID NO: 591 and a VL of SEQ ID NO: 592. In some embodiments, the Ab comprises a VH of SEQ ID NO: 599 and a VL of SEQ ID NO: 600. In some embodiments, the Ab comprises a VH of SEQ ID NO: 880 and a VL of SEQ ID NO: 663. In some embodiments, the Ab comprises a VH of SEQ ID NO: 1387 and a VL of SEQ ID NO: 1363. These examples are non-limiting the combinations of VH and VK as shown in Table 7, Table 9, Table 10, Table 12, or Table 14 are also provided.


In some embodiments, the therapeutic compound or polypeptide comprises a formula of an anti-PD-1 heavy and light chain, wherein the PD-1 heavy chain is linked to a MAdCAM antibody (scFV), such as those provided herein at the C-terminus of the PD-1 IgG heavy chain. The polypeptide can have the formula of A1-A2-Linker1-A4-Linker2-A5 and A6, wherein A1 is a PD-1 heavy chain, A6 is a PD-1 light chain; A2 is a IgG constant domain (e.g. IgG1 Constant domain), Linker 1 is as provided herein, such as, but not limited to, a glycine/serine linker, which can be a sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22) or GGGGSGGGGSGGGGS (SEQ ID NO: 30), or GGGSEGGGSEGGGSE (SEQ ID NO: 1546) which are simply a non-limiting example and the linker can have varying number of GGGGS (SEQ ID NO: 23) or GGGGA repeats (SEQ ID NO: 29) and in some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the GGGGS (SEQ ID NO: 23) or GGGGA repeats (SEQ ID NO: 29) (repeats disclosed as SEQ ID NOS 1550-1551, respectively); A4 is VH domain, such as those set forth in Table 7; Linker 2 is as provided herein, such as, but not limited to, a glycine/serine linker, which can be a sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22), GGGSEGGGSEGGGSE (SEQ ID NO: 1546), or GGGGSGGGGSGGGGS (SEQ ID NO: 30), which are simply a non-limiting example and the linker can have varying number of GGGGS (SEQ ID NO: 23) or GGGGA repeats (SEQ ID NO: 29) and in some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the GGGGS (SEQ ID NO: 23) or GGGGA repeats (SEQ ID NO: 29) (repeats disclosed as SEQ ID NOS 1550-1551, respectively); and A5 is VK/VL domain, such as those set forth in Table 7. In some embodiments, Linker 2 is GGGGSGGGGSGGGGS (SEQ ID NO: 30). In some embodiments, the A4-Linker2-A5 is a scFV antibody, such as those set forth in Table 6. The linkers shown in Table 6 can be substituted with the linker of GGGGSGGGGSGGGGS (SEQ ID NO: 30). In some embodiments, the A4-Linker2-A5 comprises the HCDR sets (e.g., HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) sets as set forth in Table 6 or Table 7. For the avoidance of doubt, a CDR set refers to the CDRs illustrated for each of the different antibody clones provided for in the tables. In some embodiments, A4 comprises a peptide of SEQ ID NO: 414 and A5 comprises a peptide of SEQ ID NO: 415. In some embodiments, A4 comprises a peptide of SEQ ID NO: 591 and A5 comprises a peptide of SEQ ID NO: 592. In some embodiments, A4 comprises a peptide of SEQ ID NO: 599 and A5 comprises a peptide of SEQ ID NO: 600. These examples are non-limiting the combinations of VH and VK as shown in Table 7, Table 12, or Table 14 are also provided.


In some embodiments, A2 comprises a sequence of









(SEQ ID NO: 44)


ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV





HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP





KSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVS





HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK





EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC





LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW





QQGNVFSCSVMHEALHNHYTQKSLSLSPG






Once expressed the heavy and light chains of the PD-1 antibody bind to one another to form the compound comprising the anti-PD-1 antibody linked to the anti-MAdCAM antibody. The anti-MAdCAM antibody can be any antibody that binds to MAdCAM, such as those provided for herein.


In some embodiments, the therapeutic comprises one or more sequences selected from the sequence in the following table:

















TABLE 12








Fc-










scFv

Intra






Fab VH
IgG1 Constant
Linker
scFv VH
scFv
scFv VK




Ab
Seq
Domain Seq
Seq
Seq
Linker
Seq
Fab VL
CK







PMAB1
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

591)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB2
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGSSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYGYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:







VTVSS
SFFLYSKLTVDKSRW

1347)


1359)




(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB3
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGSSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1439)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB4
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGSSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYGYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1363)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1347)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB5
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGSSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1363)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1439)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB6
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYGYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1440)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB7
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1441)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB8
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYGYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1363)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:







VTVSS
SFFLYSKLTVDKSRW









(SEQ
QQGNVFSCSVMHEAL

1440)


1359)




ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB9
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1363)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1441)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB10
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKENWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYGYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1442)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB11
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKENWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1395)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB12
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKENWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYGYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1363)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1442)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB13
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1363)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1395)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB14
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYGYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1443)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB15
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



SYDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYD

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1444)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1446)
(SEQ ID NO: 44)











PMAB16
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



SYDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYD

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1445)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1446)
(SEQ ID NO: 44)











PMAB17
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



SYDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYGYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTD
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1442)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1447)
(SEQ ID NO: 44)











PMAB18
QVQLVQ
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIQMTQS
RTVAAPSV



SGAEVK
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PSSLSAS
FIFPPSDE



KPGASV
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
VGDRVTI
QLKSGTAS



KVSCKA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
TCQASRD
VVCLLNNF



SGYSFT
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
IKNYLAW
YPREAKVQ



TYYMHW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
YQQKPGK
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
APKLLIY
SGNSQESV



QGLEWM
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
AASSLQS
TEQDSKDS



GIIAPS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
GVPSRFS
TYSLSSTL



GGSTSY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
GSGSGTD
TLSKADYE



AQKFQG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
FTLTISS
KHKVYACE



RVTMTR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
LQPEDFA
VTHQGLSS



DTSTST
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
TYYCQQS
PVTKSFNR



VYMELS
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YSTPPTF
GEC (SEQ



SLRSED
LPAPIEKTISKAKGQ

DRPYYYD

GQGTKVE
GPGTKVD
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
IK (SEQ
45)



ASGWVY
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
ID NO:




WGQGTL
YPSDIAVEWESNGQP

(SEQ ID

1367)
1449)




VTVSS
ENNYKTTPPVLDSDG

NO:







(SEQ
SFFLYSKLTVDKSRW

1445)







ID NO:
QQGNVFSCSVMHEAL









1448)
HNHYTQKSLSLSPG










(SEQ ID NO: 44)











PMAB19
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1353)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB20
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDYWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1391)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB21
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFAMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1450)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB22
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMS
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1451)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB23
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1452)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB24
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

AISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1453)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB25
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGSSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1454)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB26
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1455)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB27
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

STNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1456)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB28
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTYYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1457)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB29
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYAAS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1458)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB30
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYAQS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1459)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB31
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDASKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1460)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB32
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDQSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1379)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB33
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMA

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1461)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB34
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMG

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP



592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

(SEQ ID


1359)




VTVSS
SFFLYSKLTVDKSRW

NO:







(SEQ
QQGNVFSCSVMHEAL

1462)







ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB35
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMQ

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1463)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB36
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
ISRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1363)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

591)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB37
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSSSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1364)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

591)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB38
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRYLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1365)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

591)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV


39
SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLNW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1366)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

591)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV


40
SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQS
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1464)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

591)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB41
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

YSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1465)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

591)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB42
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSTPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1466)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

591)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB43
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPRTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID


ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:

1467)
1359)




VTVSS
SFFLYSKLTVDKSRW

591)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB44
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPTYYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1390)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB45
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYDYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1468)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB46
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYGYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1469)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB47
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYNYY

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1470)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB48
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYSYY

GQGTKVE
TPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1471)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB49
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYD

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1472)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB50
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYE

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1473)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB51
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYK

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1474)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB52
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
VLYSPNN
YPREAKVQ



NSDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYS

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

592)
ID NO:




WGQGTL
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1475)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1438)
(SEQ ID NO: 44)











PMAB53
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



SYDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYD

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

IDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTT
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1477)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1476)
(SEQ ID NO: 44)











PMAB54
EVQLVQ
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIQMTQS
RTVAAPSV



SGAEVK
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PSSLSAS
FIFPPSDE



KPGASV
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
VGDRVTI
QLKSGTAS



KVSCKA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
TCRASQS
VVCLLNNF



SGYSFT
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
ISSYLAW
YPREAKVQ



SYYMHW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
YQQKPGK
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
APKLLIY
SGNSQESV



QGLEWM
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
AASSLQS
TEQDSKDS



GIINPS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
GVPSRFS
TYSLSSTL



GGSTSY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
GSGSGTD
TLSKADYE



AQKFQG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
FTLTISS
KHKVYACE



RVTMTR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
LQPEDFA
VTHQGLSS



DTSTST
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
TYYCQQS
PVTKSFNR



VYMELS
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YSTPPTF
GEC (SEQ



SLRSED
LPAPIEKTISKAKGQ

DRPYYYD

GQGTKVE
GPGTKVD
ID NO:



TAVYYC
PREPQVYTLPPSREE

IDVWGKG

IK (SEQ
IK (SEQ
45)



ASGWVY
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
ID NO:




WGQGTL
YPSDIAVEWESNGQP

(SEQ ID

1367)
1479)




VTVSS
ENNYKTTPPVLDSDG

NO:







(SEQ
SFFLYSKLTVDKSRW

1477)







ID NO:
QQGNVFSCSVMHEAL









1478)
HNHYTQKSLSLSPG










(SEQ ID NO: 44)











PMAB55
EVQLVQ
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIQMTQS
RTVAAPSV



SGAEVK
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PSSLSAS
FIFPPSDE



KPGASV
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
VGDRVTI
QLKSGTAS



KVSCKA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
TCRASQS
VVCLLNNF



SGYSFT
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
ISSYLAW
YPREAKVQ



SYYMHW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
YQQKPGK
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
APKLLIY
SGNSQESV



QGLEWM
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
AASSLQS
TEQDSKDS



GIINPS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
GVPSRFS
TYSLSSTL



GGSTSY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
GSGSGTD
TLSKADYE



AQKFQG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
FTLTISS
KHKVYACE



RVTMTR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
LQPEDFA
VTHQGLSS



DTSTST
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
TYYCQQS
PVTKSFNR



VYMELS
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YSTPPTF
GEC (SEQ



SLRSED
LPAPIEKTISKAKGQ

DRPYYYD

GQGTKVE
GPGTKVD
ID NO:



TAVYYC
PREPQVYTLPPSREE

LDVWGKG

IK (SEQ
IK (SEQ
45)



ASGWVY
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
ID NO:




WGQGTL
YPSDIAVEWESNGQP

(SEQ ID

1367)
1479)




VTVSS
ENNYKTTPPVLDSDG

NO:







(SEQ
SFFLYSKLTVDKSRW

1480)







ID NO:
QQGNVFSCSVMHEAL









1478)
HNHYTQKSLSLSPG










(SEQ ID NO: 44)











PMAB56
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



SYDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYD

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

LDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTT
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1480)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1476)
(SEQ ID NO: 44)











PMAB57
QVQLVQ
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIQMTQS
RTVAAPSV



SGAEVK
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PSSLSAS
FIFPPSDE



KPGASV
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
VGDRVTI
QLKSGTAS



KVSCKA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
TCQASRD
VVCLLNNF



SGYSFT
GLYSLSSVVTVPSSS
ID NO:
FSDFWMH
(SEQ
VSRSLAW
IKNYLAW
YPREAKVQ



TYYMHW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
YQQKPGK
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWIS
22)
APKLLIY
APKLLIY
SGNSQESV



QGLEWM
THTCPPCPAPEAAGA

YISGDSG

AASSLQS
AASSLQS
TEQDSKDS



GIIAPS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
GVPSRFS
TYSLSSTL



GGSTSY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
GSGSGTD
TLSKADYE



AQKFQG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
FTLTISS
KHKVYACE



RVTMTR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
LQPEDFA
VTHQGLSS



DTSTST
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
TYYCQQS
PVTKSFNR



VYMELS
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YSTPPTF
GEC (SEQ



SLRSED
LPAPIEKTISKAKGQ

DRPYYYY

GQGTKVE
GPGTKVD
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
IK (SEQ
45)



ASGWVY
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
ID NO:




WGQGTL
YPSDIAVEWESNGQP

(SEQ ID

592)
1449)




VTVSS
ENNYKTTPPVLDSDG

NO:







(SEQ
SFFLYSKLTVDKSRW

591)







ID NO:
QQGNVFSCSVMHEAL









1448)
HNHYTQKSLSLSPG










(SEQ ID NO: 44)











PMAB60
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



SYDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KCLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYD

GCGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1543)
ID NO:




WGQGTT
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1542)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1476)
(SEQ ID NO: 44)











PMAB61
EVQLVQ
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIQMTQS
RTVAAPSV



SGAEVK
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PSSLSAS
FIFPPSDE



KPGASV
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
VGDRVTI
QLKSGTAS



KVSCKA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
TCRASQS
VVCLLNNF



SGYSFT
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
ISSYLAW
YPREAKVQ



SYYMHW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
YQQKPGK
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KCLEWVS
22)
APKLLIY
APKLLIY
SGNSQESV



QGLEWM
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
AASSLQS
TEQDSKDS



GIINPS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
GVPSRFS
TYSLSSTL



GGSTSY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
GSGSGTD
TLSKADYE



AQKFQG
HEDPEVKENWYVDGV

SRDNSKN

FTLTISS
FTLTISS
KHKVYACE



RVTMTR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
LQPEDFA
VTHQGLSS



DTSTST
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
TYYCQQS
PVTKSFNR



VYMELS
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YSTPPTF
GEC (SEQ



SLRSED
LPAPIEKTISKAKGQ

DRPYYYD

GCGTKVE
GPGTKVD
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
IK (SEQ
45)



ASGWVY
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
ID NO:




WGQGTL
YPSDIAVEWESNGQP

(SEQ ID

1543)
1479)




VTVSS
ENNYKTTPPVLDSDG

NO:







(SEQ
SFFLYSKLTVDKSRW

1542)







ID NO:
QQGNVFSCSVMHEAL









1478)
HNHYTQKSLSLSPG










(SEQ ID NO: 44)











PMAB62
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



SYDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KCLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYD

GCGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

IDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1543)
ID NO:




WGQGTT
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1544)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1476)
(SEQ ID NO: 44)











PMAB63
EVQLVQ
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIQMTQS
RTVAAPSV



SGAEVK
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PSSLSAS
FIFPPSDE



KPGASV
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
VGDRVTI
QLKSGTAS



KVSCKA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
TCRASQS
VVCLLNNF



SGYSFT
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
ISSYLAW
YPREAKVQ



SYYMHW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
YQQKPGK
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KCLEWVS
22)
APKLLIY
APKLLIY
SGNSQESV



QGLEWM
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
AASSLQS
TEQDSKDS



GIINPS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
GVPSRFS
TYSLSSTL



GGSTSY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
GSGSGTD
TLSKADYE



AQKFQG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
FTLTISS
KHKVYACE



RVTMTR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
LQPEDFA
VTHQGLSS



DTSTST
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
TYYCQQS
PVTKSFNR



VYMELS
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YSTPPTF
GEC (SEQ



SLRSED
LPAPIEKTISKAKGQ

DRPYYYD

GCGTKVE
GPGTKVD
ID NO:



TAVYYC
PREPQVYTLPPSREE

IDVWGKG

IK (SEQ
IK (SEQ
45)



ASGWVY
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
ID NO:




WGQGTL
YPSDIAVEWESNGQP

(SEQ ID

1543)
1479)




VTVSS
ENNYKTTPPVLDSDG

NO:







(SEQ
SFFLYSKLTVDKSRW

1544)







ID NO:
QQGNVFSCSVMHEAL









1478)
HNHYTQKSLSLSPG










(SEQ ID NO: 44)











PMAB64
EVQLVQ
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIQMTQS
RTVAAPSV



SGAEVK
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PSSLSAS
FIFPPSDE



KPGASV
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
VGDRVTI
QLKSGTAS



KVSCKA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
TCRASQS
VVCLLNNF



SGYSFT
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
ISSYLAW
YPREAKVQ



SYYMHW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
YQQKPGK
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KCLEWVS
22)
APKLLIY
APKLLIY
SGNSQESV



QGLEWM
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
AASSLQS
TEQDSKDS



GIINPS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
GVPSRFS
TYSLSSTL



GGSTSY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
GSGSGTD
TLSKADYE



AQKFQG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
FTLTISS
KHKVYACE



RVTMTR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
LQPEDFA
VTHQGLSS



DTSTST
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
TYYCQQS
PVTKSFNR



VYMELS
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YSTPPTF
GEC (SEQ



SLRSED
LPAPIEKTISKAKGQ

DRPYYYD

GCGTKVE
GPGTKVD
ID NO:



TAVYYC
PREPQVYTLPPSREE

LDVWGKG

IK (SEQ
IK (SEQ
45)



ASGWVY
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
ID NO:




WGQGTL
YPSDIAVEWESNGQP

(SEQ ID

1543)
1479)




VTVSS
ENNYKTTPPVLDSDG

NO:







(SEQ
SFFLYSKLTVDKSRW

1545)







ID NO:
QQGNVFSCSVMHEAL









1478)
HNHYTQKSLSLSPG










(SEQ ID NO: 44)











PMAB65
EVQLLE
ASTKGPSVFPLAPSS
GGGGSG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGGSGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GGS
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



SYDMSW
LGTQTYICNVNHKPS
30)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KCLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYD

GCGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

LDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1543)
ID NO:




WGQGTT
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1545)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1476)
(SEQ ID NO: 44)











PMAB66
EVQLLE
ASTKGPSVFPLAPSS
GGGSEG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGSEGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GSE
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



SYDMSW
LGTQTYICNVNHKPS
1546)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYD

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTT
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1445)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1476)
(SEQ ID NO: 44)











PMAB67
EVQLVQ
ASTKGPSVFPLAPSS
GGGSEG
EVQLLES
GGGGSG
DIQMTQS
DIQMTQS
RTVAAPSV



SGAEVK
KSTSGGTAALGCLVK
GGSEGG
GGGLVQP
GGGSGG
PSSLSAS
PSSLSAS
FIFPPSDE



KPGASV
DYFPEPVTVSWNSGA
GSE
GGSLRLS
GGSGGG
VGDRVTI
VGDRVTI
QLKSGTAS



KVSCKA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
TCRASQS
VVCLLNNF



SGYSFT
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
ISSYLAW
YPREAKVQ



SYYMHW
LGTQTYICNVNHKPS
1546)
WVRQAPG
ID NO:
YQQKPGK
YQQKPGK
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
APKLLIY
SGNSQESV



QGLEWM
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
AASSLQS
TEQDSKDS



GIINPS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
GVPSRFS
TYSLSSTL



GGSTSY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
GSGSGTD
TLSKADYE



AQKFQG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
FTLTISS
KHKVYACE



RVTMTR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
LQPEDFA
VTHQGLSS



DTSTST
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
TYYCQQS
PVTKSFNR



VYMELS
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YSTPPTF
GEC (SEQ



SLRSED
LPAPIEKTISKAKGQ

DRPYYYD

GQGTKVE
GPGTKVD
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
IK (SEQ
45)



ASGWVY
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
ID NO:




WGQGTL
YPSDIAVEWESNGQP

(SEQ ID

1367)
1479)




VTVSS
ENNYKTTPPVLDSDG

NO:







(SEQ
SFFLYSKLTVDKSRW

1445)







ID NO:
QQGNVFSCSVMHEAL









1478)
HNHYTQKSLSLSPG










(SEQ ID NO: 44)











PMAB68
EVQLLE
ASTKGPSVFPLAPSS
GGGSEG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGSEGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GSE
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



SYDMSW
LGTQTYICNVNHKPS
1546)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYD

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

IDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTT
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1477)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1476)
(SEQ ID NO: 44)











PMAB69
EVQLVQ
ASTKGPSVFPLAPSS
GGGSEG
EVQLLES
GGGGSG
DIQMTQS
DIQMTQS
RTVAAPSV



SGAEVK
KSTSGGTAALGCLVK
GGSEGG
GGGLVQP
GGGSGG
PSSLSAS
PSSLSAS
FIFPPSDE



KPGASV
DYFPEPVTVSWNSGA
GSE
GGSLRLS
GGSGGG
VGDRVTI
VGDRVTI
QLKSGTAS



KVSCKA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
TCRASQS
VVCLLNNF



SGYSFT
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
ISSYLAW
YPREAKVQ



SYYMHW
LGTQTYICNVNHKPS
1546)
WVRQAPG
ID NO:
YQQKPGK
YQQKPGK
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
APKLLIY
SGNSQESV



QGLEWM
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
AASSLQS
TEQDSKDS



GIINPS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
GVPSRFS
TYSLSSTL



GGSTSY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
GSGSGTD
TLSKADYE



AQKFQG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
FTLTISS
KHKVYACE



RVTMTR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
LQPEDFA
VTHQGLSS



DTSTST
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
TYYCQQS
PVTKSFNR



VYMELS
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YSTPPTF
GEC (SEQ



SLRSED
LPAPIEKTISKAKGQ

DRPYYYD

GQGTKVE
GPGTKVD
ID NO:



TAVYYC
PREPQVYTLPPSREE

IDVWGKG

IK (SEQ
IK (SEQ
45)



ASGWVY
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
ID NO:




WGQGTL
YPSDIAVEWESNGQP

(SEQ ID

1367)
1479)




VTVSS
ENNYKTTPPVLDSDG

NO:







(SEQ
SFFLYSKLTVDKSRW

1477)







ID NO:
QQGNVFSCSVMHEAL









1478)
HNHYTQKSLSLSPG










(SEQ ID NO: 44)











PMAB70
EVQLVQ
ASTKGPSVFPLAPSS
GGGSEG
EVQLLES
GGGGSG
DIQMTQS
DIQMTQS
RTVAAPSV



SGAEVK
KSTSGGTAALGCLVK
GGSEGG
GGGLVQP
GGGSGG
PSSLSAS
PSSLSAS
FIFPPSDE



KPGASV
DYFPEPVTVSWNSGA
GSE
GGSLRLS
GGSGGG
VGDRVTI
VGDRVTI
QLKSGTAS



KVSCKA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
TCRASQS
VVCLLNNF



SGYSFT
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
ISSYLAW
YPREAKVQ



SYYMHW
LGTQTYICNVNHKPS
1546)
WVRQAPG
ID NO:
YQQKPGK
YQQKPGK
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
APKLLIY
SGNSQESV



QGLEWM
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
AASSLQS
TEQDSKDS



GIINPS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
GVPSRFS
TYSLSSTL



GGSTSY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
GSGSGTD
TLSKADYE



AQKFQG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
FTLTISS
KHKVYACE



RVTMTR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
LQPEDFA
VTHQGLSS



DTSTST
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
TYYCQQS
PVTKSFNR



VYMELS
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YSTPPTF
GEC (SEQ



SLRSED
LPAPIEKTISKAKGQ

DRPYYYD

GQGTKVE
GPGTKVD
ID NO:



