BINDING PROTEINS AGAINST VEGF, PDGF, AND/OR THEIR RECEPTORS

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 Aug. 5, 2016, is named 12252_0202-00000_SL.txt and is 4,068,254 bytes in size.

FIELD

The invention relates to antibodies and antigen-binding fragments thereof, as well as multivalent and multispecific binding proteins, that bind vascular endothelial growth factor (VEGF) and/or platelet-derived growth factor (PDGF), as well as their receptors, and methods of making, and using the constructs in the diagnosis, prevention, and/or treatment of acute and chronic inflammatory diseases, cancer, and other disorders.

BACKGROUND

Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a role in the pathogenesis of many diseases, including ocular diseases such as age-related macular degeneration (AMD) or diabetic macular edema (DME). Vascular endothelial growth factor (VEGF) plays a role in the regulation of normal and abnormal angiogenesis (Ferrara et al, (1997) Endoer. Rev. 18:4-25). Several anti-VEGF agents are provided in the art, e.g., in U.S. Pat. No. 7,169,901, which discloses VEGF antibodies for inhibiting VEGF-induced cell proliferation, and U.S. Pat. No. 7,070,959, which discloses isolated nucleic acid molecules encoding fusion proteins capable of binding VEGF.

Targeting VEGF with currently available therapeutics is not effective in all patients or for all diseases associated with inflammation and/or angiogenesis. A significant population of non-responders present following anti-VEGF monotherapy, and the disease prevalence will only increase as the aging population increases globally.

A currently preferred treatment for wet AMD consists of intravitreal injections of an anti-VEGF agent. However, although anti-VEGF therapy reduces choroidal neovascularization, it does not have an effect on regression of the mature vasculature. Also, current agents do not provide an anti-fibrotic effect, so that once scarring of the retina occurs; visual acuity cannot be recovered. Other limitations of the existing treatments regimens include patient discomfort, the need for repeat injections with inherent complications including endophthalmitis, retinal tear and detachment, intraocular hemorrhage, and cataract formation. There is a substantial time burden on ophthalmologists to provide monthly intravitreal treatment and optical coherence tomography (OCT) measurements on a large volume patients. As a result, there is a significant medical and economic need for an AMD therapeutic with greater efficacy, or that can be delivered less frequently and still achieve optimal efficacy.

Platelet-derived growth factor (PDGF) is a growth factor involved in the regulation of blood vessels from pre-existing vessel tissue. PDGF binds to receptors on pericytes in newly-forming abnormal blood vessels. This may contribute to neovascularization of abnormal blood vessels by providing a protective perictye coating, for example, during ocular disorders such as wet AMD.

Engineered proteins, such as antibodies, fragments, and multispecific binding proteins capable of binding two or more antigens, are known in the art. Such multispecific binding proteins can be generated using cell fusion, chemical conjugation, or recombinant DNA techniques. There are a variety of multispecific binding protein structures known in the art and many structures and methods have distinct disadvantages.

Bispecific antibodies have been produced using quadroma technology. Bispecific antibodies can also be produced by chemical conjugation of two different mAbs. Other approaches include coupling of two parental antibodies with a hetero-bifunctional crosslinker, production of tandem single-chain Fv molecules, diabodies, bispecific diabodies, single-chain diabodies, and di-diabodies. In addition, a multivalent antibody construct comprising two Fab repeats in the heavy chain of an IgG and capable of binding four antigen molecules has been described (see PCT Publication No. WO 01/77342 and Miller et al. (2003) J. Immunol. 170(9):4854-61).

U.S. Pat. No. 7,612,181 (incorporated herein by reference in its entirety) provides a novel family of binding proteins capable of binding two or more antigens with high affinity, which are called dual variable domain binding proteins (DVD-Ig binding protein) or dual variable domain immunoglobulins (DVD-Ig). DVD-Ig molecules are binding proteins that may be used to bind two distinct epitopes on the same molecule or two different molecules simultaneously. DVD-Ig molecules are unique binding proteins comprised of two variable domains fused to N-terminal constant regions. The variable domains may be directly fused to one another or connected via synthetic peptide linkers of assorted length and amino acid composition. DVD-Ig binding proteins may be engineered with intact and functional Fc domains, or otherwise modified constant domains, allowing them to mediate appropriate effector functions and exhibit other desired properties. The DVD-Ig format, due to its flexibility of choice of variable domain pair, orientation of two antigen-binding domains, and the length of the linker that joins them, may provide novel therapeutic modalities.

Accordingly, while VEGF monotherapy has had some success in the art, there remains a need for constructs exhibiting better targeting, efficiency, and/or efficacy in binding to VEGF, as well as improved targeting of other pathways involved in inflammation (such as ocular inflammation), e.g., the PDGF pathway. Improved targeting of either of these molecules, alone or in combination, may lead to improvements in, e.g., preventing, diagnosing, and/or treating disorders such as angiogenic, inflammatory, and/or ocular disorders. Also, while a variety of structures have been provided in the art, with various advantages and disadvantages, new variable domain sequences can further improve the properties of binding proteins targeting VEGF and/or PDGF, or their cognate receptors.

SUMMARY

Disclosed herein are binding proteins capable of binding VEGF and/or PDGF, and/or their cognate receptors. In some embodiments, the binding proteins are antibodies to VEGF and/or PDGF, or antigen-binding fragments thereof. In some embodiments, the binding proteins are bispecific and capable of binding VEGF and PDGF. In some embodiments, the binding proteins comprise one or more sequences from any one of Tables A, 27-30, 38-42, 46-50, or 56-58, or the CDR amino acid residues from those sequences.

In various embodiments, the binding proteins are bispecific or multispecific binding proteins capable of binding one or more of VEGF and/or PDGF, and/or their cognate receptors. In some embodiments, the binding proteins are dual variable domain immunoglobulins (DVD-Igs or DVD-Ig binding proteins) using the binding protein framework disclosed in U.S. Pat. No. 7,612,181 (incorporated herein by reference in its entirety).

In some embodiments, the DVD-Ig binding proteins contain particular first and second polypeptide chains, each comprising first and second variable domains comprising sequences (e.g., sequences selected from those listed in Tables A, 27-30, 38-42, 46-50, or 56-58, or the CDR amino acid residues from those sequences) that form functional binding sites for binding targets such as VEGF and/or PDGF, or their cognate receptors. In some embodiments, the first and second polypeptide chains of the binding protein each independently comprise VD1-(X1)n-VD2-C-X2, wherein VD1 is a first variable domain; VD2 is a second variable domain; C is a constant domain; X1 is a linker; X2 is an Fc region that is either present or absent; n is 0 or 1, and wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site for VEGF, PDGF, or a cognate receptor, and the VD2 domains on the first and second polypeptide chains form a second functional target binding site for VEGF, PDGF, or a cognate receptor. In some embodiments, (a) the first polypeptide chain of the binding protein comprises VD1-(X1)n-VD2-C-X2, wherein VD1 is a first heavy chain variable domain; VD2 is a second heavy chain variable domain; C is a heavy chain constant domain; X1 is a linker; X2 is an Fc region; and n is 0 or 1 (i.e., X1 and X2 are either present or absent, depending on whether n is independently chosen to be 0 or 1 for each position); and (b) the second polypeptide chain of the binding protein comprises VD1-(X1)n-VD2-C-X2, wherein VD1 is a first light chain variable domain; VD2 is a second light chain variable domain; C is a light chain constant domain; X1 is a linker; X2 is an Fc region; and n is 0 or 1 for X1 and n is 0 for X2 (i.e., the Fc region is absent on the second polypeptide chain); and (c) wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site for VEGF, PDGF, or a cognate receptor, and the VD2 domains on the first and second polypeptide chains form a second functional target binding site for VEGF, PDGF, or a cognate receptor. In some embodiments, the VD1 position forms a binding site for VEGF and the VD2 position forms a binding site for PDGF. In some embodiments, the CDR and/or variable domains at the VD1 and VD2 positions are antibody variable domains and the constant domains are antibody constant domains. Any of the CDR and/or variable domain and/or first and second polypeptide chain sequences disclosed herein may be incorporated in these DVD-Ig binding protein structures to form binding domains for VEGF and/or PDGF, and/or their cognate receptors.

In some embodiments, both the first and second binding sites of a DVD-Ig construct disclosed herein target VEGF. In some embodiments, both the first and second binding sites target PDGF. In some embodiments, the first binding site targets VEGF and the second binding site targets PDGF. In some embodiments, the first binding site targets PDGF and the second binding site targets VEGF. In some embodiments, an Fc domain is present on one polypeptide chain and absent on the other, or absent on both polypeptide chains. In some embodiments, the sequences of the first and second variable domains on each polypeptide chain (i.e., the VD1 and VD2 positions) are independently selected from the sequences in Table A, 27-30, 38-42, 46-50, or 56-58 to form functional binding sites. In some embodiments, the sequences of the first and second variable domains each contain the three complementarity determining regions (i.e., CDRs 1-3) from the selected sequences listed in Tables A, 27-30, 38-42, 46-50, or 56-58, and are arranged in the same order as shown in the Tables, thereby forming functional binding sites (i.e., the binding domains are capable of binding to their target antigen, VEGF or PDGF). In some embodiments, the paired variable domain sequences on the first and second polypeptide chains (i.e., the VD1 sequence on the first chain paired with the VD1 sequence on the second chain and the VD2 sequence on the first chain paired with the VD2 sequence on the second chain) form functional binding sites for binding targets VEGF and/or PDGF using the sequences in the Tables. In some embodiments, the binding proteins are capable of binding to VEGF and/or PDGF with improved binding affinity and/or neutralization potency, improved in vivo efficacy, improved expression, and/or improved drug-like properties (e.g., thermal stability, storage stability, solubility, etc.).

Also disclosed herein are methods of making and using the claimed binding proteins, e.g., in the detection, inhibition, reduction, prevention, and/or treatment of cancers, tumors, fibrosis, renal disease, inflammation, age-related macular degeneration (AMD), wet AMD, diabetic retinopathy, other angiogenesis-dependent diseases, or angiogenesis-independent diseases characterized by aberrant VEGF and/or PDGF expression or activity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A and FIG. 1B are schematic representations of a Dual Variable Domain (DVD) binding protein construct.

FIG. 2A and FIG. 2B show the reactivity of anti-PDGF-BB antibodies and anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules to ECM-associated PDGF-BB.

FIG. 3 illustrates the inhibition of sprouting from a HUVEC/MSC co-culture sprouting assay by anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules.

FIG. 4 is a bar graph showing the area of subretinal neovascularization in Rho/huVEGF transgenic mice.

FIG. 5 is a bar graph showing the area of choroidal neovascularization in Rho/huVEGF transgenic mice.

FIG. 6 is a bar graph comparing choroidal neovascularization in the untreated eye among the different treatment groups.

FIG. 7 is a bar graph showing number of partial, total, and undetached eyes in Tet/opsin/VEGF mice.

DETAILED DESCRIPTION

Vascular endothelial growth factor (VEGF) is a signal protein that regulates physiological angiogenesis during embryogenesis, skeletal growth, and reproductive functions. Aberrant expression of VEGF is implicated in pathological angiogenesis and is associated with tumors, intraocular neovascular disorders, and other diseases. The VEGF family members include VEGF-A, placenta growth factor (PGF), VEGF-B, VEGF-C, and VEGF-D. Multiple isoforms of VEGF-A exist that result from alternative splicing of a single, 8-exon VEGFA gene. The biological effects of VEGF are mediated by various receptors, including two receptor tyrosine kinases, VEGF receptor-1 (VEGFR1) and VEGF receptor-2 (VEGFR2), which differ in their signaling properties. When cells are deficient in oxygen, they produce hypoxia-inducible factor (HIF) which releases VEGF and other mediators triggering a tyrosine kinase pathway leading to angiogenesis (Ferrara et al. (2003) Nat. Med. 9:669-676). In various embodiments, the binding proteins disclosed herein can bind one or more of the VEGF family members, including alternate isoforms, and/or can bind one or more of the cognate VEGF receptors.

Platelet-derived growth factor (PDGF) is a protein that stimulates growth, survival, and motility of mesenchymal cells and certain other cell types. It has significant functions during embryonal development and in the control of blood vessel formation as an adult. PDGF is composed of a dimeric glycoprotein made up of two A (-AA), two B (-BB) chains, or a combination of the two (-AB). There are five different isoforms of PDGF that moderate cellular responses through two receptors, alpha (PDGFRA) and beta (PDGFRB) (Heldin (2013) Cell Commun Sig. 11:97). PDGF plays an important role in driving the proliferation of undifferentiated mesenchyme and some progenitor populations. Overactivity or inappropriate PDGF signaling is associated with the development of certain malignant diseases, as well as non-malignant diseases characterized by excessive cell proliferation and other inflammatory disorders. In various embodiments, the binding proteins disclosed herein can bind one or more of the PDGF isoforms, and/or can bind one or more of the cognate PDGF receptors.