TAVYYC
PREPQVYTLPPSREE

LDVWGKG

IK (SEQ
IK (SEQ
45)



ASGWVY
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
ID NO:




WGQGTL
YPSDIAVEWESNGQP

(SEQ ID

1367)
1479)




VTVSS
ENNYKTTPPVLDSDG

NO:







(SEQ
SFFLYSKLTVDKSRW

1480)







ID NO:
QQGNVFSCSVMHEAL









1478)
HNHYTQKSLSLSPG










(SEQ ID NO: 44)











PMAB71
EVQLLE
ASTKGPSVFPLAPSS
GGGSEG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGSEGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GSE
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



SYDMSW
LGTQTYICNVNHKPS
1546)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KGLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYD

GQGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

LDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1367)
ID NO:




WGQGTT
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1480)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1476)
(SEQ ID NO: 44)











PMAB72
EVQLLE
ASTKGPSVFPLAPSS
GGGSEG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGSEGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GSE
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



SYDMSW
LGTQTYICNVNHKPS
1546)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KCLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYD

GCGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1543)
ID NO:




WGQGTT
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1542)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1476)
(SEQ ID NO: 44)











PMAB73
EVQLVQ
ASTKGPSVFPLAPSS
GGGSEG
EVQLLES
GGGGSG
DIQMTQS
DIQMTQS
RTVAAPSV



SGAEVK
KSTSGGTAALGCLVK
GGSEGG
GGGLVQP
GGGSGG
PSSLSAS
PSSLSAS
FIFPPSDE



KPGASV
DYFPEPVTVSWNSGA
GSE
GGSLRLS
GGSGGG
VGDRVTI
VGDRVTI
QLKSGTAS



KVSCKA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
TCRASQS
VVCLLNNF



SGYSFT
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
ISSYLAW
YPREAKVQ



SYYMHW
LGTQTYICNVNHKPS
1546)
WVRQAPG
ID NO:
YQQKPGK
YQQKPGK
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KCLEWVS
22)
APKLLIY
APKLLIY
SGNSQESV



QGLEWM
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
AASSLQS
TEQDSKDS



GIINPS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
GVPSRFS
TYSLSSTL



GGSTSY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
GSGSGTD
TLSKADYE



AQKFQG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
FTLTISS
KHKVYACE



RVTMTR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
LQPEDFA
VTHQGLSS



DTSTST
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
TYYCQQS
PVTKSFNR



VYMELS
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YSTPPTF
GEC (SEQ



SLRSED
LPAPIEKTISKAKGQ

DRPYYYD

GCGTKVE
GPGTKVD
ID NO:



TAVYYC
PREPQVYTLPPSREE

MDVWGKG

IK (SEQ
IK (SEQ
45)



ASGWVY
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
ID NO:




WGQGTL
YPSDIAVEWESNGQP

(SEQ ID

1543)
1479)




VTVSS
ENNYKTTPPVLDSDG

NO:







(SEQ
SFFLYSKLTVDKSRW

1542)







ID NO:
QQGNVFSCSVMHEAL









1478)
HNHYTQKSLSLSPG










(SEQ ID NO: 44)











PMAB74
EVQLLE
ASTKGPSVFPLAPSS
GGGSEG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGSEGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GSE
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



SYDMSW
LGTQTYICNVNHKPS
1546)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KCLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYD

GCGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

IDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1543)
ID NO:




WGQGTT
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1544)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1476)
(SEQ ID NO: 44)











PMAB75
EVQLVQ
ASTKGPSVFPLAPSS
GGGSEG
EVQLLES
GGGGSG
DIQMTQS
DIQMTQS
RTVAAPSV



SGAEVK
KSTSGGTAALGCLVK
GGSEGG
GGGLVQP
GGGSGG
PSSLSAS
PSSLSAS
FIFPPSDE



KPGASV
DYFPEPVTVSWNSGA
GSE
GGSLRLS
GGSGGG
VGDRVTI
VGDRVTI
QLKSGTAS



KVSCKA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
TCRASQS
VVCLLNNF



SGYSFT
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
ISSYLAW
YPREAKVQ



SYYMHW
LGTQTYICNVNHKPS
1546)
WVRQAPG
ID NO:
YQQKPGK
YQQKPGK
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KCLEWVS
22)
APKLLIY
APKLLIY
SGNSQESV



QGLEWM
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
AASSLQS
TEQDSKDS



GIINPS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
GVPSRFS
TYSLSSTL



GGSTSY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
GSGSGTD
TLSKADYE



AQKFQG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
FTLTISS
KHKVYACE



RVTMTR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
LQPEDFA
VTHQGLSS



DTSTST
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
TYYCQQS
PVTKSFNR



VYMELS
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YSTPPTF
GEC (SEQ



SLRSED
LPAPIEKTISKAKGQ

DRPYYYD

GCGTKVE
GPGTKVD
ID NO:



TAVYYC
PREPQVYTLPPSREE

IDVWGKG

IK (SEQ
IK (SEQ
45)



ASGWVY
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
ID NO:




WGQGTL
YPSDIAVEWESNGQP

(SEQ ID

1543)
1479)




VTVSS
ENNYKTTPPVLDSDG

NO:







(SEQ
SFFLYSKLTVDKSRW

1544)







ID NO:
QQGNVFSCSVMHEAL









1478)
HNHYTQKSLSLSPG










(SEQ ID NO: 44)











PMAB76
EVQLVQ
ASTKGPSVFPLAPSS
GGGSEG
EVQLLES
GGGGSG
DIQMTQS
DIQMTQS
RTVAAPSV



SGAEVK
KSTSGGTAALGCLVK
GGSEGG
GGGLVQP
GGGSGG
PSSLSAS
PSSLSAS
FIFPPSDE



KPGASV
DYFPEPVTVSWNSGA
GSE
GGSLRLS
GGSGGG
VGDRVTI
VGDRVTI
QLKSGTAS



KVSCKA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
TCRASQS
VVCLLNNF



SGYSFT
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
ISSYLAW
YPREAKVQ



SYYMHW
LGTQTYICNVNHKPS
1546)
WVRQAPG
ID NO:
YQQKPGK
YQQKPGK
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KCLEWVS
22)
APKLLIY
APKLLIY
SGNSQESV



QGLEWM
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
AASSLQS
TEQDSKDS



GIINPS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
GVPSRFS
TYSLSSTL



GGSTSY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
GSGSGTD
TLSKADYE



AQKFQG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
FTLTISS
KHKVYACE



RVTMTR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
LQPEDFA
VTHQGLSS



DISTST
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
TYYCQQS
PVTKSFNR



VYMELS
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YSTPPTF
GEC (SEQ



SLRSED
LPAPIEKTISKAKGQ

DRPYYYD

GCGTKVE
GPGTKVD
ID NO:



TAVYYC
PREPQVYTLPPSREE

LDVWGKG

IK (SEQ
IK (SEQ
45)



ASGWVY
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
ID NO:




WGQGTL
YPSDIAVEWESNGQP

(SEQ ID

1543)
1479)




VTVSS
ENNYKTTPPVLDSDG

NO:







(SEQ
SFFLYSKLTVDKSRW

1545)







ID NO:
QQGNVFSCSVMHEAL









1478)
HNHYTQKSLSLSPG










(SEQ ID NO: 44)











PMAB77
EVQLLE
ASTKGPSVFPLAPSS
GGGSEG
EVQLLES
GGGGSG
DIQMTQS
DIVMTQS
RTVAAPSV



SGGGLV
KSTSGGTAALGCLVK
GGSEGG
GGGLVQP
GGGSGG
PSSLSAS
PDSLAVS
FIFPPSDE



QPGGSL
DYFPEPVTVSWNSGA
GSE
GGSLRLS
GGSGGG
VGDRVTI
LGERATI
QLKSGTAS



RLSCAA
LTSGVHTFPAVLQSS
(SEQ
CAASGFT
GS
TCRASQS
NCKSSQS
VVCLLNNF



SGFTFS
GLYSLSSVVTVPSSS
ID NO:
FSSYWMH
(SEQ
ISSSLAW
VLYSPNN
YPREAKVQ



SYDMSW
LGTQTYICNVNHKPS
1546)
WVRQAPG
ID NO:
YQQKPGK
KNYLAWY
WKVDNALQ



VRQAPG
NTKVDKKVEPKSCDK

KCLEWVS
22)
APKLLIY
QQKPGQP
SGNSQESV



KGLEWV
THTCPPCPAPEAAGA

YISGSGG

AASSLQS
PKLLIYW
TEQDSKDS



SGITIS
PSVFLFPPKPKDTLM

YTNYADS

GVPSRFS
ASTRESG
TYSLSSTL



GGSTYY
ISRTPEVTCVVVDVS

VKGRFTI

GSGSGTD
VPDRFSG
TLSKADYE



ADSVKG
HEDPEVKFNWYVDGV

SRDNSKN

FTLTISS
SGSGTDF
KHKVYACE



RFTISR
EVHNAKTKPREEQYN

TLYLQMN

LQPEDFA
TLTISSL
VTHQGLSS



DNSKNT
STYRVVSVLTVLHQD

SLRAEDT

TYYCQQY
QAEDVAV
PVTKSFNR



LYLQMN
WLNGKEYKCKVSNKA

AVYYCAR

KSYPVTF
YYCQQYY
GEC (SEQ



SLRAED
LPAPIEKTISKAKGQ

DRPYYYD

GCGTKVE
TTPPTFG
ID NO:



TAVYYC
PREPQVYTLPPSREE

LDVWGKG

IK (SEQ
QGTRLEI
45)



ARGRGG
MTKNQVSLTCLVKGF

TTVTVSS

ID NO:
K (SEQ




SGWLDY
YPSDIAVEWESNGQP

(SEQ ID

1543)
ID NO:




WGQGTT
ENNYKTTPPVLDSDG

NO:


1359)




VTVSS
SFFLYSKLTVDKSRW

1545)







(SEQ
QQGNVFSCSVMHEAL









ID NO:
HNHYTQKSLSLSPG









1476)
(SEQ ID NO: 44)









In some embodiments, the therapeutic comprises one or more sequences, or a combination thereof, selected from the Table 12.


In some embodiments, the PD-1-MAdCAM antibody comprises an anti-PD-1 Fab as provided for in the following table

















TABLE 13





Clone










(Fab)
Fab VH Seg
Fab VL Seq
HCDR1
HCDR2
HCDR3
LCDR1
LCDR2
LCDR3







PMAB1
EVQLLESGGGL
DIVMTQSPDS
FTFSN
VSGIT
ARGRG
KSSQSV
WASTRE
QQYYTT



VQPGGSLRLSC
LAVSLGERAT
SDMS
ISGGS
GSGWL
LYSPNN
S (SEQ
PPT



AASGFTFSNSD
INCKSSQSVL
(SEQ
TYYA
DY
KNYLA
ID NO:
(SEQ



MSWVRQAPGKG
YSPNNKNYLA
ID NO:
(SEQ
(SEQ
(SEQ
1485)
ID NO:



LEWVSGITISG
WYQQKPGQPP
1481)
ID NO:
ID NO:
ID NO:

1486)



GSTYYADSVKG
KLLIYWASTR

1482)
1483)
1484)





RFTISRDNSKN
ESGVPDRESG









TLYLQMNSLRA
SGSGTDFTLT









EDTAVYYCARG
ISSLQAEDVA









RGGSGWLDYWG
VYYCQQYYTT









QGTLVTVSS
PPTFGQGTRL









(SEQ ID NO:
EIK (SEQ









1438)
ID NO:










1359)











PMAB15
EVQLLESGGGL
DIVMTQSPDS
FTFSS
VSGIT
ARGRG
KSSQSV
WASTRE
QQYYTT



VQPGGSLRLSC
LAVSLGERAT
YDMS
ISGGS
GSGWL
LYSPNN
S (SEQ
PPT



AASGFTFSSYD
INCKSSQSVL
(SEQ
TYYA
DY
KNYLA
ID NO:
(SEQ



MSWVRQAPGKG
YSPNNKNYLA
ID NO:
(SEQ
(SEQ
(SEQ
1485)
ID NO:



LEWVSGITISG
WYQQKPGQPP
1487)
ID NO:
ID NO:
ID NO:

1486)



GSTYYADSVKG
KLLIYWASTR

1482)
1483)
1484)





RFTISRDNSKN
ESGVPDRFSG









TLYLQMNSLRA
SGSGTDFTLT









EDTAVYYCARG
ISSLQAEDVA









RGGSGWLDYWG
VYYCQQYYTT









QGTLVTVSS
PPTFGQGTRL









(SEQ ID NO:
EIK (SEQ









1446)
ID NO:










1359)











PMAB17
EVQLLESGGGL
DIVMTQSPDS
FTFSS
VSGIT
ARGRG
KSSQSV
WASTRE
QQYYTT



VQPGGSLRLSC
LAVSLGERAT
YDMS
ISGGS
GSGWL
LYSPNN
S (SEQ
PPT



AASGFTFSSYD
INCKSSQSVL
(SEQ
TYYA
DY
KNYLA
ID NO:
(SEQ



MSWVRQAPGKG
YSPNNKNYLA
ID NO:
(SEQ
(SEQ
(SEQ
1485)
ID NO:



LEWVSGITISG
WYQQKPGQPP
1487)
ID NO:
ID NO:
ID NO:

1486)



GSTYYADSVKG
KLLIYWASTR

1482)
1483)
1484)





RFTISRDNSKN
ESGVPDRESG









TLYLQMNSLRA
SGSGTDFTLT









EDTAVYYCARG
ISSLQAEDVA









RGGSGWLDYWG
VYYCQQYYTT









QGTDVTVSS
PPTFGQGTRL









(SEQ ID NO:
EIK (SEQ









1447)
ID NO:










1359)











PMAB18
QVQLVQSGAEV
DIQMTQSPSS
YSFTT
MGIIA
ASGWV
QASRDI
AASSLQ
QQSYST



KKPGASVKVSC
LSASVGDRVT
YYMH
PSGGS
Y
KNYLA
S (SEQ
PPT



KASGYSFTTYY
ITCQASRDIK
(SEQ
TSYA
(SEQ
(SEQ
ID NO:
(SEQ



MHWVRQAPGQG
NYLAWYQQKP
ID NO:
(SEQ
ID NO:
ID NO:
1491)
ID NO:



LEWMGIIAPSG
GKAPKLLIYA
628)
ID NO:
1489)
1490)

1492)



GSTSYAQKFQG
ASSLQSGVPS

1488)







RVTMTRDTSTS
RFSGSGSGTD









TVYMELSSLRS
FTLTISSLQP









EDTAVYYCASG
EDFATYYCQQ









WVYWGQGTLVT
SYSTPPTFGP









VSS (SEQ ID
GTKVDIK









NO: 1448)
(SEQ ID










NO: 1449)











PMAB53
EVQLLESGGGL
DIVMTQSPDS
FTFSS
VSGIT
ARGRG
KSSQSV
WASTRE
QQYYTT



VQPGGSLRLSC
LAVSLGERAT
YDMS
ISGGS
GSGWL
LYSPNN
S (SEQ
PPT



AASGFTFSSYD
INCKSSQSVL
(SEQ
TYYA
DY
KNYLA
ID NO:
(SEQ



MSWVRQAPGKG
YSPNNKNYLA
ID NO:
(SEQ
(SEQ
(SEQ
1485)
ID NO:



LEWVSGITISG
WYQQKPGQPP
1487)
ID NO:
ID NO:
ID NO:

1486)



GSTYYADSVKG
KLLIYWASTR

1482)
1483)
1484)





RFTISRDNSKN
ESGVPDRESG









TLYLQMNSLRA
SGSGTDFTLT









EDTAVYYCARG
ISSLQAEDVA









RGGSGWLDYWG
VYYCQQYYTT









QGTTVTVSS
PPTFGQGTRL









(SEQ ID NO:
EIK (SEQ









1476)
ID NO:










1359)








PMAB54
EVQLVQSGAEV
DIQMTQSPSS
YSFTS
MGIIN
ASGWV
RASQSI
AASSLQ
QQSYST



KKPGASVKVSC
LSASVGDRVT
YYMH
PSGGS
Y
SSYLA
S (SEQ
PPT



KASGYSFTSYY
ITCRASQSIS
(SEQ
TSYA
(SEQ
(SEQ
ID NO:
(SEQ



MHWVRQAPGQG
SYLAWYQQKP
ID NO:
(SEQ
ID NO:
ID NO:
1491)
ID NO:



LEWMGIINPSG
GKAPKLLIYA
766)
ID NO:
1489)
1214)

1492)



GSTSYAQKFQG
ASSLQSGVPS

977)







RVTMTRDTSTS
RFSGSGSGTD









TVYMELSSLRS
FTLTISSLQP









EDTAVYYCASG
EDFATYYCQQ









WVYWGQGTLVT
SYSTPPTFGP









VSS (SEQ ID
GTKVDIK









NO: 1478)
(SEQ ID










NO: 1479)









In some embodiments, the therapeutic comprises one or more sequences, or a combination thereof, selected from the Table 13.


In some embodiments, the PD-1-MAdCAM antibody comprises an anti-MAdCAM scFv as provided for in the following table:

















TABLE 14





Clone










(SCFv)
scFv VH Seq
scFv VL Seq
HCDR1
HCDR2
HCDR3
LCDR1
LCDR2
LCDR3







PMAB1
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1495)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









591)
NO: 592)











PMAB2
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SAISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SSGST
PYGYY
SSSLA
(SEQ
PVT



AASGFTFSSYW
ITCRASQSIS
(SEQ
YYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
SSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWVSAISGSS
GKAPKLLIYA
NO:
ID
ID
1502)

1498)



GSTYYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1500)
1501)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYGYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1347)
NO: 1367)











PMAB3
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SAISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SSGST
PYYYY
SSSLA
(SEQ
PVT



AASGFTFSSYW
ITCRASQSIS
(SEQ
YYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
SSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWVSAISGSS
GKAPKLLIYA
NO:
ID
ID
1502)

1498)



GSTYYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1500)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1439)
NO: 1367)











PMAB5
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SAISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SSGST
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSSYW
ITCRASQSIS
(SEQ
YYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWVSAISGSS
GKAPKLLIYA
NO:
ID
ID
1504)

1498)



GSTYYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1500)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1439)
NO: 1363)











PMAB6
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SAISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SGGST
PYGYY
SSSLA
(SEQ
PVT



AASGFTFSSYW
ITCRASQSIS
(SEQ
YYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
SSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISAISGSG
GKAPKLLIYA
NO:
ID
ID
1502)

1498)



GSTYYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1505)
1501)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYGYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1440)
NO: 1367)











PMAB7
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SAISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SGGST
PYYYY
SSSLA
(SEQ
PVT



AASGFTFSSYW
ITCRASQSIS
(SEQ
YYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
SSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISAISGSG
GKAPKLLIYA
NO:
ID
ID
1502)

1498)



GSTYYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1505)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1441)
NO: 1367)











PMAB8
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SAISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SGGST
PYGYY
SRSLA
(SEQ
PVT



AASGFTESSYW
ITCRASQSIS
(SEQ
YYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISAISGSG
GKAPKLLIYA
NO:
ID
ID
1504)

1498)



GSTYYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1505)
1501)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYGYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1440)
NO: 1363)











PMAB9
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SAISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SGGST
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSSYW
ITCRASQSIS
(SEQ
YYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISAISGSG
GKAPKLLIYA
NO:
ID
ID
1504)

1498)



GSTYYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1505)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1441)
NO: 1363)











PMAB10
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SAISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SGGST
PYGYY
SSSLA
(SEQ
PVT



AASGFTESSYW
ITCRASQSIS
(SEQ
YYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
SSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWVSAISGSG
GKAPKLLIYA
NO:
ID
ID
1502)

1498)



GSTYYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1505)
1501)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYGYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1442)
NO: 1367)











PMAB11
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SAISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SGGST
PYYYY
SSSLA
(SEQ
PVT



AASGFTFSSYW
ITCRASQSIS
(SEQ
YYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
SSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWVSAISGSG
GKAPKLLIYA
NO:
ID
ID
1502)

1498)



GSTYYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1505)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1395)
NO: 1367)








PMAB12
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SAISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SGGST
PYGYY
SRSLA
(SEQ
PVT



AASGFTFSSYW
ITCRASQSIS
(SEQ
YYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWVSAISGSG
GKAPKLLIYA
NO:
ID
ID
1504)

1498)



GSTYYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1505)
1501)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYGYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1442)
NO: 1363)











PMAB13
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SAISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SGGST
PYYYY
SRSLA
(SEQ
PVT



AASGFTESSYW
ITCRASQSIS
(SEQ
YYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWVSAISGSG
GKAPKLLIYA
NO:
ID
ID
1504)

1498)



GSTYYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1505)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1395)
NO: 1363)











PMAB14
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SYISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SGGYT
PYGYY
SSSLA
(SEQ
PVT



AASGFTFSSYW
ITCRASQSIS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
SSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWVSYISGSG
GKAPKLLIYA
NO:
ID
ID
1502)

1498)



GYTNYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1506)
1501)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYGYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1443)
NO: 1367)











PMAB15
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SAISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SGGST
PYYYD
SSSLA
(SEQ
PVT



AASGFTESSYW
ITCRASQSIS
(SEQ
YYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
SSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWVSAISGSG
GKAPKLLIYA
NO:
ID
ID
1502)

1498)



GSTYYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1505)
1507)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYDMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1444)
NO: 1367)











PMAB16
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SYISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SGGYT
PYYYD
SSSLA
(SEQ
PVT



AASGFTFSSYW
ITCRASQSIS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
SSLAWYQQKP
ID
(SEQ
SEQ
ID NO:
1497)
ID NO:



LEWVSYISGSG
GKAPKLLIYA
NO:
ID
ID
1502)

1498)



GYTNYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1506)
1507)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYDMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1445)
NO: 1367)











PMAB19
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSSFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1508)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1353)
NO: 592)











PMAB20
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDYW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1509)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1391)
NO: 592)











PMAB21
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FAMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFA
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1510)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1450)
NO: 592)











PMAB22
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMS
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MSWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1511)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1451)
NO: 592)











PMAB23
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWVSYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1452)
NO: 592)











PMAB24
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SAISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISAISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1512)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1453)
NO: 592)











PMAB25
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
SSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGSS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1513)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1454)
NO: 592)








PMAB26
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DGGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDG
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1514)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1455)
NO: 592)











PMAB27
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGST
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GSTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1515)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1456)
NO: 592)











PMAB28
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
YYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTYYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1516)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1457)
NO: 592)











PMAB29
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYAASVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1458)
NO: 592)











PMAB30
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYAQSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1459)
NO: 592)











PMAB31
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDASKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1460)
NO: 592)











PMAB32
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDQSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1379)
NO: 592)











PMAB33
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEç
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMASLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1461)
NO: 592)











PMAB34
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMGSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO
(SEQ ID