Binding Proteins

Disclosed herein are binding proteins capable of binding one or more of VEGF, PDGF, and their cognate receptors. In some embodiments, the binding protein is an antibody or an antigen-binding fragment thereof. In an embodiment, the binding protein is an antibody, a monoclonal antibody, a murine antibody, a human antibody, a humanized antibody, a bispecific antibody, a chimeric antibody, a Fab, a Fab′, a F(ab′)₂, an ScFv, an SMIP, an affibody, an avimer, a versabody, a nanobody, a fynomab, a domain antibody, or an antigen binding fragment of any of the foregoing. In an embodiment, the binding protein comprises antibody heavy chain variable domain sequences and antibody light chain variable domain sequences that are capable of binding one or more of VEGF, PDGF, and their cognate receptors. In an embodiment, the binding protein comprises the paired heavy and light chain variable domain sequences of any of the binding sites disclosed in Tables 27-30, 38-42, 46-50, or the CDR sequences from those variable domains. The CDR sequences of the variable domains in the Tables are identified in bold.

In some embodiments, the binding proteins disclosed herein is bispecific or multispecific. The bispecific or multispecific construct may be monovalent or bivalent. Various bispecific or multispecific constructs are known in the art (see e.g., Spiess et al. (2015) Mol. Immunol. 67; 95-106). Bispecific or multispecific constructs include, but are not limited to, an asymmetric bispecific antibody, an asymmetric bispecific IgG4, a CrossMab binding protein, a bispecific antibody, a bispecific binding protein, a multispecific binding protein, a DAF (dual action Fab antibody; two-in-one), a DAF (dual action Fab antibody; four-in-one), a DutaMab, a DT-IgG, a knobs-in-holes binding protein, a Charge pair binding protein, a Fab-arm exchange binding protein, a SEEDbody, a Triomab (Triomab quadroma bispecific or removab bispecific), a LUZ-Y, a Fcab, a κλ-body, an iMab (innovative multimer), and an Orthogonal Fab. In some embodiments, the bispecific or multispecific construct is a DVD-Ig binding protein, an IgG(H)-scFv, an scFv-(H)IgG, an IgG(L)-scFv, an scFv-(L)IgG, an IgG(L, H)-Fv, an IgG(H)-V, a V(H)-IgG, an IgG(L)-V, a V(L)-IgG, a KIH IgG-scFab, a 2scFv-IgG, an IgG-2scFv, an scFv4-Ig, a Zybody, or a DVI-IgG (four-in-one). In some embodiments, the bispecific or multispecific construct also can be a nanobody (or VHH), a bispecific tandem nanobody, a bispecific trivalent tandem nanobody, a nanobody-HSA, a BiTE (bispecific T-cell engager) binding protein, a Diabody, a DART (dual affinity retargeting) binding protein, a TandAb (tetravalent bispecifc tandem antibody), an scDiabody, an scDiabody-CH3, a Diabody-CH3, a Triple Body, a Miniantibody, a Minibody, a TriBi minibody, an scFv-CH3 KIH, a Fab-scFv, an scFv-CH-CL-scFv, a F(ab′)2, a F(ab′)2 scFv2, an scFv-KIH, a Fab-scFv-Fc, a Tetravalent HCAb, an scDiabody-Fc, a Diabody-Fc, a Tandem scFv-Fc, a Fabsc, a bsFc-1/2, a CODV-Ig (cross-over dual variable immunoglobulin), a biclonics antibody or an Intrabody. Bispecific or multispecific constructs also include, for example, a Dock and Lock binding protein, an ImmTAC, an HSAbody, an scDiabody-HSA, a Tandem scFv-Toxin, an IgG-IgG binding protein, a Cov-X-Body, and an scFv1-PEG-scFv2. In some embodiments, the bispecific or multispecific construct is a DVD-Ig binding protein, a CrossMab binding protein, a diabody, a tandem single-chain Fv molecule, a bispecific diabody, a single-chain diabody molecule, or a di-diabody. In some embodiments, the binding protein is a DVD-Ig binding protein. See, e.g., U.S. Pat. No. 7,612,181 (incorporated herein by reference in its entirety). The bispecific or multispecific construct may comprise one or more binding sites for VEGF, PDGF, and/or their receptors. The bispecific or multispecific construct may comprise binding sites only for VEGF, PDGF, and/or their receptors, or may comprise additional binding sites for other antigen targets. The bispecific or multispecific construct may comprise binding sites for more than one epitope on VEGF, PDGF, and/or their receptors, e.g., using different CDR sets or variable domains from those disclosed herein to form binding sites targeting different epitopes.

In various embodiments, the binding protein is capable of binding VEGF, and comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs 1-3 from SEQ ID NO: 18, CDRs 1-3 from SEQ ID NO: 19 and CDRs 1-3 from SEQ ID NO: 20, CDRs 1-3 from SEQ ID NO: 21 and CDRs 1-3 from SEQ ID NO: 22, CDRs 1-3 from SEQ ID NO: 23 and CDRs 1-3 from SEQ ID NO: 24, CDRs 1-3 from SEQ ID NO: 25 and CDRs 1-3 from SEQ ID NO: 26, CDRs 1-3 from SEQ ID NO: 27 and CDRs 1-3 from SEQ ID NO: 28, CDRs 1-3 from SEQ ID NO: 29 and CDRs 1-3 from SEQ ID NO: 30, CDRs 1-3 from SEQ ID NO: 31 and CDRs 1-3 from SEQ ID NO: 32, CDRs 1-3 from SEQ ID NO: 33 and CDRs 1-3 from SEQ ID NO: 34, CDRs 1-3 from SEQ ID NO: 35 and CDRs 1-3 from SEQ ID NO: 36, CDRs 1-3 from SEQ ID NO: 37 and CDRs 1-3 from SEQ ID NO: 38, CDRs 1-3 from SEQ ID NO: 39 and CDRs 1-3 from SEQ ID NO: 40, CDRs 1-3 from SEQ ID NO: 41 and CDRs 1-3 from SEQ ID NO: 42, or CDRs 1-3 from SEQ ID NO: 43 and CDRs 1-3 from SEQ ID NO: 44. In an embodiment, the binding protein is capable of binding VEGF, and comprises SEQ ID NO: 17 and SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, or SEQ ID NO: 43 and SEQ ID NO: 44. Any of said binding proteins capable of binding VEGF may also be capable of binding PDGF, and may comprise any of the PDGF binding sequences as described herein.

In various embodiments, the binding protein is capable of binding PDGF, and comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs 1-3 from SEQ ID NO: 2, CDRs 1-3 from SEQ ID NO: 3 and CDRs 1-3 from SEQ ID NO: 4, CDRs 1-3 from SEQ ID NO: 5 and CDRs 1-3 from SEQ ID NO: 6, CDRs 1-3 from SEQ ID NO: 7 and CDRs 1-3 from SEQ ID NO: 8, CDRs 1-3 from SEQ ID NO: 9 and CDRs 1-3 from SEQ ID NO: 10, CDRs 1-3 from SEQ ID NO: 11 and CDRs 1-3 from SEQ ID NO: 12, CDRs 1-3 from SEQ ID NO: 13 and CDRs 1-3 from SEQ ID NO: 14, CDRs 1-3 from SEQ ID NO: 15 and CDRs 1-3 from SEQ ID NO: 16, or CDRs 1-3 from SEQ ID NO: 211 and CDRs 1-3 from SEQ ID NO: 212. In an embodiment, the binding protein is capable of binding PDGF, and comprises SEQ ID NO: 1 and SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, or SEQ ID NO: 211 and SEQ ID NO: 212. Any of said binding proteins capable of binding PDGF may also be capable of binding VEGF, and may comprise any of the VEGF binding sequences as described herein.

In an embodiment, the binding protein is a bispecific or multispecific antibody capable of binding one or more of VEGF, PDGF, and their cognate receptors, or another multispecific construct capable of binding the targets. In certain embodiments, the treatment is with bispecific antibodies that have been produced by quadroma technology (Milstein and Cuello (1983) Nature 305(5934): 537-40), by chemical conjugation of two different monoclonal antibodies (Staerz et al. (1985) Nature 314(6012): 628-31), or by knob-into-hole or similar approaches which introduces mutations in the Fc region (Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90(14): 6444-6448). In some embodiments, the multispecific binding protein is a dual variable domain immunoglobulin (DVD-Ig), e.g., as disclosed in U.S. Pat. No. 7,612,181 (incorporated herein by reference in their entirety). In an embodiment, the DVD-Ig binding protein comprises one or more binding sites comprising the paired heavy and light chain variable domain sequences of any of the binding sites disclosed in Tables 27-30, 38-42, 46-50, or 56-58, or the CDR sequences from those variable domains. For instance, a binding site for VEGF can comprise a paired set of heavy and light chain variable domain sequences from any one of Tables 27 or 38-42, or the CDR regions from those sequences, while the PDGF can comprise the paired heavy and light chain variable domain sequences in Tables 28 or 46-50, or the CDR regions from those sequences. The CDR regions of some of these sequences are shown in Table A and in Table 57.

In some embodiments, a multispecific binding protein disclosed herein is capable of binding VEGF and PDGF, and allows for fewer injections or a lower concentration of active agent, as compared to combination antibody therapy.

In some embodiments, the DVD-Ig binding protein comprises first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-X2, wherein: VD1 is a first variable domain; VD2 is a second variable domain; C is a constant domain; X1 is a linker; X2 is an Fc region that is either present or absent; n is independently 0 or 1 on the first and second chains, and wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site and the VD2 domains on the first and second polypeptide chains form a second functional target binding site. In some embodiments, the binding protein is capable of binding one or more of VEGF, PDGF, and their cognate receptors, e.g., using a paired set of sequences from any one of Tables 27-30, 38-42, 46-50, or 56-58. In some embodiments, the binding protein comprises VD1 sequences on the first and second polypeptide chains (i.e., a VD1 sequence on the first chain paired with a VD1 sequence on the second chain) that together form a binding domain capable of binding a target selected from VEGF, PDGF, and their cognate receptors. In some embodiments, the binding protein is capable of binding VEGF at both the VD1 and VD2 positions. In some embodiments, the binding protein is capable of binding PDGF at both the VD1 and VD2 positions. In some embodiments, the binding protein is capable of binding VEGF at the VD1 position and PDGF at the VD2 position. In some embodiments, the binding protein is capable of binding PDGF at the VD1 position and VEGF at the VD2 position.

When a binding protein comprises the CDRs from a sequence selected from any one of Tables 27-30, 38-42, 46-50, or 56-58, the CDRs are arranged in the order specified by the sequence in the Table and separated by suitable framework sequences to form a functional binding site. The paired sequences selected from the Tables that form a functional binding site for a target (e.g., a binding site for VEGF and/or PDGF), or the CDRs from those sequences, may be placed in either the VD1 or VD2 positions on the first and second polypeptide chains to form a binding site at either the VD1 or VD2 domain.

The binding proteins disclosed herein comprise VD1 and VD2 binding domains that are capable of binding to first and second target antigens. As used herein, a VD1 domain or a VD2 domain, or a VD1 position or VD2 position, may refer to either the variable domain sequence on one polypeptide chain (e.g., a VD1 heavy chain sequence) or to the variable domain sequences on both the first and second polypeptide chain (e.g., a VD1 heavy chain sequence and a VD1 light chain sequence) that together form the functional binding site, as indicated by the context in which it is discussed.

In some embodiments, a DVD-Ig binding protein can comprise two first and two second polypeptide chains forming four functional binding sites on two arms of the construct. An example of a four chain structure having two arms, each arm comprising a first and second polypeptide chain and two functional binding sites, is shown in FIG. 1.