1462)
NO: 592)











PMAB35
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMQSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1463)
NO: 592)











PMAB36
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSIS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1504)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









591)
NO: 1363)











PMAB37
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SSSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
SSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1517)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









591)
NO: 1364)











PMAB38
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRYLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RYLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1518)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









591)
NO: 1365)











PMAB39
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLN
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLNWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1519)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









591)
NO: 1366)











PMAB40
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQSKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1520)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
SKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









591)
NO: 1464)











PMAB41
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYYSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1521)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YYSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









591)
NO: 1465)











PMAB42
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKST



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1522)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSTPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









591)
NO: 1466)











PMAB43
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYY
SRSLA
(SEQ
PRT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1523)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1503)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYYMDVWG
YKSYPRTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO
(SEQ ID









591)
NO: 1467)











PMAB44
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PTYYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1524)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPTYYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1390)
NO: 592)











PMAB45
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYDYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1525)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYDYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1468)
NO: 592)











PMAB46
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYGYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEç
NYA
MDVW
SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1501)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYGYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1469)
NO: 592)











PMAB47
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYNYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1526)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYNYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1470)
NO: 592)











PMAB48
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYSYY
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1527)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYSYYMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1471)
NO: 592)











PMAB49
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYD
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1507)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYDMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1472)
NO: 592)











PMAB50
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYE
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1528)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYEMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1473)
NO: 592)











PMAB51
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYK
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1529)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYKMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1474)
NO: 592)











PMAB52
EVQLLESGGGL
DIQMTQSPSS
FTFSD
SYISG
CARDR
RASQSV
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
FWMH
DSGYT
PYYYS
SRSLA
(SEQ
PVT



AASGFTFSDFW
ITCRASQSVS
(SEQ
NYA
MDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
RSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWISYISGDS
GKAPKLLIYA
NO:
ID
ID
1496)

1498)



GYTNYADSVKG
ASSLQSGVPS
1493)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1494)
1530)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYSMDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1475)
NO: 592)











PMAB53
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SYISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SGGYT
PYYYD
SSSLA
(SEQ
PVT



AASGFTESSYW
ITCRASQSIS
(SEQ
NYA
IDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
SSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWVSYISGSG
GKAPKLLIYA
NO:
ID
ID
1502)

1498)



GYTNYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1506)
1531)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYDIDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1477)
NO: 1367)











PMAB55
EVQLLESGGGL
DIQMTQSPSS
FTFSS
SYISG
CARDR
RASQSI
SSLQS
QQYKSY



VQPGGSLRLSC
LSASVGDRVT
YWMH
SGGYT
PYYYD
SSSLA
(SEQ
PVT



AASGFTFSSYW
ITCRASQSIS
(SEQ
NYA
LDVW
(SEQ
ID NO:
(SEQ



MHWVRQAPGKG
SSLAWYQQKP
ID
(SEQ
(SEQ
ID NO:
1497)
ID NO:



LEWVSYISGSG
GKAPKLLIYA
NO:
ID
ID
1502)

1498)



GYTNYADSVKG
ASSLQSGVPS
1499)
NO:
NO:






RFTISRDNSKN
RFSGSGSGTD

1506)
1532)






TLYLQMNSLRA
FTLTISSLQP









EDTAVYYCARD
EDFATYYCQQ









RPYYYDLDVWG
YKSYPVTFGQ









KGTTVTVSS
GTKVEIK









(SEQ ID NO:
(SEQ ID









1480)
NO: 1367)









In some embodiments, the therapeutic comprises one or more sequences, or a combination thereof, selected from the Table 14.


In some embodiments, the therapeutic a Fab PD-1 antibody fused via a linker to a scFv MAdCAM antibody. In some embodiments, the Fab PD-1 antibody is fused to a IgG1 constant domain, wherein said IgG1 constant domain is fused to scFv MAdCAM antibody via a Fc-scFv linker. In some embodiment the scFv MAdCAM antibody comprises an internal scFv linker. In some embodiments, the linker is a peptide linker. In some embodiments, the peptide linker is a glycine/serine linker as provided herein.


In some embodiments, the PD-1-MAdCAM antibody comprises one or more sequences as shown in Table 12. In some embodiments, the MAdCAM antibody comprises a combination of one or more sequence as shown in Table 12. In some embodiments, the anti-PD-1 antibody is in the Fab format and the anti-MAdCAM antibody is in a scFV format as illustrated in Table 12. In some embodiments, the Fab portion of the antibody comprises a CDR1 from any one of clones PMAB1-54 of Table 13, a CDR2 from any one of clones PMAB1-54 of Table 13, and a CDR3 from any one of clones PMAB1-54 of Table 13. In some embodiments, the Fab portion of the antibody comprises a LCDR1 from any one of clones PMAB1-54 of Table 13, a LCDR2 from any one of clones PMAB1-54 of Table 13, and a LCDR3 from any one of clones PMAB1-54 of Table 13. In some embodiments, the scFv portion of the antibody comprises a CDR1 from any one of clones PMAB1-55 of Table 14, a CDR2 from any one of clones PMAB1-55 of Table 14, and a CDR3 from any one of clones PMAB1-55 of Table 14. In some embodiments, the scFv portion of the antibody comprises a LCDR1 from any one of clones PMAB1-55 of Table 14, a LCDR2 from any one of clones PMAB1-55 of Table 14, and a LCDR3 from any one of clones PMAB1-55 of Table 14. In some embodiments, the amino acid residues of the CDRs shown above contain mutations. In some embodiments, the CDRs contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions or mutations. In some embodiments, the substitution is a conservative substitution.


In some embodiments, the PD-1-MAdCAM antibody has a VH region selected from any one of clones PMAB1-77 of Table 12 and a VL region selected from any one of clones PMAB1-77 as set forth in of Table 12. In some embodiments, the antibody comprises a Fab CDR1 from any one of clones PMAB1-54 of Table 13, a Fab CDR2 from any one of clones PMAB1-54 of Table 13, and a Fab CDR3 from any one of clones PMAB1-54 of Table 13, a scFv CDR1 from any one of clones PMAB1-55 of Table 14, a Fab CDR2 from any one of clones PMAB1-55 of Table 14, and a Fab CDR3 from any one of clones PMAB1-55 of Table 14.


In some embodiments, the variable heavy chain has a Fab HCDR1, HCDR2, and a HCDR3 as set forth for PMAB1 in Table 13. In some embodiments, the variable heavy chain has a Fab HCDR1, HCDR2, and a HCDR3 as set forth for PMAB15 in Table 13. In some embodiments, the variable heavy chain has a Fab HCDR1, HCDR2, and a HCDR3 as set forth for PMAB17 in Table 13. In some embodiments, the variable heavy chain has a Fab HCDR1, HCDR2, and a HCDR3 as set forth for PMAB18 in Table 13. In some embodiments, the variable heavy chain has a Fab HCDR1, HCDR2, and a HCDR3 as set forth for PMAB53 in Table 13. In some embodiments, the variable heavy chain has a Fab HCDR1, HCDR2, and a HCDR3 as set forth for PMAB54 in Table 13.


In some embodiments, the variable light chain has a Fab LCDR1, LCDR2, and a LCDR3 as set forth for PMAB1 in Table 13. In some embodiments, the variable light chain has a Fab LCDR1, LCDR2, and a LCDR3 as set forth for PMAB15 in Table 13. In some embodiments, the variable light chain has a Fab LCDR1, LCDR2, and a LCDR3 as set forth for PMAB17 in Table 13. In some embodiments, the variable light chain has a Fab LCDR1, LCDR2, and a LCDR3 as set forth for PMAB18 in Table 13. In some embodiments, the variable light chain has a Fab LCDR1, LCDR2, and a LCDR3 as set forth for PMAB53 in Table 13. In some embodiments, the variable light chain has a Fab LCDR1, LCDR2, and a LCDR3 as set forth for PMAB54 in Table 13.


In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB1 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB2 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB3 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB5 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB6 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB7 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB8 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB9 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB10 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB11 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB12 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB13 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB14 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB15 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB16 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB19 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB20 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB21 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB22 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB23 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB24 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB25 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB26 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB27 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB28 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB29 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB30 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB31 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB32 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB33 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB34 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB35 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB36 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB37 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB38 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB39 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB40 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB41 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB42 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB43 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB44 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB45 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB46 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB47 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB48 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB49 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB50 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB51 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB52 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB53 in Table 14. In some embodiments, the variable heavy chain has a scFv HCDR1, HCDR2, and a HCDR3 as set forth for PMAB55 in Table 14.


In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB1 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB2 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB3 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB5 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB6 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB7 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB8 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB9 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB10 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB11 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB12 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB13 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB14 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB15 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB16 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB19 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB20 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB21 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB22 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB23 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB24 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB25 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB26 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB27 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB28 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB29 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB30 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB31 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB32 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB33 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB34 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB35 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB36 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB37 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB38 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB39 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB40 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB41 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB42 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB43 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB44 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB45 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB46 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB47 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB48 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB49 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB50 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB51 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB52 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB53 in Table 14. In some embodiments, the variable light chain has a scFv LCDR1, LCDR2, and a LCDR3 as set forth for PMAB55 in Table 14.


In some embodiments, the CDRS are swapped for one another. For example, the Fab HCDR1 of clone PMAB1 can be substituted for the Fab HCDR1 of clone PMAB2, or vice versa. This CDR swapping can be done for any of the Fab HCDRs of the clones provided herein (e.g., HCDR1 for HCDR1; HCDR2 for HCDR2; or HCDR3 for HCDR3) or the Fab LCDRs (e.g., LCDR1 for LCDR1; LCDR2 for LCDR2; or LCDR3 for LCDR3). Furthermore, the CDR swapping can be done for any of the scFv HCDRs of the clones provided herein (e.g., HCDR1 for HCDR1; HCDR2 for HCDR2; or HCDR3 for HCDR3) or the scFv LCDRs (e.g., LCDR1 for LCDR1; LCDR2 for LCDR2; or LCDR3 for LCDR3). Therefore, in some embodiments, the antibody comprises a Fab HCDR1 as set forth in any of PMAB1-54 of Table 13, a HCDR2 as set forth in any of PMAB1-54 of Table 13, a HCDR3 as set forth in any of PMAB1-54 of Table 13, a LCDR1 as set forth in any of PMAB1-54 of Table 13, a LCDR2 as set forth in any of PMAB1-54 of Table 13, a LCDR3 as set forth in any of PMAB1-54 of Table 13, or a variant of any of the foregoing. In some embodiments, the antibody comprises a scFv HCDR1 as set forth in any of PMAB1-55 of Table 14, a HCDR2 as set forth in any of PMAB1-55 of Table 14, a HCDR3 as set forth in any of PMAB1-55 of Table 14, a LCDR1 as set forth in any of PMAB1-55 of Table 14, a LCDR2 as set forth in any of PMAB1-55 of Table 14, a LCDR3 as set forth in any of PMAB1-55 of Table 14, or a variant of any of the foregoing.


In some embodiments, the VH comprises a sequence as set forth in Table 12. In some embodiments, the VK comprises a sequence as set forth in Table 12. In some embodiments, the Ab comprises a VH and a VK as set forth for the clones in Table 12. In some embodiments, the VH and VK are linked by a linker. In some embodiments, the linker is a peptide linker as provided for herein. In some embodiments, the peptide linker is the linker as provided for in Table 12.


Polypeptides Derived from Reference, e.g., Human Polypeptides


In some embodiments, a component of a therapeutic molecule is derived from or based on a reference molecule, e.g., in the case of a therapeutic molecule for use in humans, from a naturally occurring human polypeptide. E.g., In some embodiments, all or a part of a CD39 molecule, a CD73 molecule, a cell surface molecule binder, a donor specific targeting moiety, an effector ligand binding molecule, an ICIM binding/modulating moiety, an IIC binding/modulating moiety, an inhibitory immune checkpoint molecule ligand molecule, an inhibitory molecule counter ligand molecule, a SM binding/modulating moiety, a specific targeting moiety, a target ligand binding molecule, or a tissue specific targeting moiety, can be based on or derived from a naturally occurring human polypeptide. E.g., a PD-L1 molecule can be based on or derived from a human PD-L1 sequence.


In some embodiments, a therapeutic compound component, e.g., a PD-L1 molecule:

    • a) comprises all or a portion of, e.g., an active portion of, a naturally occurring form of the human polypeptide;
    • b) comprises all or a portion of, e.g., an active portion of, a human polypeptide having a sequence appearing in a database, e.g., GenBank database, on Jan. 11, 2017, a naturally occurring form of the human polypeptide that is not associated with a disease state;
    • c) comprises a human polypeptide having a sequence that differs by no more than 1, 2, 3, 4, 5, 10, 20, or 30 amino acid residues from a sequence of a) orb);
    • d) comprises a human polypeptide having a sequence that differs at no more than by 1, 2, 3, 4, 5 10, 20, or 30% its amino acids residues from a sequence of a) or b);
    • e) comprises a human polypeptide having a sequence that does not differ substantially from a sequence of a) or b); or
    • f) comprises a human polypeptide having a sequence of c), d), or e) that does not differ substantially in a biological activity, e.g., ability to enhance or inhibit an immune response, from a human polypeptide having the sequence of a) or b).


In some embodiments, therapeutic compounds can comprise a plurality of effector binding/modulating moieties. For example, a therapeutic compound can comprise two or more of the following selected from:


(a) an ICIM binding/modulating moiety; (b) an IIC binding/modulating moiety; (c) an SM binding/modulating moiety, or (d) an ICSM binding/modulating moiety. In some embodiments, for example, a therapeutic compound can comprise a plurality, e.g., two, ICIM binding/modulating moieties (wherein they are the same or different); by way of example, two that activate or agonize PD-1; a plurality, e.g., two, IIC binding/modulating moieties; (wherein they are the same or different); a plurality, e.g., two, SM binding/modulating moieties (wherein they are the same or different), or a plurality, e.g., tow, ICSM binding/modulating moieties (wherein they are the same or different). In some embodiments, the therapeutic compound can comprise an ICIM binding/modulating moiety and an IIC binding/modulating moiety; an ICIM binding/modulating moiety and an SM binding/modulating moiety; an IIC binding/modulating moiety and an SM binding/modulating moiety, an ICIM binding/modulating moiety and an ICSM binding/modulating moiety; an IIC binding/modulating moiety and an ICSM binding/modulating moiety; or an ICSM binding/modulating moiety and an SM binding/modulating moiety. In some embodiments, the therapeutic compound comprises a plurality of targeting moieties. In some embodiments, the targeting moieties can be the same or different.


Pharmaceutical Compositions and Kits

In another aspect, the present embodiments provide compositions, e.g., pharmaceutically acceptable compositions, which include a therapeutic compound described herein, formulated together with a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible.


The carrier can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, local, ophthalmic, topical, spinal or epidermal administration (e.g. by injection or infusion). As used herein, the term “carrier” means a diluent, adjuvant, or excipient with which a compound is administered. In some embodiments, pharmaceutical carriers can also be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carriers can also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents can be used. The carriers can be used in pharmaceutical compositions comprising the therapeutic compounds provided for herein.


The compositions and compounds of the embodiments provided for herein may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liposomes and suppositories. The preferred form depends on the intended mode of administration and therapeutic application. Typical compositions are in the form of injectable or infusible solutions. In some embodiments, the mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In some embodiments, the therapeutic molecule is administered by intravenous infusion or injection. In another embodiment, the therapeutic molecule is administered by intramuscular or subcutaneous injection. In another embodiment, the therapeutic molecule is administered locally, e.g., by injection, or topical application, to a target site. The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.


Therapeutic compositions typically should be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high therapeutic molecule concentration. Sterile injectable solutions can be prepared by incorporating the active compound (i.e., therapeutic molecule) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.


As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. In certain embodiments, the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.


In certain embodiments, a therapeutic compound can be orally administered, for example, with an inert diluent or an assimilable edible carrier. The compound (and other ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. To administer a compound by other than parenteral administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. Therapeutic compositions can also be administered with medical devices known in the art.


Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.


An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of a therapeutic compound is 0.1-30 mg/kg, more preferably 1-25 mg/kg. Dosages and therapeutic regimens of the therapeutic compound can be determined by a skilled artisan. In certain embodiments, the therapeutic compound is administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 to 40 mg/kg, e.g., 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, 1 to 10 mg/kg, 5 to 15 mg/kg, 10 to 20 mg/kg, 15 to 25 mg/kg, or about 3 mg/kg. The dosing schedule can vary from e.g., once a week to once every 2, 3, or 4 weeks. In one embodiment, the therapeutic compound is administered at a dose from about 10 to 20 mg/kg every other week. The therapeutic compound can be administered by intravenous infusion at a rate of more than 20 mg/min, e.g., 20-40 mg/min, and typically greater than or equal to 40 mg/min to reach a dose of about 35 to 440 mg/m2, typically about 70 to 310 mg/m2, and more typically, about 110 to 130 mg/m2. In embodiments, the infusion rate of about 110 to 130 mg/m2 achieves a level of about 3 mg/kg. In other embodiments, the therapeutic compound can be administered by intravenous infusion at a rate of less than 10 mg/min, e.g., less than or equal to 5 mg/min to reach a dose of about 1 to 100 mg/m2, e.g., about 5 to 50 mg/m2, about 7 to 25 mg/m2, or, about 10 mg/m2. In some embodiments, the therapeutic compound is infused over a period of about 30 min. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.


The pharmaceutical compositions may include a “therapeutically effective amount” or a “prophylactically effective amount” of a therapeutic molecule. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of a therapeutic molecule may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the therapeutic compound to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a therapeutic molecule t is outweighed by the therapeutically beneficial effects. A “therapeutically effective dosage” preferably inhibits a measurable parameter, e.g., immune attack at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects. The ability of a compound to inhibit a measurable parameter, e.g., immune attack, can be evaluated in an animal model system predictive of efficacy in transplant rejection or autoimmune disorders. Alternatively, this property of a composition can be evaluated by examining the ability of the compound to inhibit, such inhibition in vitro by assays known to the skilled practitioner.


A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.


Also within the scope of the embodiments is a kit comprising a therapeutic compound described herein. The kit can include one or more other elements including: instructions for use; other reagents, e.g., a label, a therapeutic agent, or an agent useful for chelating, or otherwise coupling, a therapeutic molecule to a label or other therapeutic agent, or a radioprotective composition; devices or other materials for preparing the a therapeutic molecule for administration; pharmaceutically acceptable carriers; and devices or other materials for administration to a subject.


In some embodiments, an isolated nucleic acid is provided, wherein the nucleic acid encodes a polypeptide, an antibody, or antigen binding fragment thereof, as provided for herein. In some embodiments, an expression vector comprising the nucleic acid is provided. In some embodiment, a host cell comprising the isolated nucleic acid as provided for herein, or the vector as provided for herein is provided. In some embodiments, a method of making a polypeptide or antibody as provided for herein is provided. In some embodiments, the method comprises culturing a host cell as provided for herein to make the polypeptide or antibody as provided for herein. In some embodiments, a method of producing an antibody or antigen binding fragment thereof as provide for herein comprises (a) culturing a host cell comprising one or more nucleic acids encoding the antibody or antigen binding fragment thereof in a culture medium under conditions favorable for expression of the one or more nucleic acids and (b) optionally recovering the antibody or antigen binding fragment thereof from the culture medium. In some embodiments, a method of making or producing a polypeptide, or an antibody, or antigen binding fragment thereof, is provided, wherein the polypeptide, or the antibody, or antigen binding fragment thereof, comprises a heavy chain variable region and a light chain variable region, wherein: the heavy chain variable region comprises a variable heavy CDR1 (HCDR1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1499, a variable heavy CDR2 (HCDR2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1506, and variable heavy CDR3 (HCDR3) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1507, 1531 or 1532; and the light chain variable region comprises a variable light CDR1 (LCDR1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1502, a variable light CDR2 (LCDR2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1497, and a variable light CDR3 (LCDR3) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1498. In some embodiments, a method of making or producing a polypeptide, or an antibody, or antigen binding fragment thereof, is provided, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NOs: 1445, 1477, or 1480 and the light chain variable region comprises an amino acid of SEQ ID NO: 1367.


In some embodiments, a method of making or producing a polypeptide, or an antibody, or antigen binding fragment thereof, is provided, wherein the polypeptide, or the antibody, or antigen binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a variable heavy CDR1 (HCDR1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1499, a variable heavy CDR2 (HCDR2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1506, and variable heavy CDR3 (HCDR3) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1507, 1531 or 1532; and the light chain variable region comprises a variable light CDR1 (LCDR1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1502, a variable light CDR2 (LCDR2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1497, and a variable light CDR3 (LCDR3) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1498, wherein the method comprises (a) culturing a host cell comprising one or more nucleic acids encoding the antibody or antigen binding fragment thereof in a culture medium under conditions favorable for expression of the one or more nucleic acids encoding the heavy chain variable region comprising a variable heavy CDR1 (HCDR1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1499, a variable heavy CDR2 (HCDR2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1506, and variable heavy CDR3 (HCDR3) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1507, 1531 or 1532; and the light chain variable region comprising a variable light CDR1 (LCDR1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1502, a variable light CDR2 (LCDR2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1497, and a variable light CDR3 (LCDR3) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1498; and (b) optionally recovering the antibody or antigen binding fragment thereof from the culture medium.


In some embodiments, a method of making or producing a polypeptide, or an antibody, or antigen binding fragment thereof, is provided, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NOs: 1445, 1477, or 1480 and the light chain variable region comprises an amino acid of SEQ ID NO: 1367, wherein the method comprises (a) culturing a host cell comprising one or more nucleic acids encoding the antibody or antigen binding fragment thereof in a culture medium under conditions favorable for expression of the one or more nucleic acids encoding the heavy chain variable region comprising an amino acid sequence of SEQ ID NOs: 1445, 1477, or 1480 and the light chain variable region comprising an amino acid of SEQ ID NO: 1367; and (b) optionally recovering the antibody or antigen binding fragment thereof from the culture medium.