In an embodiment, a DVD-Ig binding protein is disclosed that is capable of binding VEGF and PDGF, wherein the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs 1-3 from SEQ ID NO: 2, CDRs 1-3 from SEQ ID NO: 3 and CDRs 1-3 from SEQ ID NO: 4, CDRs 1-3 from SEQ ID NO: 5 and CDRs 1-3 from SEQ ID NO: 6, CDRs 1-3 from SEQ ID NO: 7 and CDRs 1-3 from SEQ ID NO: 8, CDRs 1-3 from SEQ ID NO: 9 and CDRs 1-3 from SEQ ID NO: 10, CDRs 1-3 from SEQ ID NO: 11 and CDRs 1-3 from SEQ ID NO: 12, CDRs 1-3 from SEQ ID NO: 13 and CDRs 1-3 from SEQ ID NO: 14, CDRs 1-3 from SEQ ID NO: 15 and CDRs 1-3 from SEQ ID NO: 16, or CDRs 1-3 from SEQ ID NO: 211 and CDRs 1-3 from SEQ ID NO: 212. In an embodiment, the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, or SEQ ID NO: 211 and SEQ ID NO: 212.

In an embodiment, the DVD-Ig binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs 1-3 from SEQ ID NO: 18, CDRs 1-3 from SEQ ID NO: 19 and CDRs 1-3 from SEQ ID NO: 20, CDRs 1-3 from SEQ ID NO: 21 and CDRs 1-3 from SEQ ID NO: 22, CDRs 1-3 from SEQ ID NO: 23 and CDRs 1-3 from SEQ ID NO: 24, CDRs 1-3 from SEQ ID NO: 25 and CDRs 1-3 from SEQ ID NO: 26, CDRs 1-3 from SEQ ID NO: 27 and CDRs 1-3 from SEQ ID NO: 28, CDRs 1-3 from SEQ ID NO: 29 and CDRs 1-3 from SEQ ID NO: 30, CDRs 1-3 from SEQ ID NO: 31 and CDRs 1-3 from SEQ ID NO: 32, CDRs 1-3 from SEQ ID NO: 33 and CDRs 1-3 from SEQ ID NO: 34, CDRs 1-3 from SEQ ID NO: 35 and CDRs 1-3 from SEQ ID NO: 36, CDRs 1-3 from SEQ ID NO: 37 and CDRs 1-3 from SEQ ID NO: 38, CDRs 1-3 from SEQ ID NO: 39 and CDRs 1-3 from SEQ ID NO: 40, CDRs 1-3 from SEQ ID NO: 41 and CDRs 1-3 from SEQ ID NO: 42, or CDRs 1-3 from SEQ ID NO: 43 and CDRs 1-3 from SEQ ID NO: 44; and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs 1-3 from SEQ ID NO: 2, CDRs 1-3 from SEQ ID NO: 3 and CDRs 1-3 from SEQ ID NO: 4, CDRs 1-3 from SEQ ID NO: 5 and CDRs 1-3 from SEQ ID NO: 6, CDRs 1-3 from SEQ ID NO: 7 and CDRs 1-3 from SEQ ID NO: 8, CDRs 1-3 from SEQ ID NO: 9 and CDRs 1-3 from SEQ ID NO: 10, CDRs 1-3 from SEQ ID NO: 11 and CDRs 1-3 from SEQ ID NO: 12, CDRs 1-3 from SEQ ID NO: 13 and CDRs 1-3 from SEQ ID NO: 14, CDRs 1-3 from SEQ ID NO: 15 and CDRs 1-3 from SEQ ID NO: 16, or CDRs 1-3 from SEQ ID NO: 211 and CDRs 1-3 from SEQ ID NO: 212. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, or SEQ ID NO: 43 and SEQ ID NO: 44; and the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, or SEQ ID NO: 211 and SEQ ID NO: 212.

In various embodiments, the DVD-Ig binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 35 and CDRs-1-3 from SEQ ID NO: 36, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 35 and SEQ ID NO: 36, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. In any of these embodiments, the binding site for VEGF may be the outer binding domain or VD1 position as described herein, and the binding site for PDGF may be the inner domain or VD2 position as described herein. In various embodiments, any of the DVD-Ig binding proteins disclosed herein can comprise one or more of the X1 linkers shown in Table 55. In an embodiment, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10(dR) linker. In an embodiment, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10 linker. In an embodiment, the X1 linker on the heavy chain is an HG-short linker and the X1 linker on the light chain is an LK-long linker.

In various embodiments, any of the antibodies, binding proteins, or DVD-Ig binding proteins disclosed herein can comprise a human IgG (e.g., an IgG1) heavy chain constant region on the first polypeptide chain comprising substitutions of leucines at positions 234 and 235 with alanines, and optionally also (or alternatively) a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering. In various embodiments, the antibody, binding protein, or DVD-Ig binding protein can also comprise a human kappa or lambda light chain constant region on the second polypeptide chain. In an embodiment, the light chain comprises a wild-type human kappa light chain constant region sequence.

In an embodiment, the DVD-Ig binding protein is capable of binding VEGF and PDGF, and comprises PR-1610561 (comprising SEQ ID NOs: 131 and 132). In an embodiment, the binding protein comprises a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, and optionally also comprising a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence. In an embodiment, the binding protein comprises an IgG1 constant region with substitution of leucines at positions 234 and 235 with alanines, and a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence. In some embodiments, the L234A, L235A, and H435 mutations are present in a DVD-Ig binding protein comprising PR-1610561 (comprising SEQ ID NOs: 131 and 132). In some embodiments, the binding protein carrying the constant region mutations has increased ocular duration over an antibody, but is rapidly cleared from systemic circulation (e.g., by altering FcRn recognition), as compared to an antibody or as compared to the same binding protein lacking the constant region mutations. In some embodiments, the high ocular duration allows for less frequent administration and/or fewer overall injections while achieving a comparable or improved efficacy as compared to administration of a combination of anti-VEGF and anti-PDGF antibodies or as compared to administration of the binding protein lacking the constant region mutations. In some embodiments, the binding protein carrying the constant region mutations has decreased ADCC and CDC effector functions mediated by binding to extracellular matrix-associated VEGF-A and/or PDGF-BB, as compared to administration of the binding protein lacking the constant region mutations. In some embodiments, the binding protein carrying the constant region mutations does not bind to one or more Fc-gamma receptors. In some embodiments, systemic levels of the binding protein in a patient drops below detectable levels after less than 20, 25, 30, 35, or 40 hours following administration at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg/kg, or more (or any concentration in between) in an intravenous bolus dose.

In an embodiment, the DVD-Ig binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs-1-3 from SEQ ID NO: 18, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs-1-3 from SEQ ID NO: 2. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, and the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2. In an embodiment, the DVD-Ig binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 39 and CDRs-1-3 from SEQ ID NO: 40, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 39 and SEQ ID NO: 40, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. In any of these embodiments, the binding site for VEGF may be the outer binding domain or VD1 sequence as described herein, and the binding site for PDGF may be the inner domain or VD2 sequence as described herein. In various embodiments, the binding proteins can comprise one or more of the X1 linkers shown in Table 55. In an embodiment, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10(dR) linker. In an embodiment, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10 linker. In an embodiment, the X1 linker on the heavy chain is an HG-short linker and the X1 linker on the light chain is an LK-long linker. In an embodiment, the binding protein is capable of binding VEGF and PDGF, and comprises PR-1572102 (comprising SEQ ID NOs: 88 and 89) or PR-1572105 (comprising SEQ ID NOs: 94 and 95) or PR1611292 (comprising SEQ ID NOs: 141 and 142). In an embodiment, the binding protein comprises a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, and optionally also comprising a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence.

In an embodiment, the DVD-Ig binding protein comprises the first and second polypeptide chains of any of the DVD-Ig binding proteins disclosed in Tables 56-58. The CDR sequences of the variable domains in Tables 56-58 are in bold and the linker sequences are italicized.

In an embodiment, the DVD-Ig binding protein comprises the first and second polypeptide chains of PR-1563988 (comprising SEQ ID NOs: 45 and 46), PR-1563990 (comprising SEQ ID NOs: 47 and 48), PR-1563998 (comprising SEQ ID NOs: 49 and 50), PR-1564009 (comprising SEQ ID NOs: 51 and 52), PR-1564010 (comprising SEQ ID NOs: 53 and 54), PR-1564011 (comprising SEQ ID NOs: 55 and 56), PR-1564012 (comprising SEQ ID NOs: 57 and 58), PR-1564013 (comprising SEQ ID NOs: 59 and 60), PR-1565031 (comprising SEQ ID NOs: 76 and 77), PR-1565032 (comprising SEQ ID NOs: 78 and 79), PR-1565035 (comprising SEQ ID NOs: 80 and 81), PR-1572102 (comprising SEQ ID NOs: 88 and 89), PR-1572103 (comprising SEQ ID NOs: 90 and 91), PR-1572104 (comprising SEQ ID NOs: 92 and 93), PR-1572105 (comprising SEQ ID NOs: 94 and 95), PR-1572106 (comprising SEQ ID NOs: 96 and 97), PR-1575832 (comprising SEQ ID NOs: 99 and 100), PR-1575834 (comprising SEQ ID NOs: 101 and 102), PR-1575835 (comprising SEQ ID NOs: 103 and 104), PR-1577165 (comprising SEQ ID NOs: 105 and 106), PR-1577166 (comprising SEQ ID NOs: 107 and 108), PR-1577547 (comprising SEQ ID NOs: 109 and 110), PR-1577548 (comprising SEQ ID NOs: 111 and 112), PR-1577550 (comprising SEQ ID NOs: 113 and 114), PR-1578137 (comprising SEQ ID NOs: 116 and 117), PR-1610560 (comprising SEQ ID NOs: 129 and 130), PR-1610561 (comprising SEQ ID NOs: 131 and 132), PR-1610562 (comprising SEQ ID NOs: 133 and 134), PR-1610563 (comprising SEQ ID NOs: 135 and 136), PR-1611291 (comprising SEQ ID NOs: 139 and 140), PR-1611292 (comprising SEQ ID NOs: 141 and 142), PR-1612489 (comprising SEQ ID NOs: 161 and 162), PR-1612491 (comprising SEQ ID NOs: 163 and 164), PR-1612492 (comprising SEQ ID NOs: 165 and 166), PR-1612495 (comprising SEQ ID NOs: 171 and 172), PR-1612496 (comprising SEQ ID NOs: 173 and 174), PR-1612499 (comprising SEQ ID NOs: 177 and 178), PR-1612500 (comprising SEQ ID NOs: 179 and 180), PR-1612501 (comprising SEQ ID NOs: 181 and 182), PR-1612502 (comprising SEQ ID NOs: 183 and 184), PR-1613183 (comprising SEQ ID NOs: 185 and 186), PR-1613184 (comprising SEQ ID NOs: 187 and 188), PR-1613185 (comprising SEQ ID NOs: 189 and 190), PR-1613190 (comprising SEQ ID NOs: 199 and 200), PR-1565040 (comprising SEQ ID NOs: 3844 and 3845), PR-1565042 (comprising SEQ ID NOs: 3837 and 3838), PR-1565044 (comprising SEQ ID NOs: 213 and 214), PR-1565051 (comprising SEQ ID NOs: 215 and 216), PR-1565083 (comprising SEQ ID NOs: 217 and 218), PR-1565084 (comprising SEQ ID NOs: 219 and 220), PR-1565085 (comprising SEQ ID NOs: 221 and 222), PR-1565086 (comprising SEQ ID NOs: 223 and 224), PR-1571821 (comprising SEQ ID NOs: 225 and 226), PR-1571823 (comprising SEQ ID NOs: 227 and 228), PR-1575521 (comprising SEQ ID NOs: 229 and 230), PR-1571824 (comprising SEQ ID NOs: 231 and 232), PR-1571825 (comprising SEQ ID NOs: 233 and 234), PR-1571826 (comprising SEQ ID NOs: 235 and 236), PR-1571827 (comprising SEQ ID NOs: 237 and 238), PR-1571828 (comprising SEQ ID NOs: 239 and 240), PR-1571830 (comprising SEQ ID NOs: 241 and 242), PR-1571831 (comprising SEQ ID NOs: 243 and 244), PR-1571832 (comprising SEQ ID NOs: 245 and 246), PR-1571836 (comprising SEQ ID NOs: 247 and 248), PR-1577053 (comprising SEQ ID NOs: 249 and 250), or PR-1577056 (comprising SEQ ID NOs: 251 and 252.

In some embodiments, a binding protein, including a DVD-Ig binding protein, antibody, or fragment thereof, is capable of binding VEGF and/or PDGF and has at least about 80%, 90%, 95%, or 99% homology to CDRs 1-3 or to the full variable domains of any of the sequences in Tables 27, 28, 38-42, or 46-50. As used herein, the term percent (%) homology defines the percentage of residues in the amino acid sequence variant that are identical after aligning the sequences and introducing gaps and other spacing, e.g., using the BLAST alignment software.