In some embodiments, embodiments provided herein also include, but are not limited to:

    • 1. An antibody that binds to MAdCAM, wherein the antibody comprises one or more amino acid sequence as provided in Table 9, Table 10, Table 11, Table 12, Table 14, or Table 15.
    • 2. The antibody of embodiment 1, or antigen binding fragment thereof, wherein the antibody, or antigen binding fragment thereof, comprises:
      • (i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of any of the CDR1 sequences set forth in Table 9, Table 14, or Table 15; the heavy chain CDR2 has the amino acid sequence of any of the CDR2 sequences set forth in Table 9, Table 14, or Table 15; and the heavy chain CDR3 has the amino acid sequence of any of the CDR3 sequences set forth in Table 9, Table 14, or Table 15, or variants of any of the foregoing; and
      • (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of any of the CDR1 sequences set forth in Table 9, Table 14, or Table 15; the light chain CDR2 has the amino acid sequence of any of the CDR2 sequences set forth in Table 9, Table 14, or Table 15; and the light chain CDR3 has the amino acid sequence of any of the CDR3 sequences set forth in Table 9, Table 14, or Table 15, or variants of any of the foregoing.
    • 3. The antibody of any one of embodiments 1-2, or antigen binding fragment thereof, wherein the antibody, or antigen binding fragment thereof, comprises:
      • i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NOs: 359; the heavy chain CDR2 has the amino acid sequence of SEQ ID NOs: 170, and the heavy chain CDR3 has the amino acid sequence of SEQ ID NOs: 360, or 1431, or variants of any of the foregoing; and
      • (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NOs: 361, or 1408; the light chain CDR2 has the amino acid sequence of SEQ ID NOs: 362, and the light chain CDR3 has the amino acid sequence of SEQ ID NOs: 363, or variants of any of the foregoing.
    • 4. The antibody of any one of embodiments 1-2, or antigen binding fragment thereof, wherein the antibody, or antigen binding fragment thereof, comprises:
      • i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence SEQ ID NO: 359, the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 170, and the heavy chain CDR3 has the amino acid sequence of SEQ ID NO:360, or variants of any of the foregoing; and
      • (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 361, the light chain LCDR2 has the amino acid sequence of SEQ ID NO: 362, and the light chain CDR3 has the amino acid sequence of SEQ ID NO: 363, or variants of any of the foregoing.
    • 5. The antibody of any one of embodiments 1-2, or antigen binding fragment thereof, wherein the antibody, or antigen binding fragment thereof, comprises:
      • i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence SEQ ID NO: 359, the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 170, and the heavy chain CDR3 has the amino acid sequence of SEQ ID NO: 1431, or variants of any of the foregoing; and
      • (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 1408, the light chain LCDR2 has the amino acid sequence of SEQ ID NO: 362, and the light chain CDR3 has the amino acid sequence of SEQ ID NO: 363, or variants of any of the foregoing.
    • 6. The antibody of any one of embodiments 1-2, or antigen binding fragment thereof, wherein the antibody, or antigen binding fragment thereof, comprises:
      • i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NOs: 135; the heavy chain CDR2 has the amino acid sequence of SEQ ID NOs: 381, and the heavy chain CDR3 has the amino acid sequence of SEQ ID NOs: 1342, or variants of any of the foregoing; and
      • (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NOs: 383; the light chain CDR2 has the amino acid sequence of SEQ ID NOs: 241, and the light chain CDR3 has the amino acid sequence of SEQ ID NOs: 652, or variants of any of the foregoing.
    • 7. The antibody of any one of embodiments 1-2, or antigen binding fragment thereof, wherein the antibody, or antigen binding fragment thereof, comprises:
      • i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence SEQ ID NO: 135, the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 381, and the heavy chain CDR3 has the amino acid sequence of SEQ ID NO: 1342, or variants of any of the foregoing; and
      • (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 383, the light chain LCDR2 has the amino acid sequence of SEQ ID NO: 241, and the light chain CDR3 has the amino acid sequence of SEQ ID NO: 652, or variants of any of the foregoing.
    • 8. The antibody of any one of the preceding embodiments, wherein the heavy chain variable region and the light chain variable region are in a scFv format.
    • 9. The antibody of any one of the preceding embodiments, wherein the heavy chain variable region and the light chain variable region are in a Fab format.
    • 10. The antibody of any one of embodiments 6-7, wherein the heavy chain variable region and the light variable chain region are linked with a peptide linker, such as a glycine/serine linker.
    • 11. The antibody of embodiment 1, or antigen binding fragment thereof, wherein the antibody comprises a VK/VL sequence as shown in Table 9, Table 10, Table 11, Table 12, Table 14, or Table 15.
    • 12. The antibody of embodiment 9, wherein the VK/VL sequence comprises a sequence of SEQ ID NOs: 592, 663, 667, 669, 670, 671, 673, 674, 675, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 689, 690, 692, 694, 696, 698, 700, 702, 704, 706, 708, 710, 713, 715, 717, 719, 721, 723, 725, 727, 729, 731, 733, 735, 737, 739, 741, 743, 745, 747, 749, 751, 753, 755, 757, 759, 761, 763, 765, 768, 770, 772, 774, 776, 778, 780, 782, 784, 786, 788, 790, 792, 794, 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832, 834, 836, 838, 840, 841, 843, 845, 847, 848, 850, 852, 853, 855, 857, 859, 861, 863, 864, 866, 868, 870, 872, 874, 875, 876, 878, 882, 1360, 1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1374, 1375, 1376, 1380, 1381, 1382, 1383, 1384, 1385, 1386, 1464, 1465, 1466, 1467, 1535, 1536, 1537, or 1543.
    • 11. The antibody of embodiments 1, 9, or 10, or antigen binding fragment thereof, wherein the antibody comprises a VH sequence as shown in Table 9, Table 10, Table 11, Table 12, Table 14, or Table 15.
    • 12. The antibody of embodiment 11, wherein the VH sequence comprises a sequence of SEQ ID NOs: 591, 662, 664, 665, 666, 668, 672, 676, 688, 691, 693, 695, 697, 699, 701, 703, 705, 707, 709, 711, 712, 714, 716, 718, 720, 722, 724, 726, 728, 730, 732, 734, 736, 738, 740, 742, 744, 746, 748, 750, 752, 754, 756, 758, 760, 762, 764, 767, 769, 771, 773, 775, 777, 779, 781, 783, 785, 787, 789, 791, 793, 795, 797, 799, 801, 803, 805, 807, 809, 811, 813, 815, 817, 819, 821, 823, 825, 827, 829, 831, 833, 835, 837, 839, 841, 842, 844, 846, 849, 851, 854, 856, 858, 860, 862, 865, 867, 869, 871, 873, 877, 879, 880, 881, 1346, 1347, 1348, 1349, 1350, 1351, 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1377, 1378, 1379, 1387, 1388, 1389, 1390, 1391, 1392, 1393, 1394, 1395, 1396, 1397, 1398, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1450, 1451, 1452, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1469, 1470, 1471, 1472, 1473, 1474, 1475, 1477, 1480, 1533, 1534, 1542, 1544, or 1545.
    • 13. The antibody of embodiment 1, or antigen binding fragment thereof, wherein the antibody comprises a VK sequence as shown in Table 9, Table 10, Table 11, Table 12, Table 14, or Table 15, and a VH sequence as shown in Table 9, Table 10, Table 11, Table 12, Table 14, or Table 15.
    • 14. The antibody of embodiment 13, or antigen binding fragment thereof, wherein the antibody comprises a VK of SEQ ID NO: 592, or a variant thereof and a VH sequence of SEQ ID NO: 591, or a variant thereof.
    • 15. The antibody of embodiment 13 or antigen binding fragment thereof, wherein the antibody comprises a VK of SEQ ID NO: 1363, or a variant thereof, and a VH sequence of SEQ ID NO: 1387, or a variant thereof.
    • 16. An antibody, or antigen binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
      • the heavy chain variable region comprises a variable heavy CDR1 (HCDR1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1499, a variable heavy CDR2 (HCDR2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1506, and variable heavy CDR3 (HCDR3) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1507, 1531 or 1532; and
      • the light chain variable region comprises a variable light CDR1 (LCDR1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1502, a variable light CDR2 (LCDR2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1497, and a variable light CDR3 (LCDR3) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1498.
    • 17. The antibody of embodiment 16, wherein the heavy chain variable region comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1499, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1506, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1507.
    • 18. The antibody of embodiment 16, wherein the heavy chain variable region comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1499, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1506, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1531.
    • 19. The antibody of embodiment 16, wherein the heavy chain variable region comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1499, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1506, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1532.
    • 20. The antibody of any one of embodiments 16-19, wherein the light chain variable region comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1502, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1497, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1498.
    • 21. An antibody, or antigen binding fragment thereof, wherein the antibody comprises: a light chain variable region comprising an amino acid sequence having at least 90% identity an amino acid sequence selected from SEQ ID NOs: 592, 663, 667, 669, 670, 671, 673, 674, 675, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 689, 690, 692, 694, 696, 698, 700, 702, 704, 706, 708, 710, 713, 715, 717, 719, 721, 723, 725, 727, 729, 731, 733, 735, 737, 739, 741, 743, 745, 747, 749, 751, 753, 755, 757, 759, 761, 763, 765, 768, 770, 772, 774, 776, 778, 780, 782, 784, 786, 788, 790, 792, 794, 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832, 834, 836, 838, 840, 841, 843, 845, 847, 848, 850, 852, 853, 855, 857, 859, 861, 863, 864, 866, 868, 870, 872, 874, 875, 876, 878, 882, 1360, 1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1374, 1375, 1376, 1380, 1381, 1382, 1383, 1384, 1385, 1386, 1464, 1465, 1466, 1467, 1535, 1536, 1537, or 1543; and the variable heavy chain comprising an amino acid sequence having at least 90% identity an amino acid sequence selected from SEQ ID NOs: 591, 662, 664, 665, 666, 668, 672, 676, 688, 691, 693, 695, 697, 699, 701, 703, 705, 707, 709, 711, 712, 714, 716, 718, 720, 722, 724, 726, 728, 730, 732, 734, 736, 738, 740, 742, 744, 746, 748, 750, 752, 754, 756, 758, 760, 762, 764, 767, 769, 771, 773, 775, 777, 779, 781, 783, 785, 787, 789, 791, 793, 795, 797, 799, 801, 803, 805, 807, 809, 811, 813, 815, 817, 819, 821, 823, 825, 827, 829, 831, 833, 835, 837, 839, 841, 842, 844, 846, 849, 851, 854, 856, 858, 860, 862, 865, 867, 869, 871, 873, 877, 879, 880, 881, 1346, 1347, 1348, 1349, 1350, 1351, 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1377, 1378, 1379, 1387, 1388, 1389, 1390, 1391, 1392, 1393, 1394, 1395, 1396, 1397, 1398, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1450, 1451, 1452, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1469, 1470, 1471, 1472, 1473, 1474, 1475, 1477, 1480, 1533, 1534, 1542, 1544, or 1545.
    • 22. The antibody of any one of embodiments 16-21, or antigen binding fragment thereof, wherein the heavy chain variable region comprises an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 1445, 1477, or 1480 and the light chain variable region comprises an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 1367.
    • 23. The antibody of any one of embodiments 16-22, or antigen binding fragment thereof, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NOs: 1445, 1477, or 1480 and the light chain variable region comprises an amino acid of SEQ ID NO: 1367.
    • 24. The antibody of embodiment 23, or antigen binding fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1445.
    • 25. The antibody of embodiment 23, or antigen binding fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1477.
    • 26. The antibody of embodiment 23, or antigen binding fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1480.
    • 27. The antibody of any one of embodiments 16-26, or antigen binding fragment thereof, wherein the heavy chain variable region and the light chain variable region are in a scFv format or a Fab format.
    • 28. The antibody of any one of embodiments 16-27, or antigen binding fragment thereof, wherein the heavy chain variable region and the light chain variable region are in a scFv format.
    • 29. The antibody of any one of embodiments 16-28, or antigen binding fragment thereof, wherein the heavy chain variable region and the light variable chain region are linked with a peptide linker.
    • 30. The antibody of embodiment 29, wherein the peptide linker is a glycine/serine linker.
    • 31. The antibody of embodiment 30, wherein the peptide linker comprises a sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22), GGGGSGGGGSGGGGS (SEQ ID NO: GGGGSGGGGS (SEQ ID NO: 619), GGGGS (SEQ ID NO: 23), or GGGSEGGGSEGGGSE (SEQ ID NO: 1546), or any combination thereof.
    • 32. The antibody of any of the preceding embodiments, wherein the antibody is linked or associated with an effector molecule.
    • 33. The antibody of embodiment 32, wherein the effector molecule is a IL-2 mutein.
    • 34. The antibody of embodiment 33, wherein the IL-2 mutein comprises one or more mutations of E15Q, H16N, Q22 E, D84N, E95Q, Q126 E, N29S, Y31S, Y31H, K35R, T37A, K48 E, N71R, L53I, L56I, L80I, L118I, V69A, Q74P, N88D, N88R, C125A or C125S.
    • 35. The antibody of embodiments 33 or 34, wherein the IL-2 mutein comprises a L53I, L56I, L80I, or L118I mutation.
    • 36. The antibody of any one of embodiments 33-35, wherein the IL-2 mutein comprises a N88D mutation.
    • 37. The antibody of any one of embodiments 33-36, wherein the IL-2 mutein comprises a E15Q, H16N, Q22 E, D84N, E95Q, or Q126 E mutation.
    • 38. The antibody of embodiments 36 or 37, wherein the IL-2 mutein comprises a N29S, Y31S, Y51H, K35R, T37A, K48 E, V69A, N71R, Q74P, N88D, N88R, C125A, or C125S mutation.
    • 39. The antibody of any one of embodiments 33-38, wherein the IL-2 mutein is fused or linked to a Fc peptide.
    • 40. The antibody of embodiment 39, wherein the Fc peptide comprises a mutation at one or more of positions of L234, L235 and G237 according to the EU numbering system or L247, L248, and G250 according to the Kabat numbering system.
    • 41. The antibody of embodiment 39, wherein the Fc peptide comprises a L234A mutation, a L235A mutation, and/or a G237A mutation according to the EU numbering system.
    • 42. The antibody of embodiment 32, wherein the antibody linked to the effector molecule comprises a first polypeptide chain and a second a polypeptide chain that form a targeted effector polypeptide, wherein
      • the first chain comprises a polypeptide having the formula of:
      • VH—Hc-Linker-C1, wherein VH is the heavy chain variable domain of the antibody of any one of embodiments 1-29; Hc is a heavy chain constant domain, such as a CH1-CH2-CH3 domain (SEQ ID NO: 44), the Linker is a glycine/serine linker, and C1 is the IL-2 mutein fused or linked to a Fc protein, wherein the Fc protein is fused or linked at the N-terminus or the C-terminus of the IL-2 mutein; and
      • the second chain comprises a polypeptide having the formula of VL-Lc, wherein VL is a light chain variable domain of the antibody of any one of embodiments 1-31, and the L c domain is a kappa light chain constant domain.
    • 43. A polypeptide having a formula of:
      • Ab-ConstantDomain-LinkerA-IL2 Mutein-LinkerB-FcRegion,
      • wherein the Ab is a heavy chain variable region of any one of embodiments 1-31;
      • the ConstantDomain is an IgG constant domain, such as IgG1 constant domain, IgG2 constant domain, IgG3 constant domain, or IgG4;
      • Linker A is a linker, such as those provided herein including a peptide linker,
      • IL2 Mutein is an IL-2 mutein, such as those provided for herein;
      • Linker B is a peptide linker; and
      • FcRegion is a Fc region, such as those provided for herein.
    • 44. The polypeptide of embodiment 43, wherein, the heavy chain variable region is a heavy chain variable region as provided for in Table 9, Table 10, or Table 11, or any variant thereof
    • 45. The polypeptide of embodiment 43, wherein, the heavy chain variable region is a heavy chain variable region of Clone ID: 6, 75, or 79 of Table 7, MIAB126 or MIAB197 of Table 9, MIAB204 of Table 11, or any variant thereof.
    • 46. The polypeptide of embodiment 43, wherein the heavy chain variable comprises the CDRs of the heavy domain of 6, 75, or 79 of Table 7, MIAB126 or MIAB197 of Table 9, MIAB204 of Table 11, or any variant thereof
    • 47. The polypeptide of embodiment 43, wherein heavy chain variable region comprises a sequence of SEQ ID NO: 591, SEQ ID NO: 880, or SEQ ID NO: 1387, or any variant thereof
    • 48. The polypeptide of embodiment 43, wherein the heavy chain variable region comprises:
      • a first CDR of SEQ ID NO: 359, a second CDR of SEQ ID NO: 170, and a third CDR of SEQ ID NO: 360, or any variant thereof;
      • a first CDR of SEQ ID NO: 359, a second CDR of SEQ ID NO: 170, and a third CDR of SEQ ID NO: 1431, or any variant thereof;
      • a first CDR of SEQ ID NO: 135, a second CDR of SEQ ID NO: 381, and a third CDR of SEQ ID NO: 1342, or any variant thereof;
      • a first CDR of SEQ ID NO: 1499, a second CDR of SEQ ID NO: 1506, and a third CDR of SEQ ID NO: 1507, or any variant thereof;
      • a first CDR of SEQ ID NO: 1499, a second CDR of SEQ ID NO: 1506, and a third CDR of SEQ ID NO: 1531, or any variant thereof; or
      • a first CDR of SEQ ID NO: 1499, a second CDR of SEQ ID NO: 1506, and a third CDR of SEQ ID NO: 1532, or any variant thereof
    • 49. The polypeptide of any one of embodiments 41-46, wherein LinkerA comprises a sequence of (GGGGS)n (SEQ ID NO: 1550), (GGGGA)n (SEQ ID NO: 1551), (GGGSE)n (SEQ ID NO: 1547), or a mixture thereof, wherein each n is independently 1-10.
    • 50. The polypeptide of embodiment 43, wherein the IL-2 mutein comprises a sequence of any one of SEQ ID NOs: 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41.
    • 51. The polypeptide of any one of embodiments 43-50, wherein the IL-2 mutein comprises a T3A mutation.
    • 52. The polypeptide of any one of embodiments 43-51, wherein Linker B is a linker, such as a peptide linker that comprises a sequence of (GGGGS)n (SEQ ID NO: 1550), (GGGGA)n (SEQ ID NO: 1551), (GGGSE)n (SEQ ID NO: 1547), or a mixture thereof, wherein each n is independently 1-10.
    • 53. The polypeptide of any one of embodiments 43-52, wherein the FcRegion comprises a peptide of having a sequence of SEQ ID NO: 21, or SEQ ID NO: 44.
    • 54. The polypeptide of any one of embodiments 43-53, wherein the polypeptide comprises a second polypeptide having a formula of VL-ConstantDomainLight, wherein VL is a light chain variable domain of the antibody of any one of embodiments 1-29 and the ConstantDomainLight is a IgG light chain constant domain.
    • 55. The polypeptide of embodiment 54, wherein VL comprises a sequence of SEQ ID NO: 592, SEQ ID NO: 1363, or a VL sequence as provided for in Table 9, Table 10, Table 11, Table 14, or Table 15, or any variant thereof.
    • 56. The polypeptide of embodiment 54, wherein the VL comprises:
      • a first CDR of SEQ ID NO: 361, a second CDR of SEQ ID NO: 362, and a third CDR of SEQ ID NO: 363;
      • a first CDR of SEQ ID NO: 1408, a second CDR of SEQ ID NO: 362, and a third CDR of SEQ ID NO: 363; or
      • a first CDR of SEQ ID NO: 383, a second CDR of SEQ ID NO: 241, and a third CDR of SEQ ID NO: 652.
    • 57. The polypeptide of any one of embodiments 43-56, wherein the ConstantDomainLight comprises a sequence of SEQ ID NO: 45.
    • 58. A polypeptide comprising the formula of IL2 Mutein-LinkerA-FcRegion-LinkerB-Ab, wherein:
      • IL2 Mutein is any IL-2 mutein provided for herein;
      • LinkerA and Linker B are, each, independently, a linker as provided herein;
      • the FcRegion is Fc peptide, such as provided herein; and
      • the Ab is a tissue targeting moiety, such as those provided herein.
    • 59. The polypeptide of embodiment 58, wherein the Ab is an antibody that binds to MAdCAM or another cell surface target as provided herein.
    • 60. The polypeptide of embodiment 59, wherein the antibody that binds to MAdCAM is an antibody of any one of embodiments 1-31.
    • 61. The polypeptide of embodiment 60, wherein the antibody is in a scFV format.
    • 62. The polypeptide of embodiment 61, wherein the antibody in scFV format is an antibody as provided in Table 11, Table 14, Table 15, or any variant thereof
    • 63. The polypeptide of embodiment 60, wherein the antibody that binds to MAdCAM comprises CDRs as set forth in Table 9, Table 14, or Table 15, or any variant thereof
    • 64. The antibody of embodiment 63, wherein the effector molecule is an antibody that binds to PD-1.
    • 65. The antibody of embodiment 64, wherein the antibody that binds to PD-1 is a PD-1 agonist.
    • 66. The antibody of embodiment 64, wherein the PD-1 antibody is in a Fab format.
    • 67. The antibody of embodiment 64, wherein the PD-1 antibody is an antibody as provided in Table 12, or Table 13.
    • 68. The antibody of embodiment 64, wherein the antibody that binds to PD-1 comprises CDRs as set forth in Table 13, or any combination thereof.
    • 69. A polypeptide comprising a MAdCAM targeting moiety that binds to a target cell expressing MAdCAM and an effector binding/modulating moiety,
      • wherein the MAdCAM targeting moiety is an antibody of any one of embodiments 1-31,
      • wherein the effector binding/modulating moiety is a IL-2 mutein polypeptide (IL-2 mutein), wherein the IL-2 mutein comprises the sequence of SEQ ID NO: 41.
    • 70. The polypeptide of embodiment 69, wherein the IL-2 mutein binds to a receptor expressed by an immune cell.
    • 71. The polypeptide of embodiment 69, wherein the compound has the formula from N-terminus to C-terminus:
      • R1—Linker Region A—R2 or R3—Linker Region B—R4, wherein,
      • R1, R2, R3, and R4, each independently comprises the effector binding/modulating moiety, the targeting moiety, or is absent, provided that at least one of R1 and R2 is not absent, and at least one of R3 and R4 is not absent.
    • 72. The polypeptide of embodiment 71, wherein the polypeptide having the formula of R1— Linker Region A—R2 and the polypeptide having the formula of R3—Linker Region B—R4 interact with one another to form a polypeptide complex.
    • 73. The polypeptide of embodiment 71, wherein the polypeptide having the formula of R1— Linker Region A—R2 and the polypeptide having the formula of R3—Linker Region B—R4 do not interact with one another to form a polypeptide complex.
    • 74. The polypeptide of embodiment 71, wherein one or both of Linker Region A and Linker Region B comprises an Fc region.
    • 75. The polypeptide of embodiment 71, wherein one of R1 and R2 is the IL-mutein and one of R1 and R2 is an anti-MAdCAM antibody of any one of embodiments 1-31.
    • 76. The polypeptide of embodiment 71, wherein R1 is the IL-mutein and R2 is an anti-MAdCAM antibody of any one of embodiments 1-31.
    • 77. The polypeptide of embodiment 71, wherein one of R1 is anti-MAdCAM antibody of any one of embodiments 1-31 and one R2 is an anti-PD-1 antibody.
    • 78. The polypeptide of embodiment 71, wherein one of R3 and R4 is the IL-2 mutein and one of R3 and R4 is an anti-MAdCAM antibody of any one of embodiments 1-31.
    • 79. The polypeptide of embodiment 71, wherein R3 is the IL-2 mutein and R4 is an anti-MAdCAM antibody.
    • 80. The polypeptide of embodiment 71, wherein R3 is an anti-MAdCAM antibody of any one of embodiments 1-29 and one R4 is the IL-2 mutein.
    • 81. The polypeptide of any of embodiments 71-80, wherein the linker is absent.
    • 82. The polypeptide of any of embodiments 71-80, wherein the linker is a Fc region.
    • 83. The polypeptide of any of embodiments 71-80, wherein the linker is a glycine/serine linker.
    • 84. The polypeptide of embodiment 83, wherein the linker is











(SEQ ID NO: 22)



GGGGSGGGGSGGGGSGGGGS,







(SEQ ID NO: 30)



GGGGGGGGSGGGGS,







(SEQ ID NO: 619)



GGGGSGGGGS,







(SEQ ID NO: 23)



GGGGS,



or







(SEQ ID NO: 1546)



GGGSEGGGSEGGGSE.