In an embodiment, the binding protein has an on rate constant (K_on) to one or more targets of at least about 10²M⁻¹s⁻¹; at least about 10³M⁻¹s⁻¹; at least about 10⁴M⁻¹s⁻¹; at least about 10⁵M⁻¹s⁻¹; or at least about 10⁶M⁻¹s⁻¹, as measured by surface plasmon resonance. In an embodiment, the binding protein has an on rate constant (K_on) to one or more targets from about 10²M⁻¹s⁻¹to about 10³M⁻¹s⁻¹; from about 10³M⁻¹s⁻¹to about 10⁴M⁻¹s⁻¹; from about 10⁴M⁻¹s⁻¹to about 10⁵M⁻¹s⁻¹; or from about 10⁵M⁻¹s⁻¹to about 10⁶M⁻¹s⁻¹, as measured by surface plasmon resonance.

In an embodiment, the binding protein has an off rate constant (K_off) for one or more targets of at most about 10⁻³s⁻¹; at most about 10⁻⁴s⁻¹; at most about 10⁻⁵s⁻¹; or at most about 10⁻⁶s⁻¹, as measured by surface plasmon resonance. In an embodiment, the binding protein has an off rate constant (K_off) to one or more targets of about 10⁻³s⁻¹to about 10⁻⁴s⁻¹; of about 10⁻⁴s⁻¹to about 10⁻⁵s⁻¹; or of about 10⁻⁵s⁻¹to about 10⁻⁶s⁻¹, as measured by surface plasmon resonance.

In an embodiment, the binding protein has a dissociation constant (K_d) to one or more targets of at most about 10⁻⁷M; at most about 10⁻⁸M; at most about 10⁻⁹M; at most about 10⁻¹⁰M; at most about 10⁻¹¹M; at most about 10⁻¹²M; or at most 10⁻¹³M. In an embodiment, the binding protein has a dissociation constant (K_d) to its targets of about 10⁻⁷M to about 10⁻⁸M; of about 10⁻⁸M to about 10⁻⁹M; of about 10⁻⁹M to about 10⁻¹⁰M; of about 10⁻¹⁰M to about 10⁻¹¹M; of about 10⁻¹¹M to about 10⁻¹²M; or of about 10⁻¹²to M about 10⁻¹³M.

In an embodiment, the binding protein is a conjugate further comprising an agent. In an embodiment, the agent is an immunoadhesion molecule, an imaging agent, a therapeutic agent, or a cytotoxic agent. In an embodiment, the imaging agent is a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, or biotin. In another embodiment, the radiolabel is ³H, ¹⁴C, ³⁵S, ⁹⁰Y, ⁹⁹Tc, ¹¹¹In, ¹²⁵I, ¹³¹I, ¹⁷⁷Lu, ¹⁶⁶Ho, or ¹⁵³Sm. In yet another embodiment, the therapeutic or cytotoxic agent is an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, toxin, or an apoptotic agent, or an immunosuppressive agent.

In an embodiment, the binding protein is a crystallized binding protein and exists as a crystal. In an embodiment, the crystal is a carrier-free pharmaceutical controlled release crystal. In another embodiment, the crystallized binding protein has a greater half-life in vivo than the soluble counterpart of the binding protein. In yet another embodiment, the crystallized binding protein retains biological activity.

In certain embodiments, a binding protein disclosed herein can compete for binding to VEGF, PDGF, and/or a cognate receptor with any of the antibodies, binding proteins, or bispecific antibodies disclosed herein. In certain embodiments, a binding protein disclosed herein can compete for binding with an antibody, binding protein, or bispecific antibody comprising CDRs and/or variable domains selected from those identified in Tables 27, 28, 38-42, or 46-50. In certain embodiments, a binding protein disclosed herein can compete for binding with PR-1610561 (comprising SEQ ID NOs: 131 and 132) or a binding protein comprising the CDRs and/or variable domains of PR-1610561. In certain embodiments, a binding protein disclosed herein can compete for binding with PR-1572102 (comprising SEQ ID NOs: 88 and 89) or PR-1572105 (comprising SEQ ID NOs: 94 and 95) or PR1611292 (comprising SEQ ID NOs: 141 and 142).

According to certain embodiments, a binding protein disclosed herein can bind to the same epitope of VEGF, PDGF, and/or a cognate receptor as any of the antibodies, binding proteins, or bispecific antibodies disclosed herein. In certain embodiments, a binding protein disclosed herein can bind to the same epitope of VEGF, PDGF, and/or a cognate receptor bound by an antibody, binding protein, or bispecific antibody comprising CDRs and/or variable domains selected from those identified in Tables 27, 28, 38-42, or 46-50. In certain embodiments, a binding protein disclosed herein can bind to the same epitope as PR-1610561 (comprising SEQ ID NOs: 131 and 132) or a binding protein comprising the CDRs and/or variable domains of PR-1610561. In certain embodiments, a binding protein disclosed herein binds to the same epitope as PR-1572102 (comprising SEQ ID NOs: 88 and 89) or PR-1572105 (comprising SEQ ID NOs: 94 and 95) or PR1611292 (comprising SEQ ID NOs: 141 and 142).

In certain embodiments, competitive binding can be evaluated using a cross-blocking assay, such as the assay described in ANTIBODIES, A LABORATORY MANUAL, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1^stedition 1988, 2^ndedition 2014). In some embodiments, competitive binding is identified when a test antibody or binding protein reduces binding of a reference antibody or binding protein (e.g., a binding protein comprising CDRs and/or variable domains selected from those identified in Tables 27, 28, 38-42, or 46-50) to VEGF, PDGF, and/or a cognate receptor by at least about 50% in the cross-blocking assay (e.g., 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, or more, or any percentage in between), and/or vice versa. In some embodiments, competitive binding can be due to shared or similar (e.g., partially overlapping) epitopes, or due to steric hindrance where antibodies or binding proteins bind at nearby epitopes. See, e.g., Tzartos, Methods in Molecular Biology, vol. 66, Epitope Mapping Protocols, pages 55-66, Humana Press Inc. (1998). In some embodiments, competitive binding can be used to sort groups of binding proteins that share similar epitopes, e.g., those that compete for binding can be “binned” as a group of binding proteins that have overlapping or nearby epitopes, while those that do not compete are placed in a separate group of binding proteins that do not have overlapping or nearby epitopes

In an embodiment, the binding protein described herein is glycosylated. For example, the glycosylation pattern may be a human glycosylation pattern.

In various embodiments, a pharmaceutical composition comprising a binding protein disclosed herein and a pharmaceutically acceptable carrier is provided. In a further embodiment, the pharmaceutical composition comprises at least one additional agent such as a therapeutic agent for treating a disorder or a diagnostic agent. For example, the additional agent may be a therapeutic agent, an imaging agent, a cytotoxic agent, an angiogenesis inhibitor (including but not limited to an anti-VEGF antibody or a VEGF-trap), a kinase inhibitor (including but not limited to a KDR and a TIE-2 inhibitor), a co-stimulation molecule blocker (including but not limited to anti-B7.1, anti-B7.2, CTLA4-Ig, anti-CD20), an adhesion molecule blocker (including but not limited to an anti-LFA-1 antibody, an anti-E/L selectin antibody, a small molecule inhibitor), an anti-cytokine antibody or functional fragment thereof (including but not limited to an anti-IL-18, an anti-TNF, and an anti-IL-6/cytokine receptor antibody), methotrexate, cyclosporin, rapamycin, FK506, a detectable label or reporter, a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an erythropoietin, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an epinephrine or analog, a cytokine, or a cytokine antagonist.

In various embodiments, a binding protein disclosed herein binds to VEGF and comprises CDRs and/or variable domains selected from those identified in Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding protein comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of the CDR sets listed in Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding protein comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding protein is a bispecific or multispecific binding protein, comprising CDRs and/or variable domains selected from Tables A, 2.4.1-2.4.9, 27, and 38-42. The binding protein may further comprise heavy and light chain constant domains selected from Table 3. In some embodiments, the binding protein is also capable of binding to PDGF.

In some embodiments, a binding protein disclosed herein binds to PDGF and comprises CDRs and/or variable domains selected from those identified in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding protein comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of the CDR sets listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding protein comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding protein is a bispecific or multispecific binding protein, comprising CDRs and/or variable domains selected from Tables A, 1.4.1-1.4.7, 28, and 46-50. The binding protein may further comprise heavy and light chain constant domains selected from Table 3. In some embodiments, the binding protein is also capable of binding to VEGF.

In some embodiments, a binding protein disclosed herein binds to VEGF and PDGF, wherein the binding site for VEGF comprises CDRs and/or variable domains selected from those identified in Tables A, 2.4.1-2.4.9, 27, and 38-42 and the binding site for PDGF comprises CDRs and/or variable domains selected from those identified in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding sites for VEGF and PDGF comprises CDRs and/or variable domains selected from any of the variable domains listed in Tables 56-59, 95, and 96. In some embodiments, binding proteins disclosed herein comprise binding sites for VEGF and PDGF comprising the paired CDRs and/or variable domains from any one of the bispecific binding proteins selected from Tables 56-59, 95, and 96. In some embodiments, the binding proteins are DVD-Ig binding proteins, or any of the other bispecific or multispecific formats disclosed herein. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.

In some embodiments, a binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs-1-3 from SEQ ID NO: 18, and the binding site for PDGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 35 and CDRs-1-3 from SEQ ID NO: 36, and the binding site for PDGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 39 and CDRs-1-3 from SEQ ID NO: 40, and the binding site for PDGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, and the binding site for PDGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 35 and SEQ ID NO: 36, and the binding site for PDGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 39 and SEQ ID NO: 40, and the binding site for PDGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.

In some embodiments, a binding protein is capable of binding VEGF and PDGF, wherein the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs-1-3 from SEQ ID NO: 2, and the binding site for VEGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16, and the binding site for VEGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2, and the binding site for VEGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16, and the binding site for VEGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 2.4.1-2.4.9, 27, and 38-42. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.

In some embodiments, a binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs-1-3 from SEQ ID NO: 18, and the binding site PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs-1-3 from SEQ ID NO: 2. In some embodiments, the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 35 and CDRs-1-3 from SEQ ID NO: 36, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. In some embodiments, the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 39 and CDRs-1-3 from SEQ ID NO: 40, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.

In some embodiments, a binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, and the binding site PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 35 and SEQ ID NO: 36, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 39 and SEQ ID NO: 40, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.

In some embodiments, the binding protein is a DVD-Ig binding protein, capable of binding VEGF and PDGF. In some embodiment, the heavy chain of the binding protein comprises a DVD-Ig heavy chain variable domain and paired DVD-Ig light chain variable domain selected from Tables 56-59, 95, and 96. In some embodiments, the binding protein comprises DVD-Ig heavy and light chain variable domains of SEQ ID NO: 131 and SEQ ID NO: 132. In some embodiments, the binding protein comprises DVD-Ig heavy and light chain variable domains of SEQ ID NO: 88 and SEQ ID NO: 89. In some embodiments, the binding protein comprises DVD-Ig heavy and light chain variable domains of SEQ ID NO: 94 and SEQ ID NO: 95. In some embodiments, the binding protein comprises DVD-Ig heavy and light chain variable domains of SEQ ID NO: 141 and SEQ ID NO: 142. The DVD-Ig binding protein described herein may further comprise heavy and light chain constant domains selected from Table 3.

In certain embodiments, a binding protein disclosed herein is a DVD-Ig binding protein, comprising first and second polypeptide chains of SEQ ID NO: 131 and SEQ ID NO: 132. In some embodiments, the DVD-Ig binding protein comprises first and second polypeptide chains of SEQ ID NO: 88 and SEQ ID NO: 89. In some embodiments, the DVD-Ig binding protein comprises first and second polypeptide chains of SEQ ID NO: 94 and SEQ ID NO: 95. In some embodiments, the DVD-Ig binding protein comprises first and second polypeptide chains of SEQ ID NO: 141 and SEQ ID NO: 142.

Binding Protein Properties

The development and production of a binding protein for use as a human therapeutic agent, e.g., as an anti-inflammatory agent or oncologic agent, may require more than the identification of a binding protein capable of binding to a desired target or targets. The binding proteins disclosed herein exhibit favorable properties in one or more of the following categories (a) the binding kinetics (on-rate, off-rate and affinity) for both the inner and outer antigen-binding domains, (b) potencies in various biochemical and cellular bioassays, (c) in vivo efficacies in relevant tumor models, (d) pharmacokinetic and pharmacodynamics properties, (e) manufacturability, including protein expression level in selected cell lines, scalability, post-translational modification, physicochemical properties such as monomer percentage, solubility, and stability (intrinsic, freeze/thaw, storage stability, etc.), (f) formulation properties, (g) potential immunogenicity risk, (h) toxicological properties, and (i) binding mode and valency. Binding mode and valency may affect binding properties and cellular potencies of a molecule.