    • 85. The polypeptide of embodiment 69, wherein the IL-2 mutein comprises a IL-2 sequence of SEQ ID NO: 6, wherein peptide comprises a mutation at a position that corresponds to position 53, 56, 80, or 118 of SEQ ID NO: 6.

    • 86. The polypeptide of any one of embodiments 69-85, wherein the IL-2 mutein comprises a IL-2 sequence of SEQ ID NO: 6, wherein peptide comprises a mutation at a position that corresponds to position 53, 56, 80, or 118 of SEQ ID NO: 6.

    • 87. The polypeptide of embodiment 86, wherein the mutation is a L to I mutation at position 53, 56, 80, or 118.

    • 88. The polypeptide of embodiment 87, wherein the mutation is a L to I mutation at position 53, 56, 80, or 118.

    • 89. The polypeptide of embodiment 69-88, further comprising a mutation at one or more positions of 29, 31, 35, 37, 48, 69, 71, 74, 88, and 125 in SEQ ID NO: 6.

    • 90. The polypeptide of any one of embodiments 69-89, wherein the mutein further comprises a mutation at one or more of positions E15, H16, Q22, D84, E95, or Q126 or 1, 2, 3, 4, 5, or each of positions E15, H16, Q22, D84, E95, or Q126 is wild-type.

    • 91. The polypeptide of any one of embodiments 69-90, wherein the mutation in the mutein is one or more of E15Q, H16N, Q22 E, D84N, E95Q, or Q126 E.

    • 92. The polypeptide of any one of embodiments 69-91, wherein the mutein comprises a V69A mutation.

    • 93. The polypeptide of any one of embodiments 69-92, wherein the mutein comprises a Q74P mutation.

    • 94. The polypeptide of any one of embodiments 69-93, wherein the mutein comprises a N88D or a N88R mutation.

    • 95. The polypeptide of any one of embodiments 69-94, wherein the mutein comprises a C125A or C125S mutation.

    • 96. The polypeptide of any one of embodiments 69-95, wherein the IL-2 mutein is fused or linked to a Fc peptide, such as a protein comprising a sequence of SEQ ID NO: 59; or SEQ ID NO: 44, 23, and 41.

    • 97. The polypeptide of embodiment 96, wherein the Fc peptide comprises a mutation at one or more of positions of L234, L247, L235, L248, G237, and G250.

    • 98. The polypeptide of embodiment 96, wherein the mutation is L to A or G to A mutation.

    • 99. The polypeptide of embodiment 96, wherein the Fc peptide comprises L247A, L248A, and G250A mutations.

    • 100. The polypeptide of embodiment 99, wherein the Fc peptide comprises a L234A mutation, a L235A mutation, and/or a G237A mutation.

    • 101. The polypeptide of embodiment 69, wherein the polypeptide comprises a first chain and a second chain that form the polypeptide, wherein
      • the first chain comprises:
      • VH—Hc-Linker-C1, wherein VH is a variable heavy domain that binds to MAdCAM expressed on a cell with a VL domain of the second chain; Hc is a heavy chain of antibody comprising CH1-CH2-CH3 domain, the Linker is a glycine/serine linker, and C1 is a IL-2 mutein fused to a Fc protein in either the N-terminal or C-terminal orientation; and
      • the second chain comprises:
      • VL-Lc, wherein VL is a variable light chain domain that binds to MAdCAM expressed on a cell with the VH domain of the first chain, and the Lc domain is a light chain CK domain,
      • Wherein VL and VH comprises a sequence of an antibody of any one of embodiments 1-31.

    • 102. The polypeptide of embodiment 101, wherein the IL-2 mutein comprises a mutation at a position that corresponds to position 53, 56, 80, or 118 of SEQ ID NO: 6.

    • 103. The polypeptide of embodiment 102, wherein the mutation is a L to I mutation at position 53, 56, 80, or 118.

    • 104. The polypeptide of embodiment 101, wherein the mutein further comprises a mutation at a position that corresponds to position 69, 75, 88, or 125, or any combination thereof.

    • 105. The polypeptide of embodiment 101, comprises a mutation selected from the group consisting of: at one of L531, L561, L80I, and L118I and the mutations of V69A, Q74P, N88D or N88R, and optionally C125A or C125S.

    • 106. The polypeptide of embodiment 105, wherein the IL-2 mutein comprises a L531 mutation.

    • 107. The polypeptide of embodiment 105, wherein the IL-2 mutein comprises a L561 mutation.

    • 108. The polypeptide of embodiment 105, wherein the IL-2 mutein comprises a L80I mutation.

    • 109. The polypeptide of embodiment 105, wherein the IL-2 mutein comprises a L118I mutation.

    • 110. The polypeptide of any one of embodiments 105-109, wherein the IL-2 mutein comprises a T3A mutation.

    • 111. The polypeptide of embodiment 102 or 105, wherein the IL-2 mutein does not comprises any other mutations.

    • 112. The polypeptide of embodiment 105, wherein the Fc protein comprises L247A, L248A, and G250A mutations or a L234A mutation, a L235A mutation, and/or a G237A mutation according to KABAT numbering.

    • 113. The polypeptide of embodiment 105, wherein the Linker comprises a sequence of














(SEQ ID NO: 30)



GGGGSGGGGSGGGGS,







(SEQ ID NO: 22)



GGGGSGGGGSGGGGSGGGGS,



or







(SEQ ID NO: 1546)



GGGSEGGGSEGGGSE.








    • 114. The polypeptide of any one of embodiments 1-113, wherein the polypeptide comprises a Fc peptide comprising a sequence described herein.

    • 115. A method of treating a subject with inflammatory bowel disease, the method comprising administering a polypeptide or antibody of any of embodiments 1-114 to the subject to treat the inflammatory bowel disease.

    • 116. The method of embodiment 115, wherein the subject with inflammatory bowel disease has Crohn's disease.

    • 117. The method of embodiment 115, wherein the subject with inflammatory bowel disease has ulcerative colitis.

    • 118. A method of treating a subject with auto-immune hepatitis, the method comprising administering a polypeptide or antibody of any of embodiments 1-114 to the subject to treat the auto-immune hepatitis.

    • 119. A method of treating primary sclerosing cholangitis the method comprising administering a polypeptide or antibody of any of embodiments 1-114 to the subject to treat the primary sclerosing cholangitis.

    • 120. A method of treating Type 1 diabetes the method comprising administering a polypeptide or antibody of any of embodiments 1-114 to the subject to treat the Type 1 diabetes.

    • 121. A method of treating a transplant subject comprising administering a therapeutically effective amount of a polypeptide or antibody of any of embodiments 1-114 to the subject, thereby treating a transplant (recipient) subject.

    • 122. A method of treating GVHD in a subject having a transplanted a donor tissue comprising administering a therapeutically effective amount of a polypeptide or antibody of any of embodiments 1-114 to the subject.

    • 123. A method of treating a subject having, or at risk, or elevated risk, for having, an autoimmune disorder, comprising administering a therapeutically effective amount of a polypeptide or antibody of any of embodiments 1-114, thereby treating the subject.

    • 124. An isolated nucleic acid encoding a polypeptide, an antibody, or antigen binding fragment thereof, of any of embodiments 1-114.

    • 125. An expression vector comprising the nucleic acid of embodiment 124.

    • 126. A host cell comprising the isolated nucleic acid of embodiment 124 or the vector of embodiment 125.

    • 127. A method of making a polypeptide or antibody of any of embodiments 1-114 comprising culturing a host cell of embodiment 126 to make the polypeptide or antibody of any of embodiments 1-114.

    • 128. A method of producing an antibody or antigen binding fragment thereof of any one of embodiments 1-114 comprising (a) culturing a host cell comprising one or more nucleic acids encoding the antibody or antigen binding fragment thereof in a culture medium under conditions favorable for expression of the one or more nucleic acids and (b) optionally recovering the antibody or antigen binding fragment thereof from the culture medium.

    • 129. A method of making or producing a polypeptide, or an antibody, or antigen binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
      • the heavy chain variable region comprises a variable heavy CDR1 (HCDR1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1499, a variable heavy CDR2 (HCDR2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1506, and variable heavy CDR3 (HCDR3) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1507, 1531 or 1532; and
      • the light chain variable region comprises a variable light CDR1 (LCDR1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1502, a variable light CDR2 (LCDR2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1497, and a variable light CDR3 (LCDR3) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1498.

    • 130. A method of making or producing a polypeptide, or an antibody, or antigen binding fragment thereof, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NOs: 1445, 1477, or 1480 and the light chain variable region comprises an amino acid of SEQ ID NO: 1367.

    • 131. A method of making or producing a polypeptide, or an antibody, or antigen binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
      • the heavy chain variable region comprises a variable heavy CDR1 (HCDR1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1499, a variable heavy CDR2 (HCDR2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1506, and variable heavy CDR3 (HCDR3) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1507, 1531 or 1532; and
      • the light chain variable region comprises a variable light CDR1 (LCDR1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1502, a variable light CDR2 (LCDR2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1497, and a variable light CDR3 (LCDR3) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1498,
      • wherein the method comprises (a) culturing a host cell comprising one or more nucleic acids encoding the antibody or antigen binding fragment thereof in a culture medium under conditions favorable for expression of the one or more nucleic acids encoding:
      • the heavy chain variable region comprising a variable heavy CDR1 (HCDR1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1499, a variable heavy CDR2 (HCDR2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1506, and variable heavy CDR3 (HCDR3) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1507, 1531 or 1532; and
      • the light chain variable region comprising a variable light CDR1 (LCDR1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1502, a variable light CDR2 (LCDR2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1497, and a variable light CDR3 (LCDR3) having at least 90% identity to the amino acid sequence of SEQ ID NO: 1498; and
      • (b) optionally recovering the antibody or antigen binding fragment thereof from the culture medium.

    • 132. A method of making or producing a polypeptide, or an antibody, or antigen binding fragment thereof, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NOs: 1445, 1477, or 1480 and the light chain variable region comprises an amino acid of SEQ ID NO: 1367, wherein the method comprises (a) culturing a host cell comprising one or more nucleic acids encoding the antibody or antigen binding fragment thereof in a culture medium under conditions favorable for expression of the one or more nucleic acids encoding: the heavy chain variable region comprising an amino acid sequence of SEQ ID NOs: 1445, 1477, or 1480 and the light chain variable region comprising an amino acid of SEQ ID NO: 1367; and (b) optionally recovering the antibody or antigen binding fragment thereof from the culture medium.

    • 133. A protein comprising a peptide or set of peptides as provided in Table 9, Table 10, Table 11, Table 12, Table 13, or Table 12.

    • 134. The protein of embodiment 130, wherein the protein comprises a set of sequences as set forth in a row of Table 9, Table 10, Table 11, Table 12, Table 13, or Table 12.

    • 135. A protein comprising:
      • i) a peptide comprising a sequence of SEQ ID NOs: 359, 170, 360, 361, 362, and 363, or any variant of any of the foregoing;
      • ii) a peptide comprising a sequence of SEQ ID NOs: 359, 170, and 360, or any variant of any of the foregoing;
      • iii) a peptide comprising a sequence of SEQ ID NOs: 361, 362, and 363, or any variant of any of the foregoing;
      • iv) a peptide comprising a sequence of SEQ ID NOs: 1387, 44, 23, 41, 1363, and 45, or any variant of any of the foregoing;
      • v) a peptide comprising a sequence of SEQ ID NOs: 359, 170, 1431, 1408, 362, 363, or any variant of any of the foregoing;
      • vi) a peptide comprising a sequence of SEQ ID NOs: 359, 170, 1431, or any variant of any of the foregoing;
      • vii) a peptide comprising a sequence of SEQ ID NOs: 1408, 362, 363, or any variant of any of the foregoing;
      • vii) a peptide comprising a sequence of SEQ ID NOs: 880, 44, 23, 41, 663, and 45, or any variant of any of the foregoing;
      • ix) a peptide comprising a sequence of SEQ ID NOs: 135, 381, 1342, 383, 241, and 652, or any variant of any of the foregoing;
      • x) a peptide comprising a sequence of SEQ ID NOs: 135, 381, and 1342, or any variant of any of the foregoing; or
      • xi) a peptide comprising a sequence of SEQ ID NOs: 383, 241, and 652, or any variant of any of the foregoing.

    • 136. A pharmaceutical composition comprising a polypeptide, antibody, or a protein of any of embodiments 1-114 or 133-135 and a pharmaceutically acceptable carrier.

    • 137. A pharmaceutical composition comprising any peptide comprising a sequence as provided for herein.

    • 138. Use of a polypeptide or antibody of any of embodiments 1-114, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of inflammatory bowel disease.

    • 139. Use of a polypeptide or antibody of any of embodiments 1-114, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of inflammatory bowel disease, such as Crohn's disease, or ulcerative colitis.

    • 140. Use of a polypeptide or antibody of any of embodiments 1-114, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of Crohn's disease, or ulcerative colitis.

    • 141. Use of a polypeptide or antibody of any of embodiments 1-114, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of an auto-immune hepatitis, a primary sclerosing cholangitis, a Type 1 diabetes, a transplant, a GVHD, an elevated risk, or a risk, for having, an autoimmune disorder.

    • 142. Use of a polypeptide or antibody of any of embodiments 1-114, or a pharmaceutical composition comprising the same, for the treatment of inflammatory bowel disease.

    • 143. Use of a polypeptide or antibody of any of embodiments 1-114, or a pharmaceutical composition comprising the same, for the treatment of an auto-immune hepatitis, a primary sclerosing cholangitis, a Type 1 diabetes, a transplant, a GVHD, an elevated risk, or a risk, for having, an autoimmune disorder.





The following examples are illustrative, but not limiting, of the compounds, compositions and methods described herein. Other suitable modifications and adaptations known to those skilled in the art are within the scope of the following embodiments.


EXAMPLES

Non limiting examples of therapeutics, compounds, molecules, antibodies, compositions of matter, and examples may be found in PCT Application No. PCT/US2020/033707, which is hereby incorporated by reference in its entirety.


Example 1. MAdCAM Molecule Variants with Disrupted Poly Y Patch do not Show Non Specific Binding to DNA and Insulin

Non-specific DNA and Insulin binding is predictive of poor pharmacokinetics (PK). An immunosorbent plate was coated with dsDNA at a concentration of 1 μg/mL or Insulin at 5 μg/mL in PBS pH 7.4, 75 ul/well, and incubated overnight at 4° C. Wells were washed with PBS pH 7.4 containing 0.05% Tween-20 (wash buffer) three times, and then blocked with 200 ul/well 1% BSA in PBS pH 7.4 (block buffer) for two hours at room temperature. After three washes with wash buffer, TAs and controls Lenzilumab and Elotuzumab were diluted to 100 nM in PBS containing 1% BSA and 0.05% Tween-20 (assay buffer). The diluted material was added to the DNA/insulin coated plate at 75 ul/well for 1 hour at room temperature. After three washes with wash buffer, a donkey anti-human FcY HRP conjugated polyclonal antibody, diluted to 1:5000 in assay buffer, was added to the plate at 75 ul/well for 1 hr at room temperature. After three washes with wash buffer and three washes with wash buffer (with no tween-20), the assay was developed with TMB, and stopped with 1N HCL. OD 450 nm was measured. The experiment included appropriate controls for non-specific binding of test articles to the plate/block in the absence of DNA or insulin. PRNT1 showed dsDNA polyreactivity score of 45.64, and Insulin polyreactivity score of 6.21; MIAB128 showed dsDNA polyreactivity score of 33.01, and Insulin polyreactivity score of 2.62; MIAB129 showed dsDNA polyreactivity score of 3.51, and Insulin polyreactivity score of 2.43; MIAB130 showed dsDNA polyreactivity score of 29.66, and Insulin polyreactivity score of 3.26; MIAB131 showed dsDNA polyreactivity score of 13.49, and Insulin polyreactivity score of 8.00; MIAB133 showed dsDNA polyreactivity score of 44.80, and Insulin polyreactivity score of 13.16; MIAB134 showed dsDNA polyreactivity score of 45.96, and Insulin polyreactivity score of 25.53; MIAB136 showed dsDNA polyreactivity score of 51.85, and Insulin polyreactivity score of 75.37; MIAB137 showed dsDNA polyreactivity score of 43.44, and Insulin polyreactivity score of 67.33; MIAB139 showed dsDNA polyreactivity score of 1.09, and Insulin polyreactivity score of 2.08; MIAB141 showed dsDNA polyreactivity score of 33.26, and Insulin polyreactivity score of 4.18; MIAB144 showed dsDNA polyreactivity score of 47.18, and Insulin polyreactivity score of 5.07; Elotuzumab control showed dsDNA polyreactivity score of 1, and Insulin polyreactivity score of 1; and Lenzilumab control showed dsDNA polyreactivity score of 52.42, and Insulin polyreactivity score of 1.52. No non-specific binding to DNA and insulin was seen with MIAB129, MIAB139, and MIAB141. MIAB129, MIAB139, and MIAB141 are not polyreactive.


Example 2. MAdCAM Molecule Variants with the A34N Substitution in LCDR1 do not Show Non Specific Binding to DNA and Insulin

Non-specific DNA and Insulin binding is predictive of poor pharmacokinetics (PK). An immunosorbent plate was coated with dsDNA at a concentration of 1 μg/mL or Insulin at 5 μg/mL in PBS pH 7.4, 75 ul/well, and incubated overnight at 4° C. Wells were washed with PBS pH 7.4 containing 0.05% Tween-20 (wash buffer) three times, and then blocked with 200 ul/well 1% BSA in PBS pH 7.4 (block buffer) for two hours at room temperature. After three washes with wash buffer, TAs and controls Lenzilumab and Elotuzumab were diluted to 100 nM in PBS containing 1% BSA and 0.05% Tween-20 (assay buffer). The diluted material was added to the DNA/insulin coated plate at 75 ul/well for 1 hour at room temperature. After three washes with wash buffer, a donkey anti-human FcY HRP conjugated polyclonal antibody, diluted to 1:5000 in assay buffer, was added to the plate at 75 ul/well for 1 hr at room temperature. After three washes with wash buffer and three washes with wash buffer (with no tween-20), the assay was developed with TMB, and stopped with 1N HCL. OD 450 nm was measured. The experiment included appropriate controls for non-specific binding of test articles to the plate/block in the absence of DNA or insulin. MIAB145 showed dsDNA polyreactivity score of 43.11, and Insulin polyreactivity score of 4.58; MIAB146 showed dsDNA polyreactivity score of 24.57, and Insulin polyreactivity score of 2.61; MIAB147 showed dsDNA polyreactivity score of 8.36, and Insulin polyreactivity score of 3.81; MIAB148 showed dsDNA polyreactivity score of 3.53, and Insulin polyreactivity score of 3.63; MIAB149 showed dsDNA polyreactivity score of 27.86, and Insulin polyreactivity score of 3.53; MIAB150 showed dsDNA polyreactivity score of 9.66, and Insulin polyreactivity score of 3.74; MIAB151 showed dsDNA polyreactivity score of 2.89, and Insulin polyreactivity score of 3.63; MIAB152 showed dsDNA polyreactivity score of 7.01, and Insulin polyreactivity score of 2.83; MIAB153 showed dsDNA polyreactivity score of 1.52, and Insulin polyreactivity score of 2.46; MIAB154 showed dsDNA polyreactivity score of 8.25, and Insulin polyreactivity score of 61.91; MIAB155 showed dsDNA polyreactivity score of 1.62, and Insulin polyreactivity score of 1.99; MIAB156 showed dsDNA polyreactivity score of 4.70, and Insulin polyreactivity score of 45.25; MIAB157 showed dsDNA polyreactivity score of 6.63, and Insulin polyreactivity score of 3.99; MIAB158 showed dsDNA polyreactivity score of 1.67, and Insulin polyreactivity score of 2.67; PRNT1 showed dsDNA polyreactivity score of 38.82, and Insulin polyreactivity score of 5.02; MIAB141 showed dsDNA polyreactivity score of 1.77, and Insulin polyreactivity score of 3.60; Elotuzumab control showed dsDNA polyreactivity score of 0.95, and Insulin polyreactivity score of 1.01; and Lenzilumab control showed dsDNA polyreactivity score of 38.04, and Insulin polyreactivity score of 7.87. No non-specific binding to DNA and insulin was seen with MIAB148, MIAB151, MIAB153, MIAB155, MIAB158 and MIAB141. MIAB148, MIAB151, MIAB153, MIAB155, MIAB158 and MIAB141 are not polyreactive.


Example 3. MAdCAM Molecule Variants with the A34N Substitution in LCDR1 Bind Human MAdCAM

Anti-human Fc biosensors were equilibrated in assay buffer (1% BSA in 1×PBS with Tween-20) for 10 minutes before the experiment was set-up. Test articles were diluted to ug/mL in assay buffer and 200 uL pipetted to 96 well plate. Human MAdCAM was titrated down, two-fold dilutions (starting at 600 nM as the highest concentration, 7-point dilution). Experiment was run using data acquisition software version 10.0 for OCTET96 RED. Test articles were captured using anti-human Fc biosensors for 180 s. Biosensors loaded with test articles were then equilibrated in assay buffer for 120 s. Association was performed in wells with huMAdCAM for 180 seconds. Dissociation was performed in wells with assay buffer for 180 s. Kinetic parameters (kon and kdis) and dissociation constant (KD) were calculated from a 1:1 global fit model using the data analysis software of the Octet96 RED software version 10. MIAB148 showed Kd (M) of 2.69 E−06, Kon (1/ms) of 1.17 E+05, and Kdis (1/s) of 3.14 E−01; MIAB151 showed Kd of 2.96 E−06, Kon of 9.87 E+04, and Kdis of 2.92 E−01; MIAB153 showed Kd of 8.36 E−06, Kon of 6.48 E+04, and Kdis of 5.43 E−01; and PRNT1 showed Kd of 1.84 E−08, Kon of 5.83 E+05, and Kdis of 1.07 E−02. MIAB148, MIAB151, and MIAB153 binds human MAdCAM with lower affinity than the parent PRNT1 molecule.


Example 4. MAdCAM Molecule Variants with Y105I or Y105W and A34N Mutations in the VH do not Show Non Specific Binding to DNA and Insulin

Non-specific DNA and Insulin binding is predictive of poor pharmacokinetics (PK). An immunosorbent plate was coated with dsDNA at a concentration of 1 μg/mL or Insulin at 5 μg/mL in PBS pH 7.4, 75 ul/well, and incubated overnight at 4° C. Wells were washed with PBS pH 7.4 containing 0.05% Tween-20 (wash buffer) three times, and then blocked with 200 ul/well 1% BSA in PBS pH 7.4 (block buffer) for two hours at room temperature. After three washes with wash buffer, TAs and controls Lenzilumab and Elotuzumab were diluted to 100 nM in PBS containing 1% BSA and 0.05% Tween-20 (assay buffer). The diluted material was added to the DNA/insulin coated plate at 75 ul/well for 1 hour at room temperature. After three washes with wash buffer, a donkey anti-human FcY HRP conjugated polyclonal antibody, diluted to 1:5000 in assay buffer, was added to the plate at 75 ul/well for 1 hr at room temperature. After three washes with wash buffer and three washes with wash buffer (with no tween-20), the assay was developed with TMB, and stopped with 1N HCL. OD 450 nm was measured. The experiment included appropriate controls for non-specific binding of test articles to the plate/block in the absence of DNA or insulin. MIAB159 showed dsDNA polyreactivity score of 9.58, and Insulin polyreactivity score of 4.66; MIAB160 showed dsDNA polyreactivity score of 42.95, and Insulin polyreactivity score of 17.80; MIAB161 showed dsDNA polyreactivity score of 25.87, and Insulin polyreactivity score of 5.00; MIAB162 showed dsDNA polyreactivity score of 21.75, and Insulin polyreactivity score of 5.31; MIAB163 showed dsDNA polyreactivity score of 28.56, and Insulin polyreactivity score of 18.53; MIAB164 showed dsDNA polyreactivity score of 25.46, and Insulin polyreactivity score of 7.07; MIAB165 showed dsDNA polyreactivity score of 19.42, and Insulin polyreactivity score of 9.53; MIAB166 showed dsDNA polyreactivity score of 37.98, and Insulin polyreactivity score of 7.89; MIAB167 showed dsDNA polyreactivity score of 26.28, and Insulin polyreactivity score of 29.56; MIAB168 showed dsDNA polyreactivity score of 7.75, and Insulin polyreactivity score of 8.35; MIAB169 showed dsDNA polyreactivity score of 3.34, and Insulin polyreactivity score of 5.59; MIAB170 showed dsDNA polyreactivity score of 2.05, and Insulin polyreactivity score of 4.73; MIAB172 showed dsDNA polyreactivity score of 26.63, and Insulin polyreactivity score of 3.79; MIAB173 showed dsDNA polyreactivity score of 29.82, and Insulin polyreactivity score of 7.10; PRNT1 showed dsDNA polyreactivity score of 34.37, and Insulin polyreactivity score of 6.91; Elotuzumab control showed dsDNA polyreactivity score of 1.05, and Insulin polyreactivity score of 1.25; and Lenzilumab control showed dsDNA polyreactivity score of 44.96, and Insulin polyreactivity score of 21.31. No non-specific binding to DNA and insulin was seen with MIAB169 and MIAB170. MIAB169 and MIAB170 are not polyreactive.


Example 5. MAdCAM Molecule Variants with the Y105I Substitution Bind Human MAdCAM

Anti-human Fc biosensors were equilibrated in assay buffer (1% BSA in 1×PBS with Tween-20) for 10 minutes before the experiment was set-up. Test articles were diluted to ug/mL in assay buffer and 200 uL pipetted to 96 well plate. Human MAdCAM was titrated down, two-fold dilutions (starting at 600 nM as the highest concentration, 7-point dilution). Experiment was run using data acquisition software version 10.0 for OCTET96 RED. Test articles were captured using anti-human Fc biosensors for 180 s. Biosensors loaded with test articles were then equilibrated in assay buffer for 120 s. Association was performed in wells with huMAdCAM for 180 seconds. Dissociation was performed in wells with assay buffer for 180 s. Kinetic parameters (kon and kdis) and dissociation constant (KD) were calculated from a 1:1 global fit model using the data analysis software of the Octet96 RED software version 10. PRNT1 showed Kd (nM) of 26.6, Kon (1/ms) of 4.16 E+05, and Kdis (1/s) of 1.11 E−02; MIAB169 showed Kd of 266, Kon of 2.78 E+05, and Kdis of 7.38 E−02; and MIAB170 showed no binding at 1 μM human MAdCAM tested. MIAB169 binds to human MAdCAM at 10 fold lower affinity than parent PRNT1.


Example 6. MAdCAM Molecule Variants with the Y105I Substitution Bind Human and Cyno MAdCAM

Anti-human Fc biosensors were equilibrated in assay buffer (1% BSA in 1×PBS with Tween-20) for 10 minutes before the experiment was set-up. Test articles were diluted to ug/mL in assay buffer and 200 uL pipetted to 96 well plate. Human MAdCAM was titrated down, two-fold dilutions (starting at 600 nM as the highest concentration, 7-point dilution). Experiment was run using data acquisition software version 10.0 for OCTET96 RED. Test articles were captured using anti-human Fc biosensors for 180 s. Biosensors loaded with test articles were then equilibriated in assay buffer for 120 s. Association was performed in wells with huMAdCAM for 180 seconds. Dissociation was performed in wells with assay buffer for 180 s. Kinetic parameters (kon and kdis) and dissociation constant (KD) were calculated from a 1:1 global fit model using the data analysis software of the Octet96 RED software version 10. PRNT1 showed Kd (nM) of 24 in human, Kd of 13 in cyno, and biphasic Kd in mouse; MIAB169 showed Kd of 340 in human, Kd of 153 in cyno, and biphasic Kd in mouse. MIAB169 showed lower affinity to human and cyno MAdCAM than parent PRNT1.


Example 7. MAdCAM Molecule Variants with the Y105I Mutation do not Show Non Specific Binding to DNA and Insulin Irrespective of Expression Host

An immunosorbent plate was coated with dsDNA at a concentration of 1 μg/mL or Insulin at 5 μg/mL in PBS pH 7.4, 75 ul/well, and incubated overnight at 4° C. Wells were washed with PBS pH 7.4 containing 0.05% Tween-20 (wash buffer) three times, and then blocked with 200 ul/well 1% BSA in PBS pH 7.4 (block buffer) for two hours at room temperature. After three washes with wash buffer, TAs and controls Lenzilumab and Elotuzumab were diluted to 100 nM in PBS containing 1% BSA and 0.05% Tween-20 (assay buffer). The diluted material was added to the DNA/insulin coated plate at 75 ul/well for 1 hour at room temperature. After three washes with wash buffer, a donkey anti-human FcY HRP conjugated polyclonal antibody, diluted to 1:5000 in assay buffer, was added to the plate at 75 ul/well for 1 hr at room temperature. After three washes with wash buffer and three washes with wash buffer (with no tween-20), the assay was developed with TMB, and stopped with 1N HCL. OD 450 nm was measured. The experiment included appropriate controls for non-specific binding of test articles to the plate/block in the absence of DNA or insulin. MIAB169-CHO showed dsDNA polyreactivity score of 1.65, and Insulin polyreactivity score of 3.38; MIAB169-HEK showed dsDNA polyreactivity score of 3.36, and Insulin polyreactivity score of 6.37; Elotuzumab control showed dsDNA polyreactivity score of 1.16, and Insulin polyreactivity score of 3.43; and Lenzilumab control showed dsDNA polyreactivity score of 49.51, and Insulin polyreactivity score of 69.23. No non-specific binding to DNA and insulin was seen with MIAB169 expressed in CHO or HEK cells.


Example 8. MAdCAM Germlined Mutants Bind Human MAdCAM

Anti-human Fc biosensors were equilibriated in assay buffer (1% BSA in 1×PBS with Tween-20) for 10 minutes before the experiment was set-up. Test articles were diluted to ug/mL in assay buffer and 200 uL pipetted to 96 well plate. Human MAdCAM was titrated down, two-fold dilutions (starting at 600 nM as the highest concentration, 7-point dilution). Experiment was run using data acquisition software version 10.0 for OCTET96 RED. Test articles were captured using anti-human Fc biosensors for 180 s. Biosensors loaded with test articles were then equilibriated in assay buffer for 120 s. Association was performed in wells with huMAdCAM for 180 seconds. Dissociation was performed in wells with assay buffer for 180 s. Kinetic parameters (kon and kdis) and dissociation constant (KD) were calculated from a 1:1 global fit model using the data analysis software of the Octet96 RED software version 10. PRNT1 showed Kd (nM) of 14, Kon (1/ms) of 6.83 E+05, and Kdis (1/s) of 9.55 E−03; MIAB137 (HCDR2 germlined) showed Kd (nM) of 203, Kon (1/ms) of 4.04 E+05, and Kdis (1/s) of 8.2 E−02; MIAB136 (HCDR1 germlined), MIAB141 (LCDR1 germlined), and MIAB141 (LCDR3 germlined) showed no binding to 150 nM human MAdCAM. MIAB137 has a reduced binding affinity to human MAdCAM.


In a separate experiment PRNT1 showed Kd (nM) of 26.5, Kon (1/Ins) of 4.29 E+05, and Kdis (Vs) of 1.14 E−02; MIAB145-001 (VK: V29I) showed Kd (nM) of 22.2, Kon (1/ms) of 4.05 E+05, and Kdis (1/s) of 8.97 E−03; MIAB146-001 (VK: R31S) showed Kd (nM) of 43.8, Kon (1/ms) of 4.49 E+05, and Kdis (1/s) of 1.97 E−02; MIAB149-001 (VK: V29I) showed Kd (nM) of 68.8, Kon (1/ms) of 3.76 E+05, and Kdis (1/s) of 2.59 E−02; and MIAB147-001 (VK: S32Y) showed no binding to 200 nM human MAdCAM. MIAB146 and MIAB149 have reduced binding affinity to human MAdCAM.


In another experiment PRNT1 showed Kd (nM) of 21.2, Kon (1/ms) of 3.85 E+05, and Kdis (1/s) of 8.16 E−03; MIAB133-001 (VH: D31S) showed Kd (nM) of 20.00, Kon (1/ms) of and Kdis (1/s) of 1.13 E−02; MIAB174-001 (VH: HCDR1: F32Y) showed Kd (nM) of 21.8, Kon (1/ms) of 4.45 E+05, and Kdis (1/s) of 9.69 E−03; MIAB175-001 (VH: HCDR1: D31S, F32Y) showed Kd (nM) of 22.6, Kon (1/ms) of 4.71 E+05, and Kdis (1/s) of 1.06 E−02; MIAB177-001 (VH: HCDR2: I48V, Y50A, D54S, S55G, Y57S, N59Y) showed Kd (nM) of 218, Kon (1/ms) of 3.91 E+05, and Kdis (1/s) of 8.51 E−02; and MIAB178-001 (VH: HCDR1: D31S, F32Y; HCDR2: Y50A, D54S, Y57S, N59Y) showed Kd (nM) of 519, Kon (1/ms) of 3.72 E+05, and Kdis (1/s) of 2.20 E−01. MIAB177 and MIAB178 have reduced affinity to MAdCAM.


In another experiment PRNT1 showed Kd (nM) of 14.8, Kon (1/ms) of 3.96 E+05, and Kdis (1/s) of 5.86 E−03; MIAB182-001 (HCDR1: D31S, F32Y; HCDR2: I48V, Y50A, D54S, S55G, Y57S, N59Y; VK: V29I) showed Kd (nM) of 119, Kon (1/ms) of 2.26 E+05, and Kdis (1/s) of 2.67 E−02; MIAB183-001 (HCDR1: D31S, F32Y; HCDR2: I48V, Y50A, D54S, S55G, Y57S, N59Y; VK: R31S) showed Kd (nM) of 362, Kon (1/ms) of 1.66 E+05, and Kdis (1/s) of MIAB184-001 (HCDR1: D31S, F32T; HCDR2: I48V, Y50A, D54S, S55G, Y57S, N59Y; VK: V29I, R31S) showed Kd (nM) of 563, Kon (1/ms) of 1.45 E+05, and Kdis (1/s) of 8.18 E−02. Germlining heavy chain with V29I reduced MAdCAM affinity by 10-fold, germlining heavy chain with R31S reduced MAdCAM affinity by 20-fold, and germlining heavy chain and light chain reduced MAdCAM affinity by 40-fold.


Example 9. MAdCAM-IL2 Molecules with the MAdCAM Y105I Mutation and IL-2 T3A Mutation do not Show Non Specific Binding to DNA and Insulin Irrespective of Expression Host

An immunosorbent plate was coated with dsDNA at a concentration of 1 μg/mL or Insulin at 5 pg/mL in PBS pH 7.4, 75 ul/well, and incubated overnight at 4° C. Wells were washed with PBS pH 7.4 containing 0.05% Tween-20 (wash buffer) three times, and then blocked with 200 ul/well 1% BSA in PBS pH 7.4 (block buffer) for two hours at room temperature. After three washes with wash buffer, TAs and controls Lenzilumab and Elotuzumab were diluted to 100 nM in PBS containing 1% BSA and 0.05% Tween-20 (assay buffer). The diluted material was added to the DNA/insulin coated plate at 75 ul/well for 1 hour at room temperature. After three washes with wash buffer, a donkey anti-human FcY HRP conjugated polyclonal antibody, diluted to 1:5000 in assay buffer, was added to the plate at 75 ul/well for 1 hr at room temperature. After three washes with wash buffer and three washes with wash buffer (with no tween-20), the assay was developed with TMB, and stopped with 1N HCL. OD 450 nm was measured. The experiment included appropriate controls for non-specific binding of test articles to the plate/block in the absence of DNA or insulin. MIAB198-CHO showed dsDNA polyreactivity score of 1.36, and Insulin polyreactivity score of 3.19; MIAB198-HEK showed dsDNA polyreactivity score of 2.02, and Insulin polyreactivity score of 3.63; Elotuzumab control showed dsDNA polyreactivity score of 1.16, and Insulin polyreactivity score of 3.43; and Lenzilumab control showed dsDNA polyreactivity score of 49.51, and Insulin polyreactivity score of 69.22. No non-specific binding to DNA and insulin was seen with MIAB198 expressed in CHO or HEK cells.


Example 10. MAdCAM-IL2 Molecules with the MAdCAM Y105I Mutation, IL-2 T3A Mutation, and Light Chain V29I Germline Mutation do not Show Non Specific Binding to DNA and Insulin and are Expression Host Dependent

An immunosorbent plate was coated with dsDNA at a concentration of 1 μg/mL or Insulin at 5 μg/mL in PBS pH 7.4, 75 ul/well, and incubated overnight at 4° C. Wells were washed with PBS pH 7.4 containing 0.05% Tween-20 (wash buffer) three times, and then blocked with 200 ul/well 1% BSA in PBS pH 7.4 (block buffer) for two hours at room temperature. After three washes with wash buffer, TAs and controls Lenzilumab and Elotuzumab were diluted to 100 nM in PBS containing 1% BSA and 0.05% Tween-20 (assay buffer). The diluted material was added to the DNA/insulin coated plate at 75 ul/well for 1 hour at room temperature. After three washes with wash buffer, a donkey anti-human FcY HRP conjugated polyclonal antibody, diluted to 1:5000 in assay buffer, was added to the plate at 75 ul/well for 1 hr at room temperature. After three washes with wash buffer and three washes with wash buffer (with no tween-20), the assay was developed with TMB, and stopped with 1N HCL. OD 450 nm was measured. The experiment included appropriate controls for non-specific binding of test articles to the plate/block in the absence of DNA or insulin. PRNT1-CHO showed dsDNA polyreactivity score of 20.59, and Insulin polyreactivity score of 7.07; PRNT1-HEK showed dsDNA polyreactivity score of 28.08, and Insulin polyreactivity score of 13.16; MIAB185-CHO showed dsDNA polyreactivity score of 3.43, and Insulin polyreactivity score of 5.07; MIAB185-HEK showed dsDNA polyreactivity score of 23.11, and Insulin polyreactivity score of 38.37; MIAB188-CHO showed dsDNA polyreactivity score of 1.41, and Insulin polyreactivity score of 4.20; MIAB188-HEK showed dsDNA polyreactivity score of 32.80, and Insulin polyreactivity score of 83.29; Elotuzumab control showed dsDNA polyreactivity score of 0.92, and Insulin polyreactivity score of 1.09; and Lenzilumab control showed dsDNA polyreactivity score of 24.07, and Insulin polyreactivity score of 7.93. No non-specific binding to DNA and insulin was seen with MIAB185 and MIAB188 expressed in CHO cells.


Example 11. MIAB197 is Stable for 1 Month at 4° C. and 37° C.

MIAB197 in acetate buffer was concentrated to 5 mg/mL using spin columns. Samples were collected at various concentrations and analyzed by size exclusion chromatography on an Agilent BioAdvance SEC 300 A column. MIAB197 at 5 mg/mL was incubated at 4 and 37° C. for up to 28 days to analyze molecule's stability over time. Samples were collected at various time points and analyzed by size exclusion chromatography on an Agilent BioAdvance SEC 300 A column. No concentration dependent aggregation was observed with MIAB197 when concentrated up to 5 mg/mL in optimized acetate buffer as seen by analytical SEC. MIAB197 at concentration of 5 mg/mL remained stable with no loss of main peak or appearance of high or low molecular weight species at 4° C. and 37° C. for 1 month.


Example 12. MIAB197 has Favorable Thermal Stability

The samples were submitted to the Nano DSC system (TA Instrument) for analysis. A temperature ramp of 1° C./min was performed with monitoring from 25° C. to 100° C. Thermograms of the blank buffer were subtracted from each antibody prior to analysis and the Tm values were calculated after deconvolution using the Nano DSC software. PRNT1 showed Tm (C) peak 1 of 64.5, peak 2 of 81.7, and peak 3 of 83.8; MIAB197 showed Tm peak 1 of 69.8, peak 2 of 81.7, and peak 3 of 84. MIAB197 has favorable thermal stability.


Example 13. MIAB197 has Desirable Characteristics for Development

To characterize the identity and purity of the samples, the samples were prepared in reducing labeling buffer before being submitted to the LabChip GXII system (PerkinElmer). rCE SDS revealed PRNT1 to comprise 26.5% light chain and 71.6% heavy chain; and MIAB197 to comprise 28.47% light chain and 71.53% heavy chain. MIAB197 has good characteristics for development.


Example 14. MIAB197 has Isoelectric Point Compatible with Manufacturing

The sample was diluted in a matrix of methyl cellulose, 4 M urea, 3-10 pharmalytes (4%), mM Arginine, and pI markers (indicated below). The mixture was submitted to an iCE3 IEF Analyzer (ProteinSimple) and pre-focused at 1,500 V followed by focusing at 3,000 V. The isoelectric points of each peak were calculated from the bracketing pI markers. Capillary isoelectric focusing (cIEF) showed isoelectric peaks of 7.72 with peak area (%) of 0.60, 7.82 with peak area of 1.94, 7.96 with peak area of 5.98, 8.11 with peak area of 10.52, 8.24 with peak area of 32.43, 8.33 with peak area of 22.95, 8.39 with peak area of 12.56, 8.44 with peak area of and 8.54 with peak area of 7.81 for PRNT1; and isoelectric peaks of 8.55 with peak area (%) of 3.63, 8.60 with peak area of 8.66, 8.69 with peak area of 18.38, 8.72 with peak area of 28.79, and 8.76 with peak area of 40.54 for MIAB197. Isoelectirc peaks for MIAB197 are all above pH 8.5, with −70% at pI of 8.7 which is favorable for manufacturability


Example 15. MIAB204 Dos not Show Non Specific Binding to DNA and Insulin

Non-specific DNA and Insulin binding is predictive of poor pharmacokinetics (PK). An immunosorbent plate was coated with dsDNA at a concentration of 111 g/mL or Insulin at 5 μg/mL in PBS pH 7.4, 75 ul/well, and incubated overnight at 4° C. Wells were washed with PBS pH 7.4 containing 0.05% Tween-20 (wash buffer) three times, and then blocked with 200 ul/well 1% BSA in PBS pH 7.4 (block buffer) for two hours at room temperature. After three washes with wash buffer, TAs and controls Lenzilumab and Elotuzumab were diluted to 100 nM in PBS containing 1% BSA and 0.05% Tween-20 (assay buffer). The diluted material was added to the DNA/insulin coated plate at 75 ul/well for 1 hour at room temperature. After three washes with wash buffer, a donkey anti-human FcY HRP conjugated polyclonal antibody, diluted to 1:5000 in assay buffer, was added to the plate at 75 ul/well for 1 hr at room temperature. After three washes with wash buffer and three washes with wash buffer (with no tween-20), the assay was developed with TMB, and stopped with 1N HCL. OD 450 nm was measured. The experiment included appropriate controls for non-specific binding of test articles to the plate/block in the absence of DNA or insulin. MIAB204 showed dsDNA polyreactivity score of 1.66, and Insulin polyreactivity score of 8.43; Elotuzumab control showed dsDNA polyreactivity score of 1.16, and Insulin polyreactivity score of 3.43; and Lenzilumab control showed dsDNA polyreactivity score of 49.51, and Insulin polyreactivity score of 69.23. MIAB204 is not polyreactive.


Example 16. MIAB204 has Favorable Thermal Stability

The samples were submitted to the Nano DSC system (TA Instrument) for analysis. A temperature ramp of 1° C./min was performed with monitoring from 25° C. to 100° C. Thermograms of the blank buffer were subtracted from each antibody prior to analysis and the Tm values were calculated after deconvolution using the Nano DSC software. PRNT1 showed Tm (C) peak 1 of 64.5, peak 2 of 81.7, and peak 3 of 83.8; MIAB204 showed Tm peak 1 of 65.4, peak 2 of 69.5, and peak 3 of 84.4. MIAB204 has favorable thermal stability.


Example 17. MIAB204 has Desirable Characteristics for Development

To characterize the identity and purity of the samples, the samples were prepared in reducing labeling buffer before being submitted to the LabChip GXII system (PerkinElmer). rCE SDS revealed PRNT1 to comprise 26.5% light chain and 71.6% heavy chain; and MIAB204 to comprise one peak comprising 80.64% and second peak comprising 19.36% of the sample. MIAB204 showed different 0-glycan occupancies. MIAB204 has good characteristics for development.


Example 18. MIAB204 has Isoelectric Point Compatible with Manufacturing

The sample was diluted in a matrix of methyl cellulose, 4 M urea, 3-10 pharmalytes (4%), 5 mM Arginine, and pI markers (indicated below). The mixture was submitted to an iCE3 IEF Analyzer (ProteinSimple) and pre-focused at 1,500 V followed by focusing at 3,000 V. The isoelectric points of each peak were calculated from the bracketing pI markers. Capillary isoelectric focusing (cIEF) showed isoelectric peaks of 7.72 with peak area (%) of 0.60, 7.82 with peak area of 1.94, 7.96 with peak area of 5.98, 8.11 with peak area of 10.52, 8.24 with peak area of 32.43, 8.33 with peak area of 22.95, 8.39 with peak area of 12.56, 8.44 with peak area of 5.21, and 8.54 with peak area of 7.81 for PRNT1; and isoelectric peaks of 7.59 with peak area (%) of 2.92, 7.84 with peak area of 5.94, 8.00 with peak area of 14.88, 8.19 with peak area of 18.64, 8.29 with peak area of 5.80, 8.33 with peak area of 10.73, 8.38 with peak area of 22.13, 8.43 with peak area of 14.04, and 8.48 with peak area of 4.92 for MIAB204. Isoelectirc peaks for MIAB204 show heterogeneity with most peaks having the pI greater than 8. MIAB204 is considered good for manufacturing.