The binding proteins disclosed herein exhibit favorable properties in some or each of the categories listed above, including surprisingly high binding affinity at both the VD1 and VD2 positions.

In some embodiments a binding protein or binding proteins disclosed herein targeting VEGF and PDGF serve to both reduce choroidal neovascularization and increase regression of mature vasculature, e.g., in ocular conditions such as AMD. In some embodiments a binding protein or binding proteins disclosed herein targeting VEGF and PDGF neutralize VEGF and PDGF simultaneously. In some embodiments, the binding protein exhibits one or more of high potency to VEGF and/or PDGF, extended ocular duration, and rapid clearance from systemic circulation. In some embodiments, the binding protein is a bispecific and allows for a single injection of an agent to both targets (VEGF and PDGDF), reducing injection volume/frequency while still retaining the drug-like products of a traditional antibody.

In some embodiments, the disclosed binding protein exhibits superior in vivo efficacy (e.g., in a preclinical model of choroidal neovascularization or AMD) as compared to existing treatments for AMD (e.g., Elyea™ and/or Lucentis™). In some embodiments, the disclosed binding protein is a DVD-Ig binding protein and exhibits a high ocular duration. In some embodiments, the DVD-Ig binding protein may be, e.g., 150-200 kDa in weight or greater, and may provide for a longer ocular duration as compared to lower weight agents such as monoclonal antibodies. In some embodiments, the binding protein disclosed herein is a DVD-Ig binding protein and has an ocular half life of at least about 4 days, or at least about 4. 6 days, or at least about 5 days, or at least about 6 days, or at least about 6.5 days, or more. In some embodiments, the DVD-Ig ocular half life is greater than the half-life of an antibody or other construct having a smaller size, while retaining a more rapid systemic clearance similar to that of the antibody. In some embodiments, the DVD-Ig binding protein has an ocular half life of at least about 4 (or at least about 4.6) days after intravitreoius administration at 0.25 mg.

In some embodiments, the disclosed binding proteins are DVD-Ig binding proteins and exhibit improved drug-like properties, including one or more of high thermostability (e.g., a T_onsetof greater than 50°, 55°, 60°, 61°, 62°, 63°, 64°, or 65° C.), a solubility of at least about 70, 72, 74, 76, 78, or 80 mg/ml, a viscosity at room temperature and at a concentration of 100 mg/ml of about 7.2 centipoise, an effective storage stability in a universal buffer, and/or high freeze-thaw stability. In some embodiments, the DVD-Ig binding protein does not exhibit a significant change in monomer percentage at low concentration after storage at 5° C. or 40° C. for 10, 15, 20, 21, 22, 23, 24, 25, or more days, and/or does not exhibit a significant increase in aggregation at 50-150 mg/ml (or 100+/−10 mg/ml) after 1, 2, 3, 4, 5, or more freeze/thaw cycles.

In certain embodiments, a binding protein exhibiting particularly favorable properties in some or each of the categories listed above is a DVD-Ig binding protein capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 35 and CDRs-1-3 from SEQ ID NO: 36, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 35 and SEQ ID NO: 36, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. In an embodiment, the binding protein is capable of binding VEGF and PDGF, and comprises PR-1610561 (comprising SEQ ID NOs: 131 and 132). In an embodiment, the binding protein comprises a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, and optionally also comprising a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence

In certain embodiments, a binding protein exhibiting particularly favorable properties in some or each of the categories listed above is a DVD-Ig binding protein capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs-1-3 from SEQ ID NO: 18, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs-1-3 from SEQ ID NO: 2. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, and the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2. In an embodiment, the binding protein is capable of binding VEGF and PDGF, and comprises PR-1572102 (comprising SEQ ID NOs: 88 and 89) or PR-1572105 (comprising SEQ ID NOs: 94 and 95) or PR1611292 (comprising SEQ ID NOs: 141 and 142). In an embodiment, the binding protein comprises a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, and optionally also comprising a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence.

For instance, in some embodiments, the binding protein disclosed herein (e.g., PR-1610561, PR-1572102, PR-1572105, or PR1611292) may exhibit one or more of the following features: enhanced in vivo efficacy in human VEGF transgenic mice, enhanced potency (as measured, e.g., via BIACORE, ELISA, or co-culture sprouting assay), improved expression (e.g., in HEK293 or CHO cells), and improved drug-like properties (e.g., thermal stability, storage stability, solubility, physicochemical properties, and/or pharmacokinetics) as compared to another binding protein or combination of binding proteins targeting VEGF and PDGF.

Preparation of Binding Proteins

In another aspect, the disclosure provides a method of making a binding protein that binds PDGF, VEGF, and/or either or both cognate receptors. In an embodiment, the method of making a binding protein comprises the steps of a) obtaining a first parent antibody, or antigen binding portion thereof, that binds PDGF, VEGF, or a cognate receptor; b) obtaining a second parent antibody, or antigen binding portion thereof, that binds PDGF, VEGF, or a cognate receptor; c) determining the sequences of the variable domains of the parent antibodies or antigen binding portions thereof; d) preparing construct(s) encoding any of the binding proteins described herein using those variable domain sequences; and e) expressing the polypeptide chains, such that a binding protein that binds PDGF, VEGF, and/or either or both cognate receptors is generated.

In any of the embodiments herein, the VD1 heavy chain variable domain, if present, and light chain variable domain, if present, can be from a first parent antibody or antigen binding portion thereof; the VD2 heavy chain variable domain, if present, and light chain variable domain, if present, can be from a second parent antibody or antigen binding portion thereof. The first and second parent antibodies can be the same or different.

In one embodiment, the first parent antibody or antigen binding portion thereof, binds a first antigen, and the second parent antibody or antigen binding portion thereof, binds a second antigen. In an embodiment, the first and second antigens are the same antigen. In another embodiment, the parent antibodies bind different epitopes on the same antigen. In another embodiment, the first and second antigens are different antigens. In another embodiment, the first parent antibody or antigen binding portion thereof, binds the first antigen with a potency different from the potency with which the second parent antibody or antigen binding portion thereof, binds the second antigen. In yet another embodiment, the first parent antibody or antigen binding portion thereof, binds the first antigen with an affinity different from the affinity with which the second parent antibody or antigen binding portion thereof, binds the second antigen.

In another embodiment, the first parent antibody or antigen binding portion thereof, and the second parent antibody or antigen binding portion thereof, are a human antibody, CDR grafted antibody, humanized antibody, and/or affinity matured antibody. The “parent antibody”, which provides at least one antigen binding specificity of the multivalent and or multispecific binding protein, may be one that is internalized (and/or catabolized) by a cell expressing an antigen to which the antibody binds; and/or may be an agonist, cell death-inducing, and/or apoptosis-inducing antibody, and the multivalent and or multispecific binding protein as described herein may display improvement(s) in one or more of these properties. Moreover, the parent antibody may lack any one or more of these properties, but may acquire one or more of them when constructed as a multivalent binding protein as described herein. For example, different Fc mutants may prevent FcR, FcR-gamma, complement, or C′ binding, or extend half-life.

In various embodiments, an isolated nucleic acid encoding any one of the binding proteins disclosed herein is also provided. Also provided is a composition comprising one or more nucleic acids wherein said one or more nucleic acids encode a nucleic acid encoding any one of the binding proteins disclosed herein. For example, the composition may comprise a nucleic acid that encodes a first polypeptide and a nucleic acid that encodes a second polypeptide, wherein said first and second polypeptide together form a binding protein as described herein. A further embodiment provides a vector (e.g., an expression vector) comprising the isolated nucleic acid disclosed herein. Also provided is a vector (e.g. an expression vector) that comprises one or more nucleic acids that encode a binding protein as described herein. Also provided is a composition comprising one or more vectors that encode a binding protein as described herein. For example, the composition may comprise a vector that encodes a first polypeptide and a vector that encodes a second polypeptide, wherein said first and second polypeptide together form a binding protein as described herein. In some embodiments, the vector is pcDNA; pTT (Durocher et al. (2002) Nucleic Acids Res. 30(2):e9; pTT3 (pTT with additional multiple cloning site; pEFBOS (Mizushima and Nagata (1990) Nucleic Acids Res. 18:17); pBV; pJV; pcDNA3.1 TOPO; pEF6 TOPO; pBOS; pHybE; or pBJ. In an embodiment, the vector is a vector disclosed in U.S. Pat. No. 8,187,836.

In another aspect, a host cell is transformed with the vector disclosed herein. In an embodiment, the host cell is a prokaryotic cell, for example, E. coli. In another embodiment, the host cell is a eukaryotic cell, for example, a protist cell, an animal cell, a plant cell, or a fungal cell. In an embodiment, the host cell is a mammalian cell including, but not limited to, CHO, COS, NSO, SP2, PER.C6, or a fungal cell, such as Saccharomyces cerevisiae, or an insect cell, such as Sf9. In an embodiment, two or more binding proteins, e.g., with different specificities, are produced in a single recombinant host cell. For example, the expression of a mixture of antibodies has been called Oligoclonics™ (Merus B.V., The Netherlands) disclosed in U.S. Pat. Nos. 7,262,028 and 7,429,486.

In various embodiments, a binding proteins disclosed herein can be prepared by culturing any one of the host cells disclosed herein in a culture medium under conditions sufficient to produce the binding protein.

One embodiment provides a composition for the release of a binding protein wherein the composition comprises a crystallized binding protein, an ingredient, and at least one polymeric carrier. In an embodiment, the polymeric carrier is poly (acrylic acid), a poly (cyanoacrylate), a poly (amino acid), a poly (anhydride), a poly (depsipeptide), a poly (ester), poly (lactic acid), poly (lactic-co-glycolic acid) or PLGA, poly (b-hydroxybutyrate), poly (caprolactone), poly (dioxanone), poly (ethylene glycol), poly ((hydroxypropyl) methacrylamide, poly [(organo)phosphazene], a poly (ortho ester), poly (vinyl alcohol), poly (vinylpyrrolidone), a maleic anhydride-alkyl vinyl ether copolymer, a pluronic polyol, albumin, alginate, cellulose, a cellulose derivative, collagen, fibrin, gelatin, hyaluronic acid, an oligosaccharide, a glycaminoglycan, a sulfated polysaccharide, or blends and copolymers thereof. In an embodiment, the ingredient is albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-β-cyclodextrin, methoxypolyethylene glycol, or polyethylene glycol.

The binding proteins provided herein, such as DVD-Ig binding proteins, may be produced by any of a number of techniques known in the art. For example, expression from host cells, wherein expression vector(s) encoding the DVD-Ig heavy and DVD-Ig light chains is (are) transfected into a host cell by standard techniques. Although it is possible to express the DVD-Ig binding proteins provided herein in either prokaryotic or eukaryotic host cells, DVD-Ig binding proteins are preferably expressed in eukaryotic cells, for example, mammalian host cells.

In an exemplary system for recombinant expression of DVD-Ig proteins, a recombinant expression vector encoding both the DVD-Ig heavy chain and the DVD-Ig light chain is introduced into dhfr-CHO cells by calcium phosphate-mediated transfection. Within the recombinant expression vector, the DVD-Ig heavy and light chain sequences are each operatively linked to CMV enhancer/AdMLP promoter regulatory elements to drive high levels of transcription of the genes. The recombinant expression vector also carries a DHFR gene, which allows for selection of CHO cells that have been transfected with the vector using methotrexate selection/amplification. The selected transformant host cells are cultured to allow for expression of the DVD-Ig heavy and light chains and intact DVD-Ig protein is recovered from the culture medium. Standard molecular biology techniques may be used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells and recover the DVD-Ig protein from the culture medium. In some embodiments, a method of synthesizing a DVD-Ig binding protein by culturing a host cell provided herein in a suitable culture medium until a DVD-Ig binding protein is synthesized is also provided. The method may further comprise isolating the DVD-Ig protein from the culture medium.

A feature of a DVD-Ig binding protein is that it can be produced and purified in a similar way to a conventional antibody. The design of the full length DVD-Ig binding protein heavy and light chains provided herein leads to assemble primarily to the desired dual-specific multivalent full length binding proteins. In an embodiment, 50%-75% of the binding protein produced by this method is a dual specific tetravalent binding protein (e.g., a DVD-Ig binding protein). In another embodiment, 75%-90% of the binding protein produced by this method is a dual specific tetravalent binding protein. In another embodiment, 90%-95% of the binding protein produced is a dual specific tetravalent binding protein. In some embodiments, at least 50%, at least 75% and at least 90% of the assembled, and expressed dual variable domain immunoglobulin molecules are the desired dual-specific tetravalent protein.