Example 19. MAdCAM-IL-2 M Molecules do not Block the Interaction Between Recombinant Human MAdCAM and Alpha4 Beta7-Positive Hut-78 T Cells

96 well plates were coated with 2.5 ug/mL recombinant human MAdCAM-Fc in PBS overnight at 4° C. Plated were blocked with DMEM containing 20% FBS for 30 minutes at 37° C., and MIAB210 (control), PRNT1, PRNT2, MIAB197, MIAB12, MIAB13, MIAB25, MIAB26, MIAB37, a benchmark molecule, a negative control molecule, and a positive control molecule were captured for 1 hour at 37° C. in PBS. Hut-78 cells were incubated in 20% FBS DMEM supplemented with 1 mM MnCl2 for 1 hour at 37° C., and the cells were added to plates for 1 hour at 37° C. Plated were washed with PBS supplemented with 1 mM MnCl2 3 times, followed by 100 uL of cell titer glo. Plates were shaken for 2 minutes, and incubated at room temperature for another 10 minutes. Luminescence was measured and revealed lack of inhibition of MAdCAM and alpha4 beta7 interaction. MAdCAM-IL-2 M bi-specifics do not block the interaction between recombinant human MAdCAM and alpha4 beta7-positive Hut-78 T cells. Optimized MAdCAM-IL-2 M bi-specifics do not block MAdCAM-alpha4 beta7 interaction in vitro and therefore should not interfere with the trafficking of alpha4 beta7-positive T cells in vivo.


Example 20. MAdCAM-IL-2 M Molecules Selectively Induce P-STAT5 Phosphorylation on Primary Tregs Versus Teff or NK Cells when Tethered to Human/Mouse MAdCAM Expressing CHO Cells

Parental CHO cells or CHO cells over-expressing human MAdCAM or murine MAdCAM were seeded onto wells of a 96 well plate (Corning) overnight. After washing 3 times with F12+10% FBS media, the plate was blocked for 1 hour with 5 uM whole human IgG. 10 nM parental MAdCAM-IL-2 M bi-specifics PRNT1 and PRNT2, or optimized variants MIAB12, MIAB13, MIAB25, MIAB26, MIAB37, MIAB204 and MIAB197 were captured for 1 hour. After washing 2 times with F12+10% FBS media, freshly-isolated human PBMCs were stimulated for 60 minutes with captured IL-2 MM bispecifics. Cells were then fixed for 10 minutes with BD Cytofix, permeabilized sequentially with BD Perm III, and BioLegend FOXP3 permeabilization buffer, blocked with human serum and stained for 30 minutes with antibodies against phospho-STAT5 A488, CD25 PE, FOXP3 AF647 and CD4 PerCP Cy5.5, CD3 BV421, CD56 BV785 and acquired on an Attune NXT with plate loader. PRNT1, PRNT2, MIAB1, MIAB12, MIAB13, MIAB25, MIAB26, MIAB37, MIAB204, and MIAB197 showed P-STAT5-positive Tregs. Accordingly, PRNT1, PRNT2, MIAB1, MIAB12, MIAB13, MIAB25, MIAB26, MIAB37 MIAB204, and MIAB197 selectively activate Tregs.


Example 21. V69A and Q74P Substitutions in the IL-2 Mutein are Beneficial in Improving Solubility of the Molecule

The pTT5 vectors containing the full length IgG1 heavy with C-terminally fused human IL-2 mutant and light chain encoding MIAB211 (control IgG1 mAb) were co-transfected at equimolar ratios into HEK cells. After 5-7 days, cell culture supernatants expressing MIAB211 (control IgG1 mAb) were harvested, and clarified by centrifugation and filtration through a filtration device. MIAB211, was captured on Mab Select column. The column was washed with PBS pH 7.4 and the captured protein was eluted using 0.1 M glycine pH 2.5, with neutralization using a tenth volume of 1 M Tris pH 8.0. The protein was buffer exchanged into PBS pH 7.4, and analyzed by size exclusion chromatography on an Agilent BioAdvance SEC 300 A column. MIAB211 (control IgG1 mAb) was aggregated with only 67% monodispersed after ProA purification as shown by size exclusion chromatography. Additional polishing procedures like cation exchange improved the monodispersity to 86% which is not suitable for assays. V69A and Q74P are beneficial in improving solubility of molecule.


Example 22. PD-1-MAdCAM Molecules with Heavy Chain Mutations Bind Human MAdCAM

Anti-human IgG Fc (AHC) biosensors were equilibrated in assay buffer for 20 minutes. Test article was diluted to 10 μg/mL in assay buffer. A seven-point two-fold serial dilution of human MAdCAM-1 was prepared in assay buffer, starting at 300 nM down to 4.69 nM. Test article was loaded on tips for 240 s followed by a 120 s association phase with MAdCAM and 120 s dissociation phase in assay buffer. Kinetic parameters (Kon and Koff) and dissociation constant (Kd) were calculated from a 1:1 global fit model using the data analysis software of the Octet96 RED software version 10. Parental molecule showed Kd (nM) of 62.8, Kon (1/ms) of 5.81 E+05, and Koff (1/s) of 3.65 E−02; PMAB19 showed Kd of 31.2, Kon of 5.40 E+05, and Koff of 1.68 E−02; PMAB20 showed Kd of 90.5, Kon of 4.11 E+05, and Koff of 3.72 E−02; PMAB23 showed Kd of 110, Kon of 3.55 E+05, and Koff of 3.89 E−02; PMAB24 showed Kd of 33.2, Kon of 4.04 E+05, and Koff of 1.34 E−02; PMAB25 showed Kd of 43.6, Kon of 4.86 E+05, and Koff of 2.12 E−02; PMAB26 showed Kd of 138, Kon of 4.76 E+05, and Koff of 6.58 E−02; PMAB27 showed Kd of 92.2, Kon of 138 E+06, and Koff of 1.28 E−01; PMAB28 showed Kd of 86.2, Kon of 1.05 E+06, and Koff of 9.02 E−02; and PMAB21 and PMAB22 showed no binding. PMAB19, PMAB20, PMAB23, PMAB24, PMAB25, PMAB26, PMAB27, and PMAB28 comprising heavy chain mutations bind to human MAdCAM.


Example 23. PD-1-MAdCAM Molecules with Light Chain Mutations Bind Human MAdCAM

Anti-human IgG Fc (AHC) biosensors were equilibrated in assay buffer for 20 minutes. Test article was diluted to 10 μg/mL in assay buffer. A seven-point serial dilution of human MAdCAM-1 was prepared in assay buffer, starting at 200 nM down to 3.13 nM. Test article was loaded on tips for 240 s followed by a 120 s association phase with MAdCAM and 120 s dissociation phase in assay buffer. Kinetic parameters (Kon and Koff) and dissociation constant (Kd) were calculated from a 1:1 global fit model using the data analysis software of the Octet96 RED software version 10. Parental molecule showed Kd (nM) of 135, Kon (1/ms) of 2.52 E+05, and Koff (1/s) of 3.41 E−02; PMAB36 showed Kd of 109, Kon of 2.98 E+05, and Koff of 3.25 E−02; PMAB37 showed Kd of 285, Kon of 2.94 E+05, and Koff of 8.38 E−02; PMAB41 showed Kd of 43.5 uM, Kon of 2.12 E+03, and Koff of 9.25 E−02; PMAB42 showed Kd of 395, Kon of 2.88 E+05, and Koff of 1.14 E−01; and PMAB38, PMAB39, PMAB40, and PMAB43 showed no binding. PMAB36, PMAB37, PMAB41, and PMAB42 comprising light chain mutations bind to human MAdCAM.


Example 24. PD-1-MAdCAM Molecules with Germline Mutations Bind Human MAdCAM

Anti-human IgG Fc (AHC) biosensors were equilibrated in assay buffer for 20 minutes. Test article was diluted to 10 μg/mL in assay buffer. A seven-point serial dilution of human MAdCAM-1 was prepared in assay buffer, starting at 200 nM down to 3.13 nM. Test article was loaded on tips for 240 s followed by a 120 s association phase with MAdCAM and 120 s dissociation phase in assay buffer. Kinetic parameters (Kon and Kdis) and dissociation constant (Kd) were calculated from a 1:1 global fit model using the data analysis software of the Octet96 RED software version 10. Parental molecule showed Kd (M) of 1.15 E−07, Kon (1/ms) of 3.06 E+05, and Kdis (1/s) of 3.51 E−02; PMAB13 showed Kd of 1.32 E−07, Kon of 5.42 E+05, and Kdis of 7.17 E−02; PMAB12 showed Kd of 6.33 E−08, Kon of 7.33 E+05, and Kdis of 4.64 E−02; PMAB11 showed Kd of 4.66 E−07, Kon of 4.19 E+05, and Kdis of 1.95 E−01; PMAB10 showed Kd of 1.46 E−07, Kon of 6.62 E+05, and Kdis of 9.67 E−02; PMAB9 showed Kd of 1.59 E−07, Kon of 4.55 E+05, and Kdis of 7.25 E−02; PMAB8 showed Kd of 7.14 E−08, Kon of 6.56 E+05, and Kdis of 4.69 E−02; PMAB7 showed Kd of 2.36 E−07, Kon of 5.76 E+05, and Kdis of 1.36 E−01; PMAB6 showed Kd of 1.50 E−07, Kon of 6.98 E+05, and Kdis of 1.05 E−01; PMAB5 showed Kd of 4.13 E−07, Kon of 2.90 E+05, and Kdis of 1.20 E−01; PMAB4 showed Kd of 4.18 E−08, Kon of 1.31 E+06, and Kdis of 5.47 E−02; PMAB3 showed Kd of 3.33 E−07, Kon of 7.17 E+05, and Kdis of 2.39 E−01; and PMAB2 showed Kd of 1.75 E−07, Kon of 7.25 E+05, and Kdis of 1.27 E−01. PD-1-MAdCAM Molecules comprising germline mutations bind to human MAdCAM.


Example 25. PD-1-MAdCAM Molecules with Single Mutations Bind Mouse MAdCAM

Anti-human IgG Fc (AHC) biosensors were equilibrated in assay buffer for 20 minutes. Test article was diluted to 10 μg/mL in assay buffer. A seven-point serial dilution of mouse MAdCAM-1 was prepared in assay buffer, starting at 500 nM down to 7.82 nM. Test article was loaded on tips for 180 s followed by a 120 s association phase with MAdCAM and 150 s dissociation phase in assay buffer. Kinetic parameters (Kon and Kdis) and dissociation constant (Kd) were calculated from a 1:1 global fit model using the data analysis software of the Octet96 RED software version 10. Parental molecule showed Kd (M) of 1.38 E−07, Kon (1/ms) of 1.48 E+05, Kdis (1/s) of 2.04 E−02, and response of 0.1387; PMAB19 showed Kd of 1.12 E−07, Kon of 1.58 E+05, Kdis of 1.77 E−02, and response of 0.1494; PMAB20 showed Kd of 1.18 E−07, Kon of 1.63 E+05, Kdis of 1.93 E−02, and response of 0.1531; PMAB23 showed Kd of 1.41 E−07, Kon of 1.26 E+05, Kdis of 1.78 E−02, and response of 0.1406; PMAB24 showed Kd of 5.24 E−08, Kon of 1.14 E+05, Kdis of 5.96 E−03, and response of 0.0549; PMAB25 showed Kd of 1.15 E−07, Kon of 1.05 E+05, Kdis of 1.20 E−02, and response of 0.1328; PMAB26 showed Kd of 1.34 E−07, Kon of 8.79 E+04, Kdis of 1.18 E−02, and response of 0.132; PMAB27 showed Kd of 1.02 E−06, Kon of 4.58 E+03, Kdis of 4.69 E−03, and response of 0.0278; PMAB28 showed Kd of 1.03 E−07, Kon of 8.59 E+04, Kdis of 8.86 E−03, and response of 0.083; PMAB36 showed Kd of 2.06 E−07, Kon of 1.22 E+05, Kdis of 2.51 E−02, and response of 0.1689; PMAB3? showed Kd of 1.76 E−07, Kon of 1.01 E+05, Kdis of 1.78 E−02, and response of 0.1518; PMAB41 showed Kd of 1.19 E−07, Kon of 2.08 E+05, Kdis of 2.46 E−02, and response of 0.1887; and PMAB42 showed Kd of 1.05 E−07, Kon of 1.62 E+05, Kdis of 1.70 E−02, and response of 0.1287. PD-1-MAdCAM Molecules comprising single mutations bind to mouse MAdCAM.


Example 26. PD-1-MAdCAM Molecules with Single Hydrophobic Patch Mutations Bind Human MAdCAM

Anti-human IgG Fc (AHC) biosensors were equilibrated in assay buffer for 20 minutes. Test article was diluted to 10 μg/mL in assay buffer. A seven-point serial dilution of human MAdCAM-1 was prepared in assay buffer, starting at 200 nM down to 3.13 nM. Test article was loaded on tips for 240 s followed by a 120 s association phase with MAdCAM and 120 s dissociation phase in assay buffer. Kinetic parameters (Kon and Koff) and dissociation constant (Kd) were calculated from a 1:1 global fit model using the data analysis software of the Octet96 RED software version 10. Parental molecule showed Kd (nM) of 116, Kon (1/ms) of 2.38 E+05, and Koff (1/s) of 2.76 E−02; PMAB45 showed Kd of 735 uM, Kon of 5.91 E+02, and Koff of 4.34 E−01; PMAB46 showed Kd of 37.9 uM, Kon of 8.16 E+03, and Koff of 3.09 E−01; PMAB47 showed Kd of 219, Kon of 3.29 E+05, and Koff of 7.20 E−02; PMAB48 showed Kd of 51 uM, Kon of 9.33 E+03, and Koff of 1.33 E−01; PMAB49 showed Kd of 142, Kon of 8.79 E+04, and Koff of 1.25 E−02; PMAB51 showed Kd of 93.5, Kon of 1.15 E+05, and Koff of 9.52 E−03; and PMAB44 and PMAB50 showed no binding. PMAB45, PMAB46, PMAB47, PMAB48, PMAB49, and PMAB51 comprising single hydrophobic patch mutations bind to human MAdCAM.


Example 27. Optimized PD-1-MAdCAM Molecules Bind Human and Mouse MAdCAM

Kinetic parameters (Kon and Koff) and dissociation constant (Kd) were assessed and calculated as described above. Binding kinetics to human MAdCAM of the parental molecule showed Kd (M) of 3.76 E−08 with a Kd error of 3.76 E−08, Kon (1/ms) of 1.06 E+06 with a Kon error of 3.32 E+04, Kdis (1/s) of 3.98 E−02 with a Kdis error of 1.36 E−03, and response of 0.0839; PMAB15 showed Kd of 7.31 E−08 with a Kd error of 3.82 E−09, Kon of 1.15 E+06 with a Kon error of 4.99 E+04, Kdis of 8.39 E−02 with a Kdis error of 2.42 E−03, and response of 0.0655; PMAB16 showed Kd of 1.34 E−07 with Kd error of 4.18 E−09, Kon of 4.72 E+05 with a Kon error of 1.26 E+04, Kdis of 6.31 E−02 with a Kdis error of 1.03 E−03, and response of 0.1856; and PMAB17 showed Kd of 1.71 E−08 with Kd error of 1.02 E−09, Kon of 3.73 E+06 with a Kon error of 1.72 E+05, Kdis of 6.36 E−02 with a Kdis error of 2.42 E−03, and response of 0.0416. Binding kinetics to mouse MAdCAM of the parental molecule showed Kd (M) of 1.24 E−07 with a Kd error of 5.96 E−09, Kon (1/ms) of 3.74 E+05 with a Kon error of 1.35 E+04, Kdis (1/s) of 4.63 E−02 with a Kdis error of 1.49 E−03, and response of 0.256; PMAB15 binding was inconclusive; PMAB16 showed Kd of 3.34 E−07 with Kd error of 1.34 E−08, Kon of 2.48 E+05 with a Kon error of 8.63 E+03, Kdis of 8.28 E−02 with a Kdis error of 1.64 E−03, and response of 0.0407; and PMAB17 binding was inconclusive. PMAB15, PMAB16, and PMAB17 bind to human MAdCAM, and PMAB16 binds to mouse MAdCAM. While the combination of germline mutations in PMAB15 and PMAB17 have the appropriate affinity for human MAdCAM, the binding to mouse MAdCAM is severely compromised.


Example 28. Optimized PD-1-MAdCAM Molecules Bind Human, Cyno, and Mouse MAdCAM

Kinetic parameters (Kon and Koff) and dissociation constant (Kd) were assessed and calculated as described above. Binding kinetics to human MAdCAM of PMAB57 showed Kd (M) of 1.22 E−07 with a Kd error of 7.08 E−09, Kon (1/ms) of 3.20 E+05 with a Kon error of 1.77 E+04, Kdis (1/s) of 3.89 E−02 with a Kdis error of 6.84 E−04, and response of 0.1804; PMAB18 showed Kd of 1.98 E−07 with a Kd error of 1.23 E−08, Kon of 2.59 E+05 with a Kon error of 1.54 E+04, Kdis of 5.11 E−02 with a Kdis error of 9.93 E−04, and response of 0.1842. Binding kinetics to cyno MAdCAM of PMAB57 showed Kd (M) of 4.99 E−08 with a Kd error of 8.00 E−10, Kon (1/ms) of 3.06 E+05 with a Kon error of 4.74 E+03, Kdis (1/s) of 1.53 E−02 with a Kdis error of 6.39 E−05, and response of 0.169; PMAB18 showed Kd of 2.26 E−08 with a Kd error of 5.51 E−10, Kon of 4.53 E+05 with a Kon error of 1.07 E+04, Kdis of 1.02 E−02 with a Kdis error of 6.08 E−05, and response of 0.1447. Binding kinetics to mouse MAdCAM of PMAB57 showed Kd (M) of 2.05 E−07 with a Kd error of 4.09 E−10, Kon (1/ms) of 2.72 E+05 with a Kon error of 5.63 E+03, and Kdis (1/s) of 5.58 E−02 with a Kdis error of 5.43 E−04; PMAB18 showed Kd of 2.01 E−07 with a Kd error of 4.41 E−10, Kon of 3.86 E+05 with a Kon error of 1.01 E+04, and Kdis of 7.76 E−02 with a Kdis error of 8.45 E−04. Optimized PD-1-MAdCAM antibody affinity for MAdCAM matches the targets across human, cyno, and mouse MAdCAM.


Example 29. Optimized PD-1-MAdCAM Molecules Bind Human, Cyno, and Mouse MAdCAM Regardless of the PD-1 Agonist

Kinetic parameters (Kon and Koff) and dissociation constant (Kd) were assessed and calculated as described above. Binding kinetics to human MAdCAM of PMAB58 showed Kd of 1.35 E−07, Kon of 7.12 E+04, and Kdis of 9.61 E−03; PMAB53 showed Kd of 4.97 E−08, Kon of 1.44 E+04, and Kdis of 7.16 E−04; PMAB56 showed Kd of 2.08 E−07, Kon of 2.36 E+04, and Kdis of 4.91 E−03; PMAB59 showed Kd of 1.40 E−07, Kon of 3.83 E+04, and Kdis of 5.37 E−03; PMAB54 showed Kd of 5.92 E−07, Kon of 2.36 E+05, and Kdis of 1.40 E−01; and PMAB55 showed Kd of 4.76 E−08, Kon of 3.43 E+04, and Kdis of 1.63 E−03. Binding kinetics to cyno MAdCAM of PMAB58 showed Kd of 9.13 E−09, Kon of 2.29 E+05, and Kdis of 2.09 E−03; PMAB53 showed Kd of 3.79 E−07, Kon of 5.71 E+04, and Kdis of 2.17 E−02; PMAB56 showed Kd of 9.65 E−08, Kon of 6.12 E+05, and Kdis of 5.91 E−02; PMAB59 showed Kd of 1.66 E−08, Kon of 1.09 E+05, and Kdis of 1.82 E−03; PMAB54 showed Kd of 1.58 E−07, Kon of 7.19 E+04, and Kdis of 1.14 E−02; and PMAB55 showed Kd of 4.43 E−08, Kon of 2.09 E+05, and Kdis 9.24 E−03. Binding kinetics to mouse MAdCAM of PMAB58 showed Kd of 3.30 E−07, Kon of 2.51 E+05, and Kdis 8.25 E−02; PMAB53 showed Kd of 1.74 E−06, Kon of 1.25 E+05, and Kdis of 2.17 E−01; PMAB56 showed Kd of 1.61 E−07, Kon of 9.12 E+03, and Kdis of 1.47 E−03; PMAB59 showed Kd of 1.31 E−07, Kon of 1.30 E+04, and Kdis of 1.70 E−03; PMAB54 showed Kd of 2.48 E−07, Kon of 5.57 E+03, and Kdis of 1.38 E−03; and PMAB55 showed Kd of 5.95 E−08, Kon of 2.20 E+04, and Kdis of 1.31 E−03. Optimized PD-1-MAdCAM antibodies bind human, cyno, and mouse MAdCAM regardless of the PD-1 agonist, but strongly favor M to L mutants such as PMAB56 and PMAB55.


Example 30. Optimized PD-1-MAdCAM Molecules are Thermally Stable

Thermal stability of PMAB58, PMAB53, PMAB56, PMAB59, PMAB54, and PMAB55 was evaluated as described above. The data showed that the onset of melting temperature for the M to L mutants, such as PMAB56 and PMAB55, was very similar to their respective parental clones. The M to I mutants, such as PMAB53 and PMAB54, had a higher Tm than the parental and M to L mutant, however the difference in Tm is not significant. The T aggregation onset was measured at 493 nm and produced similar values for PMAB58, PMAB53, and PMAB56; and PMAB59, PMAB54, and PMAB55. Overall, there was no significant difference in the temperature of aggregation onset. Freeze thaw stability was slightly better for the M to L mutants when compared to the initial POI, and the aSEC data showed that the initial peak heights were lower for the M to L mutants in comparison to the parental clone. Accordingly, the optimized PD-1-MAdCAM molecules are thermally stable.


Example 31. Y105D Mutation Decreases Polyreactive Binding to Insulin

Plates were coated overnight with dsDNA and human insulin in 1×PBS. Plates were blocked with 1×PBS with 1% BSA. Antibody binding was tested at 100 nM. Sample signal was normalized to the background signal (coated wells with 2° antibody only). The data showed good dsDNA polyreactivity scores for all samples except the Y105K mutant and negative control antibody; and good Insulin polyreactivity scores for all samples except the Y105K mutant and the negative control antibody. The Y105D mutant showed improved lower Insulin polyreactivity scores than other mutant. Polyreactive binding of the Y103G, Y105D, and Y105K mutants to dsDNA and human insulin shows that the Y105D hydrophobic patch mutation decreases polyreactive binding to human insulin compared to the parental antibody.