In various embodiments, the disclosure provides methods of expressing a dual variable domain light chain and a dual variable domain heavy chain in a single cell leading to a primary product of a dual-specific tetravalent full length binding protein, where the primary product is more than 50%, such as more than 75% and more than 90%, of all assembled protein, comprising a dual variable domain light chain and a dual variable domain heavy chain.

Therapeutic and Diagnostic Uses

Also disclosed herein, in various embodiments, are methods for diagnosing and treating a mammal (e.g., a human) comprising the step of administering to the mammal, or a sample taken from the mammal, an effective amount of a composition disclosed herein. A binding protein as described herein may be used in a method for therapy or diagnosis.

Given their ability to bind VEGF, PLGF, and/or their cognate receptors, in some embodiments, the binding proteins provided herein can be used to detect one or more of those antigens (e.g., in a biological sample, such as serum or plasma), using a conventional immunoassay, such as an enzyme linked immunosorbent assays (ELISA), a radioimmunoassay (RIA), or tissue immunohistochemistry. The binding protein is directly or indirectly labeled with a detectable substance to facilitate detection of the bound or unbound antibody. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin. An example of a luminescent material is luminol and examples of suitable radioactive materials include ³H, ¹⁴C, ³⁵S, ⁹⁰Y, ⁹⁹Tc, ¹¹¹In, ¹²⁵I, ¹³¹I, ¹⁷⁷Lu, ¹⁶⁶Ho, and ¹⁵³Sm.

In some embodiments, a method is disclosed for treating a human subject suffering from a disorder in which the target, or targets, capable of being bound by the binding proteins disclosed herein is/are detrimental, comprising administering to the human subject a binding protein disclosed herein such that the activity of the target, or targets, in the human subject is inhibited and one or more symptoms is alleviated or treatment is achieved is provided. In various embodiments, treatment comprises reducing, improving, or ameliorating one or more symptom of a disorder. Treatment includes but does not necessarily require curing (i.e., completely eliminating) a disorder or a symptom of a disorder.

The binding proteins provided herein can be used to treat humans suffering from diseases such as, for example, those associated with increased angiogenesis and/or inflammation (e.g., ocular inflammation). In an embodiment, the binding proteins provided herein or antigen-binding portions thereof, are used to treat an autoimmune disorder, asthma, ocular inflammation, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), insulin dependent diabetes mellitus, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus (SLE), multiple sclerosis, sepsis, a neurodegenerative disease, or an oncological disorder. In an embodiment, a binding protein disclosed herein is used to treat an eye disorder (e.g., an angiogenic eye disorder). In an embodiment, the eye disorder is a macular degeneration, such as wet macular degeneration, dry macular degeneration, age related macular degeneration (AMD), exudative AMD, dry eye, glaucoma, diabetic retinopathy, diabetic macular edema, central retinal vein occlusion, corneal neovascularization, iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), choroidal neovascularization, optic disc neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, macular edema, diabetic macular edema (DME), vascular retinopathy, retinal degeneration, uveitis, keratoconjunctivitis sicca, blepharitis, keratitis or another inflammatory disease of the eye.

In an embodiment, the binding proteins provided herein are capable of neutralizing the activity of their antigen targets both in vitro and in vivo. Accordingly, such binding proteins can be used to inhibit antigen activity, e.g., in a cell culture containing the antigens, in human subjects or in other mammalian subjects having the antigens with which a binding protein provided herein cross-reacts. In another embodiment, a method for reducing antigen activity in a subject suffering from a disease or disorder in which the antigen activity is detrimental is provided. A binding protein provided herein may be administered to a human subject for therapeutic purposes. In some embodiments, the binding protein (e.g., the DVD-Ig binding protein) is administered to a patient, e.g., a patient suffering from wet AMD, and can have one or more effects selected from regressing mature vasculature (e.g., via VEGF binding), reducing choroidal neovascularization (e.g., via VEGF binding), allowing access to blood vessels by stripping off pericytes (e.g., via PDGF binding), and/or providing anti-fibrotic effects to reduce visual loss from scarring (e.g., via PDGF binding). In some embodiments, the binding protein is multispecific for VEGF and PDGF, and is administered at a reduced number of injections and/or a reduced injection frequency, as compared to a combination antibody therapy.

The term “a disorder in which antigen activity is detrimental” encompasses diseases and other disorders in which the presence of the antigen in a subject suffering from the disorder has been shown to be or is suspected of being either responsible for the pathophysiology of the disorder or a factor that contributes to a worsening of the disorder. Accordingly, a disorder in which antigen activity is detrimental is a disorder in which reduction of antigen activity is expected to alleviate the symptoms and/or progression of the disorder. Such disorders may be evidenced, for example, by an increase in the concentration of the antigen in a biological fluid of a subject suffering from the disorder (e.g., an increase in the concentration of antigen in serum, plasma, synovial fluid, etc., of the subject). Non-limiting examples of disorders that can be treated with the binding proteins provided herein include those disorders discussed below and in the section pertaining to pharmaceutical compositions comprising the binding proteins.

Binding proteins disclosed herein, such as the DVD-Ig binding proteins, can be employed in some embodiments for tissue-specific delivery (target a tissue marker and a disease mediator for enhanced local PK thus higher efficacy and/or lower toxicity), including intracellular delivery (targeting an internalizing receptor and an intracellular molecule), delivering through a biological barrier, such as to the inside of the eye or brain (e.g., targeting transferrin receptor and a CNS disease mediator for crossing the blood-brain barrier). The binding proteins may also serve as carrier proteins to deliver an antigen to a specific location via binding to a non-neutralizing epitope of that antigen and also to increase the half-life of the antigen. Furthermore, the binding protein may be designed to either be physically linked to medical devices implanted into patients or target these medical devices (see Burke et al. (2006) Advanced Drug Deliv. Rev. 58(3): 437-446; Hildebrand et al. (2006) Surface and Coatings Technol. 200(22-23): 6318-6324; Drug/device combinations for local drug therapies and infection prophylaxis, Wu (2006) Biomaterials 27(11):2450-2467; Mediation of the cytokine network in the implantation of orthopedic devices, Marques (2005) Biodegradable Systems in Tissue Engineer. Regen. Med. 377-397).

In an embodiment, diseases that can be treated or diagnosed with the compositions and methods disclosed herein include, but are not limited to, primary and metastatic cancers, including carcinomas of breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gallbladder and bile ducts, small intestine, urinary tract (including kidney, bladder and urothelium), female genital tract (including cervix, uterus, and ovaries as well as choriocarcinoma and gestational trophoblastic disease), male genital tract (including prostate, seminal vesicles, testes and germ cell tumors), endocrine glands (including the thyroid, adrenal, and pituitary glands), and skin, as well as hemangiomas, melanomas, sarcomas (including those arising from bone and soft tissues as well as Kaposi's sarcoma), tumors of the brain, nerves, eyes, and meninges (including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, Schwannomas, and meningiomas), solid tumors arising from hematopoietic malignancies such as leukemias, and lymphomas (both Hodgkin's and non-Hodgkin's lymphomas).

Another embodiment provides for the use of the binding protein in the treatment of a disease or disorder, wherein the disorder is arthritis, osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft versus host disease, organ transplant rejection, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, heart failure, myocardial infarction, Addison's disease, sporadic poly glandular deficiency type I and polyglandular deficiency type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthopathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitic arthropathy, enteropathic synovitis, chlamydia, yersinia and salmonella associated arthropathy, spondyloarthopathy, atheromatous disease/arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, myalgic encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired Immunodeficiency Syndrome, Acquired Immunodeficiency Related Diseases, Hepatitis B, Hepatitis C, common varied immunodeficiency (common variable hypogammaglobulinaemia), dilated cardiomyopathy, female infertility, ovarian failure, premature ovarian failure, fibrotic lung disease, cryptogenic fibrosing alveolitis, post-inflammatory interstitial lung disease, interstitial pneumonitis, connective tissue disease associated interstitial lung disease, mixed connective tissue disease associated lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease, dermatomyositis/polymyositis associated lung disease, Sjögren's disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, fibrosis, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasulitis of the kidneys, lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjörgren's syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, idiopathic thrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo acute liver disease, chronic liver diseases, alcoholic cirrhosis, alcohol-induced liver injury, cholestasis, idiosyncratic liver disease, Drug-Induced hepatitis, Non-alcoholic Steatohepatitis, allergy and asthma, group B streptococci (GBS) infection, mental disorders (e.g., depression and schizophrenia), Th2 Type and Th1 Type mediated diseases, acute and chronic pain (different forms of pain), and cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma) abetalipoproteinemia, Acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial ectopic beats, AIDS dementia complex, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha-1-antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti cd3 therapy, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, aordic and peripheral aneuryisms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bundle branch block, Burkitt's lymphoma, burns, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chronic myelocytic leukemia (CML), chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, colorectal carcinoma, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture negative sepsis, cystic fibrosis, cytokine therapy associated disorders, Dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatologic conditions, diabetes, diabetes mellitus, diabetic ateriosclerotic disease, Diffuse Lewy body disease, dilated congestive cardiomyopathy, disorders of the basal ganglia, Down's Syndrome in middle age, drug-induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, epstein-barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, graft rejection of any organ or tissue, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallerrorden-Spatz disease, hashimoto's thyroiditis, hay fever, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, hepatitis A, His bundle arryhthmias, HIV infection/HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorders, hypersensitity reactions, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody mediated cytotoxicity, Asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza a, ionizing radiation exposure, iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, kidney transplant rejection, legionella, leishmaniasis, leprosy, lesions of the corticospinal system, lipedema, liver transplant rejection, lymphederma, malaria, malignamt Lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic/idiopathic, migraine headache, mitochondrial multi.system disorder, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Mencel Dejerine-Thomas Shy-Drager and Machado-Joseph), myasthenia gravis, mycobacterium avium intracellulare, mycobacterium tuberculosis, myelodyplastic syndrome, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic I muscular atrophies, neutropenic fever, non-hodgkins lymphoma, occlusion of the abdominal aorta and its branches, occlusive arterial disorders, okt3 therapy, orchitis/epidydimitis, orchitis/vasectomy reversal procedures, organomegaly, osteoporosis, pancreas transplant rejection, pancreatic carcinoma, paraneoplastic syndrome/hypercalcemia of malignancy, parathyroid transplant rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherlosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia, pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), post perfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, Progressive supranucleo Palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and disease, Raynoud's disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcomas, scleroderma, senile chorea, Senile Dementia of Lewy body type, seronegative arthropathies, shock, sickle cell anemia, skin allograft rejection, skin changes syndrome, small bowel transplant rejection, solid tumors, specific arrythmias, spinal ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, Subacute sclerosing panencephalitis, Syncope, syphilis of the cardiovascular system, systemic anaphalaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans, thrombocytopenia, toxicity, transplants, trauma/hemorrhage, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart diseases, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular fibrillation, viral and fungal infections, vital encephalitis/aseptic meningitis, vital-associated hemaphagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, acute coronary syndromes, acute idiopathic polyneuritis, acute inflammatory demyelinating polyradiculoneuropathy, acute ischemia, adult Still's disease, anaphylaxis, anti-phospholipid antibody syndrome, aplastic anemia, atopic eczema, atopic dermatitis, autoimmune dermatitis, autoimmune disorder associated with streptococcus infection, autoimmune enteropathy, autoimmune hearing loss, autoimmune lymphoproliferative syndrome (ALPS), autoimmune myocarditis, autoimmune premature ovarian failure, blepharitis, bronchiectasis, bullous pemphigoid, cardiovascular disease, catastrophic antiphospholipid syndrome, celiac disease, cervical spondylosis, chronic ischemia, cicatricial pemphigoid, clinically isolated syndrome (cis) with risk for multiple sclerosis, childhood onset psychiatric disorder, dacryocystitis, dermatomyositis, diabetic retinopathy, disk herniation, disk prolaps, drug induced immune hemolytic anemia, endometriosis, endophthalmitis, episcleritis, erythema multiforme, erythema multiforme major, gestational pemphigoid, Guillain-Barré syndrome (GBS), hay fever, Hughes syndrome, idiopathic Parkinson's disease, idiopathic interstitial pneumonia, IgE-mediated allergy, immune hemolytic anemia, inclusion body myositis, infectious ocular inflammatory disease, inflammatory demyelinating disease, inflammatory heart disease, inflammatory kidney disease, IPF/UIP, iritis, keratitis, keratoconjunctivitis sicca, Kussmaul disease or Kussmaul-Meier disease, Landry's paralysis, Langerhan's cell histiocytosis, livedo reticularis, macular degeneration, microscopic polyangiitis, morbus bechterev, motor neuron disorders, mucous membrane pemphigoid, multiple organ failure, myelodysplastic syndrome, myocarditis, nerve root disorders, neuropathy, non-A non-B hepatitis, optic neuritis, osteolysis, ovarian cancer, pauciarticular JRA, peripheral artery occlusive disease (PAOD), peripheral vascular disease (PVD), peripheral artery, disease (PAD), phlebitis, polyarteritis nodosa (or periarteritis nodosa), polychondritis, polymyalgia rheumatica, poliosis, polyarticular JRA, polyendocrine deficiency syndrome, polymyositis, post-pump syndrome, primary Parkinsonism, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), prostatitis, pure red cell aplasia, primary adrenal insufficiency, recurrent neuromyelitis optica, restenosis, rheumatic heart disease, sapho (synovitis, acne, pustulosis, hyperostosis, and osteitis), scleroderma, secondary amyloidosis, shock lung, scleritis, sciatica, secondary adrenal insufficiency, silicone associated connective tissue disease, sneddon-wilkinson dermatosis, spondilitis ankylosans, Stevens-Johnson syndrome (SJS), systemic inflammatory response syndrome, temporal arteritis, toxoplasmic retinitis, toxic epidermal necrolysis, transverse myelitis, TRAPS (tumor necrosis factor receptor, type 1 allergic reaction, type II diabetes, usual interstitial pneumonia (UIP), vernal conjunctivitis, viral retinitis, Vogt-Koyanagi-Harada syndrome (VKH syndrome), wet macular degeneration, wound healing, fibrosis, renal disease, wet macular degeneration, wound healing, age related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, central retinal vein occlusion, corneal neovascularization, exudative AMD, iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), choroidal neovascularization, optic disc neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, macular edema, diabetic macular edema (DME), vascular retinopathy, retinal degeneration, uveitis, or an inflammatory disease of the eye.

In some embodiments, any one of the binding proteins disclosed herein can be used to treat a disorder listed above. In certain embodiments, the binding protein used to treat any of the disorders discussed herein is one or more of the binding proteins listed in Tables 27-30, 38-42, 46-50, or 55-58. In certain embodiments, the binding protein used to treat any of the disorders discussed herein is one or more of the binding proteins listed in Tables 56-58. In certain embodiments, the binding protein is PR-1572102, PR-1572105, PR-1610561, or PR1611292.

In some embodiments, a binding protein (e.g., PR-1572102, PR-1572105, PR1611292, or PR-1610561) may be used to treat wet AMD that is non-responsive to anti-VEGF monotherapy. For instance, a binding protein targeting VEGF and PDGF (e.g., PR-1572102, PR-1572105, or PR-1610561) may lead to better regression of angiogenesis, thereby providing for a more effective treatment (this does not necessarily mean, however, that such a binding protein would have a reduced administration frequency; whether that is the case is presently unknown). The dual inhibition of both VEGF and PDGF may provide for certain improved treatment outcomes, as compared to anti-VEGF monotherapy.

In another aspect, methods of treating a patient suffering from a disorder are disclosed, comprising the step of administering any one of the binding proteins disclosed herein before, concurrently, or after the administration of a second agent, are provided. In an embodiment, the second agent is an imaging agent, cytotoxic agent, angiogenesis inhibitor, kinase inhibitor, co-stimulation molecule blocker, adhesion molecule blocker, anti-cytokine antibody or functional fragment thereof, methotrexate, cyclosporin, rapamycin, FK506, detectable label or reporter, TNF antagonist, antirheumatic, muscle relaxant, narcotic, non-steroid anti-inflammatory drug (NSAID), analgesic, anesthetic, sedative, local anesthetic, neuromuscular blocker, antimicrobial, antipsoriatic, corticosteriod, anabolic steroid, erythropoietin, immunization, immunoglobulin, immunosuppressive, growth hormone, hormone replacement drug, radiopharmaceutical, antidepressant, antipsychotic, stimulant, asthma medication, beta agonist, inhaled steroid, epinephrine or analog, cytokine, or cytokine antagonist.

Also disclosed, in various embodiments, are anti-idiotype antibodies to the binding proteins disclosed herein. An anti-idiotype antibody includes any protein or peptide-containing molecule that comprises at least a portion of an immunoglobulin molecule such as, but not limited to, at least one complementarily determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework region, or any portion thereof, that can be incorporated into a binding protein provided herein.

Also disclosed herein, in various embodiments, are methods of determining the presence, amount or concentration of VEGF and/or PDGF, or fragment thereof, in a test sample. In some embodiments, the methods comprise assaying the test sample for the antigen, or fragment thereof, by an immunoassay. The immunoassay (i) employs at least one binding protein and at least one detectable label and (ii) comprises comparing a signal generated by the detectable label as a direct or indirect indication of the presence, amount or concentration of the antigen, or fragment thereof, in the test sample to a signal generated as a direct or indirect indication of the presence, amount or concentration of the antigen, or fragment thereof, in a control or a calibrator. The calibrator is optionally part of a series of calibrators in which each of the calibrators differs from the other calibrators in the series by the concentration of the antigen, or fragment thereof. The method can comprise (i) contacting the test sample with at least one capture agent, which binds to an epitope on the antigen, or fragment thereof, so as to form a capture agent/antigen, or fragment thereof, complex, (ii) contacting the capture agent/antigen, or fragment thereof, complex with at least one detection agent, which comprises a detectable label and binds to an epitope on the antigen, or fragment thereof, that is not bound by the capture agent, to form a capture agent/antigen, or fragment thereof/detection agent complex, and (iii) determining the presence, amount or concentration of the antigen, or fragment thereof, in the test sample based on the signal generated by the detectable label in the capture agent/antigen, or fragment thereof/detection agent complex formed in (ii), wherein at least one capture agent and/or at least one detection agent is the at least one binding protein.

Alternatively, the method may comprise (i) contacting the test sample with at least one capture agent, which binds to an epitope on the antigen, or fragment thereof, so as to form a capture agent/antigen, or fragment thereof, complex, and simultaneously or sequentially, in either order, contacting the test sample with detectably labeled antigen, or fragment thereof, which can compete with any antigen, or fragment thereof, in the test sample for binding to the at least one capture agent, wherein any antigen, or fragment thereof, present in the test sample and the detectably labeled antigen compete with each other to form a capture agent/antigen, or fragment thereof, complex and a capture agent/detectably labeled antigen, or fragment thereof, complex, respectively, and (ii) determining the presence, amount or concentration of the antigen, or fragment thereof, in the test sample based on the signal generated by the detectable label in the capture agent/detectably labeled antigen, or fragment thereof, complex formed in (ii), wherein at least one capture agent is the at least one binding protein and wherein the signal generated by the detectable label in the capture agent/detectably labeled antigen, or fragment thereof, complex is inversely proportional to the amount or concentration of antigen, or fragment thereof, in the test sample.

In some embodiments, the test sample is from a patient, in which case the method can further comprise diagnosing, prognosticating, or assessing the efficacy of therapeutic/prophylactic treatment of the patient. If the method further comprises assessing the efficacy of therapeutic/prophylactic treatment of the patient, the method optionally further comprises modifying the therapeutic/prophylactic treatment of the patient as needed to improve efficacy. The method can be adapted for use in an automated system or a semi-automated system. Accordingly, the methods described herein also can be used to determine whether or not a subject has or is at risk of developing a given disease, disorder or condition. Specifically, such a method can comprise the steps of: (a) determining the concentration or amount in a test sample from a subject of analyte, or fragment thereof, (e.g., using the methods described herein, or methods known in the art); and (b) comparing the concentration or amount of analyte, or fragment thereof, determined in step (a) with a predetermined level, wherein, if the concentration or amount of analyte determined in step (a) is favorable with respect to a predetermined level, then the subject is determined not to have or be at risk for a given disease, disorder or condition. However, if the concentration or amount of analyte determined in step (a) is unfavorable with respect to the predetermined level, then the subject is determined to have or be at risk for a given disease, disorder or condition.

Additionally, in various embodiments, provided herein are methods of monitoring the progression of disease in a subject. In some embodiments, the method can comprise the steps of: (a) determining the concentration or amount in a test sample from a subject of analyte; (b) determining the concentration or amount in a later test sample from the subject of analyte; and (c) comparing the concentration or amount of analyte as determined in step (b) with the concentration or amount of analyte determined in step (a), wherein if the concentration or amount determined in step (b) is unchanged or is unfavorable when compared to the concentration or amount of analyte determined in step (a), then the disease in the subject is determined to have continued, progressed or worsened. By comparison, if the concentration or amount of analyte as determined in step (b) is favorable when compared to the concentration or amount of analyte as determined in step (a), then the disease in the subject is determined to have discontinued, regressed or improved.

Optionally, the method further comprises comparing the concentration or amount of analyte as determined in step (b), for example, with a predetermined level. Further, optionally the method comprises treating the subject with one or more pharmaceutical compositions for a period of time if the comparison shows that the concentration or amount of analyte as determined in step (b), for example, is unfavorably altered with respect to the predetermined level.

Also provided, in various embodiments, are kits for assaying a test sample for VEGF and/or PDGF, or fragment thereof. The kit may comprise at least one component for assaying the test sample for an antigen, or fragment thereof, and instructions for assaying the test sample for an antigen, or fragment thereof, wherein the at least one component includes at least one composition comprising the binding protein disclosed herein, wherein the binding protein is optionally detectably labeled.

Unless otherwise defined herein, scientific and technical terms used herein have the meanings that are commonly understood by those of ordinary skill in the art. In the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The use of “or” means “and/or” unless stated otherwise. The use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting. Any range disclosed herein is intended to encompass the endpoints of that range unless stated otherwise.

Generally, nomenclatures used in connection with cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those known and commonly used in the art. The methods and techniques provided herein are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The nomenclatures used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

That the disclosure may be more readily understood, select terms are defined below.

The term “antibody” refers to an immunoglobulin (Ig) molecule, which is may comprise four polypeptide chains, two heavy (H) chains and two light (L) chains, or it may comprise a functional fragment, mutant, variant, or derivative thereof, that retains the epitope binding features of an Ig molecule. Such fragment, mutant, variant, or derivative antibody formats are known in the art. In an embodiment of a full-length antibody, each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (CH). In the case of an IgG molecule, the CH comprises three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The CL is comprised of a single CL domain. The VH and VL can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Generally, each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. CDR regions may be determined by standard methods, e.g., those of Kabat et al. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), or subclass.

The term “bispecific antibody” refers to an antibody that binds one antigen (or epitope) on one of its two binding arms (one pair of HC/LC), and binds a different antigen (or epitope) on its second binding arm (a different pair of HC/LC). A bispecific antibody is a type of bispecific binding protein. A bispecific antibody may have two distinct antigen binding arms (in both specificity and CDR sequences), and may be monovalent for each antigen to which it binds. Bispecific antibodies include those generated by quadroma technology (Milstein and Cuello (1983) Nature 305(5934): 537-40), by chemical conjugation of two different monoclonal antibodies (Staerz et al. (1985) Nature 314(6012): 628-31), or by knob-into-hole or similar approaches which introduces mutations in the Fc region (Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90(14): 6444-6448).

The term “affinity matured” refers to an antibody or binding protein with one or more alterations in one or more CDR or framework (FR) regions thereof, which may result in an improvement in the affinity for an antigen, compared to a parent antibody or binding protein which does not possess those alteration(s). Exemplary affinity matured antibodies or binding protein will have nanomolar or even picomolar affinities for the target antigen. Affinity matured antibodies or binding protein may be produced by procedures known in the art, e.g., Marks et al. (1992) BioTechnology 10:779-783 describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of CDR and/or framework residues is described by Barbas et al. (1994) Proc. Nat. Acad. Sci. USA 91:3809-3813; Schier et al. (1995) Gene 169:147-155; Yelton et al. (1995) J. Immunol. 155:1994-2004; Jackson et al. (1995) J. Immunol. 154(7):3310-9; Hawkins et al. (1992) J. Mol. Biol. 226:889-896 and mutation at selective mutagenesis positions, contact or hypermutation positions with an activity enhancing amino acid residue as described in U.S. Pat. No. 6,914,128.