Example 32. PMAB16 has Decreased Polyreactive Binding to BVP or HEK Cell Lysate

Plates were coated with 1% Baculovirus particle (BVP) or HEK293 cell lysate (HCL) in carbonate buffer pH 9.5, 4° C. overnight. Plates were blocked with 1×PBS with 2% BSA. Antibodies were tested in triplicate for binding to BVP or HCL at 150, 50, 16.7 and 5.6 μg/mL. Signal was normalized to background signal (coated wells with 2° antibody only). BVP and HCL polyreactivity scores were lower for the PMAB16 antibody as compared to parental PMAB1 when used at 50 ug/mL or 16.7 ug/mL concentrations. Accordingly, the optimized PMAB16 antibody has decreased polyreactivity to BVP or HCL compared to the parent clone.


Example 33. PMAB16 has Decreased Isoelectric Point

The sample was diluted in a matrix of methyl cellulose, 4 M urea, 3-10 pharmalytes (4%), 5 mM Arginine, and pI markers (indicated below). The mixture was submitted to an iCE3 IEF Analyzer (ProteinSimple) and pre-focused at 1,500 V followed by focusing at 3,000 V. The isoelectric points of each peak were calculated from the bracketing pI markers. Capillary isoelectric focusing (cIEF) showed isoelectric peaks of 8.71 with peak area (%) of 5.75, 8.97 with peak area of 19.20, 9.03 with peak area of 10.63, 9.09 with peak area of 16.92, and 9.13 with peak area of 47.50 for the PMAB1 antibody; and isoelectric peaks of 8.50 with peak area (%) of 3.90, 8.58 with peak area of 6.36, 8.73 with peak area of 45.74, and 8.76 with peak area of 44.00 for PMAB16. All isoelectric peaks for PMAB16 show the pI greater than 8. PMAB16 is considered good for manufacturing.


Example 34. PMAB16 has Decreased Concentration Dependent Aggregation

Antibodies were affinity purified and buffer exchanged into phosphate buffer, pH 7.0 containing 8.5% sucrose and 100 mM NaCl. Each antibody was then concentrated using a centrifugal concentrator with samples taken at the indicated concentrations for analysis by analytical SEC. The optimized MAdCAM clone PMAB16 showed a decrease in concentration dependent aggregation compared to the parental PMAB1 antibody sequence.


Example 35. PMAB16 has Good Storage Stability

Antibodies were concentrated using a centrifugal concentrator to a final concentration of 1 mg/mL. Samples were flash frozen at the indicated time points and aggregation was measured by analytical SEC. The optimized MAdCAM antibody PMAB16 showed good storage stability over 28 days at 4° C. PMAB16 stored in the accelerated stress condition of 37° C. also showed good stability out to 21 days. Accordingly, PMAB16 has good storage stability.


Example 36. PMAB16 has Favorable Thermal Stability

The samples were submitted to the Nano DSC system (TA Instrument) for analysis. A temperature ramp of 1° C./min was performed with monitoring from 25° C. to 100° C. as described above. The data showed the Tm of PMAB16 to be lower than that of the parental molecule PMAB1, and improved storage stability at 4° C. and temperature dependent aggregation.


Example 37. Identity of PMAB16 was Verified Via Mass Spectroscopy and CE-SDS

Sample was denatured and reduced by guanidine and DTT and deglycosylated by PNGase F before SEC separation and mass spectrometry. Mass spectroscopy showed two peaks for the PMAB16 sample, with values of 75542 Da for the peak 1 and 24258 for the peak 2, consisted with the expected mass.


Sample was prepared in reducing labeling buffer before electrophoresis using the LabChip GXII system. The data showed three peaks with fluorescence values of 26.85% for peak 1, 0.76% for peak 2, and 72.39% for peak 3, consistent with expected chain compositions for PMAB16.


Example 38. Optimized MAdCAM Clones Retain Binding Specificity

Parental CHO cells or CHO cells expressing MAdCAM-1 were incubated with the indicated test articles. Bound test articles were detected by addition of a fluorescently conjugated anti-human IgG antibody. Optimized MAdCAM clones (PMAB18, PMAB59 and PMAB58) showed similar binding to the parental molecule (PMAB57).


Example 39. PMAB18 Showed Improved Tethered Activity in Jurkat Assay

MAdCAM-expressing CHO cells were allowed to adhere and form a monolayer. Test articles were added at the indicated concentrations and allowed to bind for 1 h at 37° C. All wells were washed, and PD-1 reporter Jurkat cells were added. Jurkat cells were incubated with test article loaded CHO cells for 2 h at 37° C. PMAB18 showed improved tethered PD-1 agonist activity as compared to the parent antibody.


Example 40. Optimized PD-1-MAdCAM Antibodies Co-Localize with MAdCAM-1

Fresh frozen mesenteric lymph node replicates from a 12-week BALB/c mouse were sectioned at 5 um, fixed with acetone, blocked with blockaid buffer solution for ten minutes room temperature and incubated with 1 and 10 nM titrations of test articles overnight at 4-degree Celsius. Tissues were then stained with anti-mouse MAdCAM and anti-human IgG Fc for two hours room temperature, DAPI counterstained and mounted and imaged with confocal microscopy. Clones including optimized MAdCAM (PMAB58 and PMAB18) co-localized with MAdCAM-1 expressing structures similarly to the parental clones (PMAB1 and PMAB57).


Example 41. PMAB58 Prolongs Survival in Xenogeneic Graft Versus Host Disease

Xenogeneic graft versus host disease was induced by the transfer of human PBMC into immunodeficient mice. Beginning 10 days after cell transfer, mice were treated subcutaneously weekly with PMAB1, PMAB58, or vehicle. PMAB58 improved probability of survival to over days, while the median survival time for PMAB1 was 49 days, and 41 days for vehicle. Accordingly, PMAB58 improves survival time in GVHD.


Example 42. PMAB18 Downregulates Chemokines/Cytokines in Small Intestine

Immunocompromised NSG mice were engrafted with human PBMCs 10 days prior to treatment. Mice were treated weekly with MADCAM-PD1 bispecific (3 mg/kg) for three weeks and sacrificed. Small intestine was homogenized, normalized for total protein concentration and cytokines/chemokines were measured using the 0-link proteomic platform. Data represent geometric mean and geometric standard deviation of 8 animals (log 2 scale). A student's t-test was performed on all markers; CLC4, p=0.005; IL17A, p=0.04; CXCL10, p=0.06; IFNG, p=(NPX, normalized protein expression) The vehicle data showed geoMean values of 257.9 for CCL4, 4.4 for IL17A, 14.1 for CXCL10, and 8812 for IFNG; while PMAB18 showed geoMean values of 43.8 for CCL4, 2.1 for IL17A, 3.9 for CXCL10, and 1899 for IFNG. PMAB18 reduces CCL4, IL17A, CXCL10 and IFNG in small intestine tissue from Xenogeneic graft-versus-host-disease mice. In conclusion, reduced pro-inflammatory cytokine and chemokines in target tissue suggest therapeutic effect of the MADCAM-PD1 agonist bispecific.


Example 43. PMAB18 and PMAB58 is Detectable in Gut Tissue Through 4 Weeks Post DC Dosing

Balb/c mice were SC dosed with 1 mg/kg of PMAB18 or PMAB58. Intact PMAB18 and PMAB58 was detected in gut tissue 4 weeks after subcutaneous administration into Balb/c mice (1 mg/kg dose), revealing desirable extended PK in tissues. PMAB18 and PMAB58 remained intact and exhibited good drug like properties in systemic circulation as shown in FIG. 20A and FIG. 20B.


Example 44. MAdCAM-IL-2 M Molecules Bind to Human or Murine MAdCAM

Parental CHO cells or CHO cells over-expressing human MAdCAM or murine MAdCAM were suspended in PBS+2% FBS media on a 96 well plate (Corning). Parental MAdCAM-IL-2 M bi-specifics PRNT2, or optimized variants MIAB197, MIAB1, MIAB12, MIAB13, MIAB25, MIAB26 or MIAB37 were captured for 30 mins on ice. After washing 2 times with PBS+2% FBS media, cells were stained for 30 minutes with an Anti-Human IgG detection antibody and TOPRO dye and acquired on an Attune NXT with plate loader. PRNT2 and MIAB197 bound to human MAdCAM with similar efficiency, and MIAB197 showed lower binding to murine MAdCAM than PRNT2. MAdCAM-IL-2 M bi-specifics bind to human or murine MAdCAM expressing cells and show minimum binding to parental CHO cells.


Example 45. PRNT2 Variants Bind Human, Cynomolgus, and Murine MAdCAM

Anti-human Fc biosensors were equilibriated in assay buffer (1% BSA in 1×PBS with Tween-20) for 10 minutes before the experiment was set-up. Test articles were diluted to ug/mL in assay buffer and pipetted to 96 well plate. Human MAdCAM was titrated down, three-fold dilutions. Experiment was run as explained above. Dissociation constant (KD) was calculated as explained above. PRNT2 showed Kd (nM) of 62.5 in human, 51.8 in cyno, and 159.9 in mouse; MIAB1 showed Kd (nM) of 38.4 in human, 26.5 in cyno, and 183.8 in mouse; MIAB2 showed Kd (nM) of 23.2 in human, 18.8 in cyno, and 147.3 in mouse; MIAB12 showed Kd (nM) of 19.3 in human, 19.5 in cyno, and 77.5 in mouse; MIAB13 showed Kd (nM) of 45.9 in human, 33.4 in cyno, and 6.6 in mouse; MIAB25 showed Kd (nM) of 46.9 in human, 60.8 in cyno, and 131 in mouse; MIAB26 showed Kd (nM) of 49.1 in human, 78.5 in cyno, and 9.9 in mouse; MIAB121 showed Kd (nM) of 50.4 in human, 92 in cyno, and 117.1 in mouse; MIAB122 showed Kd (nM) of 48.2 in human, 68.5 in cyno, and 130.3 in mouse; MIAB123 showed Kd (nM) of 39.7 in human, 77.9 in cyno, and 163.6 in mouse; MIAB124 showed Kd (nM) of −0.2 in human, 11.5 in cyno, and −4.9 in mouse; MIAB125 showed Kd (nM) of −2.9 in human, 0.9 in cyno, and −0.3 in mouse; MIAB126 showed Kd (nM) of 91.5 in human, 84.4 in cyno, and 248.8 in mouse; MIAB209 showed Kd (nM) of 61.1 in human, 99 in cyno, and 35.2 in mouse; MIAB205 showed Kd (nM) of 56.3 in human, 117.1 in cyno, and 42.2 in mouse; MIAB206 showed Kd (nM) of 74.3 in human, 89.5 in cyno, and 7.6 in mouse; MIAB207 showed Kd (nM) of 83.5 in human, 73.7 in cyno, and 24 in mouse; and MIAB208 showed Kd (nM) of 20.2 in human, 141.6 in cyno, and 75.1 in mouse. PRNT2 variants bind human, cyno, and mouse MAdCAM with different affinities.


Example 46. MIAB126 Improves Human/Cyno Binding without Affecting Binding to Mouse MAdCAM

Nunc Maxisorp 96-well plate was coated with 2 ug/ml MAdCAM overnight. The plate was then washed 3× with PBST. 0-500 nM of the antibody was added followed by a 300 ul 4% NFM block in PBS. Bound antibodies were detected with 1:5000 anti-Fc-HRP antibody. ELISA was developed with TMB substrate. MIAB126 variant improved affinity to human and cyno MAdCAM when compared to parent PRNT2 molecule, without change in muMAdCAM affinity.


Example 47. PRNT2 Variants Bind Human, Cynomolgus, and Murine MAdCAM

Anti-human Fc biosensors were equilibriated in assay buffer (1% BSA in 1×PBS with 0.05% Tween-20) for 10 minutes before the experiment was set-up. Test articles were diluted to as explained above. Experiment was run as explained above. Dissociation constant (KD) was calculated as explained above. PRNT2 showed Kd of 354 nM in human, 90 uM in cyno, and 6.2 nM in mouse; MIAB126 showed Kd of 3.7 nM in human, 4.9 nM in cyno, and 17 nM in mouse. Engineering has improved the affinity of variant MIAB126 to human and cyno MAdCAM without affecting the affinity of mouse MAdCAM.


Example 48. PRNT2 Variants have Favorable Thermal Stability

Intrinsic fluoresce of the samples was measured as function of increasing temperature to measure thermal transition on the “UNcle”. The data illustrated below shows that PRNT2 variants have favorable thermal stability. MIAB126 has improved thermal stability.

























Average

SD
Average

SD
Average


Average
% CV
SD Tagg



Tm1
% CV
Tm1
Tm2
% CV
Tm2
Tm3
% CV
SD Tm3
Tagg 266
Tagg
266


Sample
(° C.)
Tm1
(° C.)
(° C.)
Tm2
(° C.)
(° C.)
Tm3
(° C.)
(° C.)
266
(° C.)



























PRNT2
64.6
1.04
0.67
74.1
0.61
0.45
82.5
0.8
0.66
64.22
N/A



MIAB121
70.9
0.3
0.21
80.1
0.39
0.31
85.3
0.52
0.44
69.5
0.91
0.63


MIAB122
69.7
0.86
0.6
78.8
0.39
0.31
85
0.53
0.45
72.6
0.5
0.36


MIAB123
70
1
0.7
80.2
0.74
0.59
86
0.38
0.33
65.6
2.41
1.58


MIAB126
74.37
0.61
0.45
82.1
0.43
0.35
86.3
0.46
0.4
63.3
5.72
3.62


MIAB205
71.5
0.7
0.5
80.7
0.69
0.56
85.9
0.52
0.45
78
0.59
0.46


MIAB206
72.6
0.77
0.56
80.4
0.57
0.46
86.9
0.44
0.38
74.1
0.63
0.47


MIAB207
70.6
0.99
0.7
78.6
0.27
0.21
85.9
0.91
0.78
71.4
0.91
0.65


MIAB208
70.8
0.64
0.45
79
0.8
0.63
86.3
0.6
0.52
72.7
0.91
0.66









Example 49. MIAB126 has Low Polyreactivity

Binding to baculoviral particles is another assay to measure polyreactivity. The experiment was conducted according to the standard protocol. BVP binding was calculated as OD fold change over background, and the data shows BVP binding of (OD fold over background) 4.01 at 500 nM, 2.18 at 250 nM, and AggScore of 74.8 for PRNT2; 3.34 at 500 nM, 1.85 at 250 nM, and AggScore of 92.4 for MIAB1; 3.77 at 500 nM, 2.05 at 250 nM, and AggScore of 98.4 for MIAB2; 3.78 at 500 nM, 1.67 at 250 nM, and AggScore of 114.3 for MIAB12; 3.86 at 500 nM, 1.92 at 250 nM, and AggScore of 181.5 for MIAB13; 4.22 at 500 nM, 1.85 at 250 nM, and AggScore of 129.5 for MIAB25; 4.35 at 500 nM, 1.88 at 250 nM, and AggScore of 108.4 for MIAB26; 4.25 at 500 nM, 2.17 at 250 nM, and AggScore of 85.9 for MIAB37; 4.85 at 500 nM, 2.34 at 250 nM, and AggScore of 137.6 for MIAB121; 4.32 at 500 nM, 1.94 at 250 nM, and AggScore of 105.5 for MIAB122; 4.70 at 500 nM, 2.27 at 250 nM, and AggScore of 80.8 for MIAB123; 5.08 at 500 nM, 1.72 at 250 nM, and AggScore of 108.1 for MIAB126; 5.05 at 500 nM, 2.09 at 250 nM, and AggScore of 107.2 for MIAB209; 4.08 at 500 nM, 2.28 at 250 nM, and AggScore of 100.4 for MIAB205; 5.04 at 500 nM, 2.46 at 250 nM, and AggScore of 106.6 for MIAB206; 5.32 at 500 nM, 2.34 at 250 nM, and AggScore of 114.5 for MIAB207; 5.70 at 500 nM, 2.47 at 250 nM, and AggScore of 111.9 for MIAB208; 9.55 at 500 nM, 5.05 at 250 nM, and AggScore of 204.3 for the positive control; and 1.53 at 500 nM, 2.14 at 250 nM, and AggScore of 50.1 for Nivolumab. MIAB126 does not bind BVP and has low polyreactivity.


Example 50. MIAB126 HPLC Analytical SEC Indicated >90% POI

Analytical size exclusion chromatography conducted according to standard protocol showed single major peak at 280 nm illustrating an IgG with MW=150,000 Da.


Example 51. MIAB126 has Expected Chain Compositions

To characterize the identity and composition of the samples, the samples were prepared and analyzed as described above. CE-SDS revealed PRNT2 (non-reduced) to comprise 96.4% intact antibody; PRNT2 (reduced) to comprise 26.6% light chain and 70.6% heavy chain; MIAB126 (non-reduced) to comprise 100% intact antibody; and MIAB126 (reduced with 1 M DTT) 29.2% light chain and 70.8% heavy chain. MIAB126 has expected chain compositions.


Example 52. MAdCAM-IL-2 M Molecules Bind to Human or Murine MAdCAM

Parental CHO cells or CHO cells over-expressing human MAdCAM or murine MAdCAM were suspended in PBS+2% FBS media on a 96 well plate (Corning). Parental MAdCAM-IL-2 M bi-specifics PRNT2, or optimized variants MIAB1, MIAB12, MIAB13, MIAB25, MIAB26 or MIAB37 were captured for 30 mins on ice. After washing 2 times with PBS+2% FBS media, cells were stained for 30 minutes with an Anti-Human IgG detection antibody and TOPRO dye and acquired on an Attune NXT with plate loader. PRNT2 and MIAB197 bound to human MAdCAM with similar efficiency, and MIAB197 showed lower binding to murine MAdCAM than PRNT2. MAdCAM-IL-2 M bi-specifics bind to human or murine MAdCAM expressing cells and show minimum binding to parental CHO cells.


Example 53. MAdCAM-IL-2 M Bi-Specifics Bind to Human or Murine MAdCAM Expressing Cells and Show Minimum Binding to Parental CHO Cells

Parental CHO cells or CHO cells over-expressing human MAdCAM or murine MAdCAM were suspended in PBS+2% FBS media on a 96 well plate (Corning). Parental IL-2 MM bi-specifics PRNT1 or PRNT2, or optimized variants MIAB197, MIAB1, MIAB12, MIAB13, MIAB25, MIAB26 or MIAB37 were captured for 30 mins on ice. After washing 2 times with PBS+2% FBS media, cells were stained for 30 minutes with an Anti-Human IgG detection antibody and TOPRO dye and acquired on an Attune NXT with plate loader. The data showed binding of PRNT2, MIAB1, MIAB12, MIAB13, MIAB25, MIAB26, and MIAB37 to human and murine MAdCAM. MIAB26 showed decreased binding to murine MAdCAM. MAdCAM-IL-2 M molecules bind to human and murine MAdCAM.


The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While various embodiments have been disclosed with reference to specific aspects, it is apparent that other aspects and variations of these embodiments may be devised by others skilled in the art without departing from the true spirit and scope of the embodiments. The appended claims are intended to be construed to include all such aspects and equivalent variations.

Claims
  • 1. (canceled)
  • 2. An antibody or antigen binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1499, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1506, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1507, and wherein the light chain variable region comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1502, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1497, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1498.
  • 3-5. (canceled)
  • 6. The antibody or antigen binding fragment of claim 2, wherein the heavy chain variable region comprises an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 1445, 1477, or 1480 and the light chain variable region comprises an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 1367.
  • 7. The antibody or antigen binding fragment of claim 2, wherein the heavy chain variable region comprises an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 1445 and the light chain variable region comprises an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 1367.
  • 8. The antibody or antigen binding fragment of claim 7, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1445, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 1367.
  • 9-10. (canceled)
  • 11. The antibody or antigen binding fragment of claim 7, wherein the heavy chain variable region and the light chain variable region are in a scFv format.
  • 12. The antibody or antigen binding fragment of claim 7, wherein the heavy chain variable region and the light variable chain region are linked with a peptide linker.
  • 13. The antibody or antigen binding fragment of claim 12, wherein the peptide linker is a glycine/serine linker.
  • 14. The antibody or antigen binding fragment of claim 12, wherein the peptide linker comprises a sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22), GGGGSGGGGSGGGGS (SEQ ID NO: 30), GGGGSGGGGS (SEQ ID NO: 619), GGGGS (SEQ ID NO: 23), or GGGSEGGGSEGGGSE (SEQ ID NO: 1546), or any combination thereof.
  • 15. (canceled)
  • 16. The antibody or antigen binding fragment of claim 7, wherein the antibody, or antigen binding fragment, binds to MAdCAM.
  • 17. The antibody or antigen binding fragment of claim 7, wherein the antibody, or antigen binding fragment, is linked or associated with an effector molecule.
  • 18. The antibody or antigen binding fragment of claim 17, wherein the effector molecule is a PD-1 agonist antibody, or antigen binding fragment thereof.
  • 19-22. (canceled)
  • 23. A pharmaceutical composition comprising the antibody, or antigen binding fragment of claim 7, and a pharmaceutically acceptable carrier.
  • 24. A method of treating a subject with inflammatory bowel disease, the method comprising administering the antibody or antigen binding fragment of claim 7, or a pharmaceutical composition comprising the same, to the subject to treat the inflammatory bowel disease.
  • 25. The method of claim 24, wherein the subject with inflammatory bowel disease has Crohn's disease, or ulcerative colitis.
  • 26. A method of treating a subject with an auto-immune hepatitis, a primary sclerosing cholangitis, a Type 1 diabetes, a transplant, or a GVHD, the method comprising administering the antibody or antigen binding fragment of claim 7, or a pharmaceutical composition comprising the same, to the subject to treat the auto-immune hepatitis, the primary sclerosing cholangitis, the Type 1 diabetes, the transplant, or the GVHD.
  • 27-30. (canceled)
  • 31. A method of preventing an autoimmune disorder in a subject at risk for having the autoimmune disorder, the method comprising administering the antibody or antigen binding fragment of claim 7, or a pharmaceutical composition comprising the same, to the subject to prevent the autoimmune disorder.
CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 63/115,235, filed Nov. 18, 2020, U.S. Application No. 63/115,243, filed Nov. 18, 2020, U.S. Application No. 63/117,914, filed Nov. 24, 2020, U.S. Application No. 63/117,918, filed Nov. 24, 2020, each of which is hereby incorporated by reference in its entirety.

PCT Information
Filing Document Filing Date Country Kind
PCT/US2021/059846 11/18/2021 WO
Provisional Applications (4)
Number Date Country
63117918 Nov 2020 US
63117914 Nov 2020 US
63115243 Nov 2020 US
63115235 Nov 2020 US