The term “CDR-grafted” refers to an antibody or binding protein that comprises heavy and light chain variable region sequences in which the sequences of one or more of the CDR regions of VH and/or VL are replaced with CDR sequences of another antibody or binding protein. For example, the two antibodies or binding protein can be from different species, such as antibodies or binding protein having murine heavy and light chain variable regions in which one or more of the murine CDRs has been replaced with human CDR sequences.

The term “humanized” refers to an antibody or binding protein from a non-human species that has been altered to be more “human-like”, i.e., more similar to human germline sequences. One type of humanized antibody or binding protein is a CDR-grafted antibody or binding protein, in which non-human CDR sequences are introduced into human VH and VL sequences to replace the corresponding human CDR sequences. A humanized antibody or binding protein also encompasses a variant, derivative, analog or fragment of an antibody or binding protein that comprises framework region (FR) sequences having substantially (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% identity to) the amino acid sequence of a human antibody and at least one CDR having substantially the amino acid sequence of a non-human antibody. A humanized antibody or binding protein may comprise substantially all of at least one variable domain (Fab, Fab′, F(ab′) 2, FabC, Fv) in which the sequence of all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin (i.e., donor antibody) and the sequence of all or substantially all of the FR regions are those of a human immunoglobulin. The humanized antibody or binding protein also may include the CH1, hinge, CH2, CH3, and/or CH4 regions of the heavy chain. In an embodiment, a humanized antibody or binding protein may also comprise at least a portion of a human immunoglobulin Fc region. In some embodiments, a humanized antibody or binding protein only contains a humanized light chain. In some embodiments, a humanized antibody or binding protein only contains a humanized heavy chain. In some embodiments, a humanized antibody or binding protein only contains a humanized variable domain of a light chain and/or humanized variable domain of a heavy chain. In some embodiments, a humanized antibody or binding protein contains a humanized light chain as well as at least a variable domain of a heavy chain. In some embodiments, a humanized antibody or binding protein contains a humanized heavy chain as well as at least a variable domain of a light chain

The term “anti-idiotypic antibody” refers to an antibody raised against the amino acid sequence of the antigen combining site of another antibody. Anti-idiotypic antibodies may be administered to enhance an immune response against an antigen.

The term “biological activity” refers to any one or more biological properties of a molecule (whether present naturally as found in vivo, or provided or enabled by recombinant means). Biological properties include, but are not limited to, binding a receptor, inducing cell proliferation, inhibiting cell growth, inducing other cytokines, inducing apoptosis, and enzymatic activity.

The term “neutralizing” refers to counteracting the biological activity of an antigen when a binding protein specifically binds to the antigen. In an embodiment, a neutralizing binding protein binds to an antigen (e.g., VEGF and/or PDGF or their receptors) and reduces the antigen's biological activity by at least about 20%, about 40%, about 60%, about 80%, about 85%, about 90%, about 95%, or about 100% (or any percentage in between).

The term “specificity” refers to the ability of a binding protein to selectively bind an antigen.

The term “affinity” refers to the strength of the interaction between a binding protein and an antigen, and is determined by the sequence of the CDRs of the binding protein as well as by the nature of the antigen, such as its size, shape, and/or charge. Binding proteins may be selected for affinities that provide desired therapeutic end-points while minimizing negative side-effects. Affinity may be measured using methods known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).

The term “potency” refers to the ability of a binding protein to achieve a desired effect, and is a measurement of its therapeutic efficacy. Potency may be assessed using methods known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).

The term “cross-reactivity” refers to the ability of a binding protein to bind a target other than that against which it was raised. Generally, a binding protein will bind its target tissue(s)/antigen(s) with an appropriately high affinity, but will display an appropriately low affinity for non-target normal tissues. Methods of assessing cross-reactivity are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).

The term “biological function” refers the specific in vitro or in vivo actions of a binding protein. Binding proteins may target several classes of antigens and achieve desired therapeutic outcomes through multiple mechanisms of action. Binding proteins may target soluble proteins, cell surface antigens, as well as extracellular protein deposits. Binding proteins may agonize, antagonize, or neutralize the activity of their targets. Binding proteins may assist in the clearance of the targets to which they bind, or may result in cytotoxicity when bound to cells. Portions of two or more antibodies may be incorporated into a multivalent format to achieve distinct functions in a single binding protein molecule. The in vitro assays and in vivo models used to assess biological function are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).

A “stable” binding protein refers to one in which the binding protein retains some level of its physical stability, chemical stability and/or biological activity upon storage. Methods of stabilizing binding proteins and assessing their stability at various temperatures are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).

The term “solubility” refers to the ability of a protein to remain dispersed within an aqueous solution. The solubility of a protein in an aqueous formulation depends upon the proper distribution of hydrophobic and hydrophilic amino acid residues, and therefore, solubility can correlate with the production of correctly folded proteins. A person skilled in the art will be able to detect an increase or decrease in solubility of a binding protein using routine HPLC techniques and methods known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).

Binding proteins may be produced using a variety of host cells or may be produced in vitro, and the relative yield per effort determines the “production efficiency.” Factors influencing production efficiency include, but are not limited to, host cell type (prokaryotic or eukaryotic), choice of expression vector, choice of nucleotide sequence, and methods employed. The materials and methods used in binding protein production, as well as the measurement of production efficiency, are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).

The term “immunogenicity” means the ability of a substance to induce an immune response. Administration of a therapeutic binding protein may result in a certain incidence of an immune response. Potential elements that might induce immunogenicity in a multivalent format may be analyzed during selection of the parental antibodies, and steps to reduce such risk can be taken to optimize the parental antibodies prior to incorporating their sequences into a multivalent binding protein format. Methods of reducing the immunogenicity of antibodies and binding proteins are known to one skilled in the art (U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).

The terms “label” and “detectable label” refer to a moiety attached to a member of a specific binding pair, such as an antibody/binding protein or its analyte to render a reaction (e.g., binding) between the members of the specific binding pair, detectable. The labeled member of the specific binding pair is referred to as “detectably labeled.” Thus, the term “labeled binding protein” refers to a protein with a label incorporated that provides for the identification of the binding protein. In an embodiment, the label is a detectable marker that can produce a signal that is detectable by visual or instrumental means, e.g., incorporation of a radiolabeled amino acid or attachment to a polypeptide of biotinyl moieties that can be detected by marked avidin (e.g., streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or colorimetric methods). Examples of labels for polypeptides include, but are not limited to, the following: radioisotopes or radionuclides (e.g., ³H, ¹⁴C, ³⁵S, ⁹⁰Y, ⁹⁹Tc, ¹¹¹In, ¹²⁵I, ¹³¹I, ¹⁷⁷Lu, ¹⁶⁶Ho, or ¹⁵³Sm); chromogens, fluorescent labels (e.g., FITC, rhodamine, lanthanide phosphors), enzymatic labels (e.g., horseradish peroxidase, luciferase, alkaline phosphatase); chemiluminescent markers; biotinyl groups; predetermined polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags); and magnetic agents, such as gadolinium chelates. Representative examples of labels commonly employed for immunoassays include moieties that produce light, e.g., acridinium compounds, and moieties that produce fluorescence, e.g., fluorescein. In this regard, the moiety itself may not be detectably labeled but may become detectable upon reaction with yet another moiety.

The term “conjugate” refers to a binding protein that is chemically linked to a second chemical moiety, such as a therapeutic or cytotoxic agent. The term “agent” includes a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials. In an embodiment, the therapeutic or cytotoxic agents include, but are not limited to, pertussis toxin, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. When employed in the context of an immunoassay, the conjugate antibody may be a detectably labeled antibody used as the detection antibody.

The terms “crystal” and “crystallized” refer to a binding protein (e.g., an antibody), or antigen binding portion thereof, that exists in the form of a crystal. Crystals are one form of the solid state of matter, which is distinct from other forms such as the amorphous solid state or the liquid crystalline state. Crystals are composed of regular, repeating, three-dimensional arrays of atoms, ions, molecules (e.g., proteins such as antibodies), or molecular assemblies (e.g., antigen/antibody complexes). These three-dimensional arrays are arranged according to specific mathematical relationships that are well-understood in the field. The fundamental unit, or building block, that is repeated in a crystal is called the asymmetric unit. Repetition of the asymmetric unit in an arrangement that conforms to a given, well-defined crystallographic symmetry provides the “unit cell” of the crystal. Repetition of the unit cell by regular translations in all three dimensions provides the crystal. (See Giege and Ducruix (1999) CRYSTALLIZATION OF NUCLEIC ACIDS AND PROTEINS, A PRACTICAL APPROACH, 2nd ed., pp. 20 1-16, Oxford University Press, NY, N.Y.).

The term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked One type of vector is a “plasmid,” which refers to a circular double stranded DNA loop into which additional DNA segments may be ligated. Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. Other vectors include RNA vectors. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Certain vectors are capable of directing the expression of genes to which they are operatively linked Such vectors are referred to herein as “recombinant expression vectors” (or simply, “expression vectors”). In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, “plasmid” and “vector” may be used interchangeably as the plasmid is the most commonly used form of vector. However, other forms of expression vectors are also included, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions. A group of pHybE vectors (e.g., U.S. Pat. No. 8,187,836) may be used for parental antibody and DVD-binding protein cloning. V1, derived from pJP183; pHybE-hCg1,z,non-a V2; and pJP184, may be used for cloning of antibody and DVD heavy chains with a wild type constant region or modified constant region (e.g., a L234, L235, H435A modified IgG1 constant region). V2, derived from pJP191 (with or without modifications to the Kozak site); pHybE-hCk V3, may be used for cloning of antibody and DVD light chains with a kappa constant region. V3, derived from pJP192; pHybE-hCl V2, may be used for cloning of antibody and DVD light chains with a lambda constant region. V4, built with a lambda signal peptide and a kappa constant region, may be used for cloning of DVD light chains with a lambda-kappa hybrid V domain. V5, built with a kappa signal peptide and a lambda constant region, may be used for cloning of DVD light chains with a kappa-lambda hybrid V domain. V7, derived from pJP183; pHybE-hCg1,z,non-a V2, may be used for cloning of antibody and DVD heavy chains with a (234,235 AA) mutant constant region.

The terms “recombinant host cell” or “host cell” refer to a cell into which exogenous, e.g., recombinant, DNA has been introduced. Such terms refer not only to the particular subject cell, but to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” as used herein. In an embodiment, host cells include prokaryotic and eukaryotic cells. In an embodiment, eukaryotic cells include protist, fungal, plant and animal cells. In another embodiment, host cells include but are not limited to the prokaryotic cell line E. coli; mammalian cell lines CHO, HEK 293, COS, NSO, SP2 and PER.C6; the insect cell line Sf9; and the fungal cell Saccharomyces cerevisiae.

The term “transfection” encompasses a variety of techniques commonly used for the introduction of exogenous nucleic acid (e.g., DNA) into a host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like.

The term “cytokine” refers to a protein released by one cell population that acts on another cell population as an intercellular mediator. The term “cytokine” includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the native sequence cytokines.

The term “biological sample” refers to a quantity of a substance from a living thing or formerly living thing Such substances include, but are not limited to, blood, plasma, serum, urine, amniotic fluid, synovial fluid, endothelial cells, leukocytes, monocytes, other cells, organs, tissues, bone marrow, lymph nodes and spleen.

The term “component” refers to an element of a composition. In relation to a diagnostic kit, for example, a component may be a capture antibody, a detection or conjugate antibody, a control, a calibrator, a series of calibrators, a sensitivity panel, a container, a buffer, a diluent, a salt, an enzyme, a co-factor for an enzyme, a detection reagent, a pretreatment reagent/solution, a substrate (e.g., as a solution), a stop solution, and the like that can be included in a kit for assay of a test sample. Thus, a “component” can include a polypeptide or other analyte as above, that is immobilized on a solid support, such as by binding to an anti-analyte (e.g., anti-polypeptide) antibody. Some components can be in solution or lyophilized for reconstitution for use in an assay.

“Control” refers to a composition known to not analyte (“negative control”) or to contain analyte (“positive control”). A positive control can comprise a known concentration of analyte. A “positive control” can be used to establish assay performance characteristics and is a useful indicator of the integrity of reagents (e.g., analytes).

“Predetermined cutoff” and “predetermined level” refer generally to an assay cutoff value that is used to assess diagnostic/prognostic/therapeutic efficacy results by comparing the assay results against the predetermined cutoff/level, where the predetermined cutoff/level already has been linked or associated with various clinical parameters (e.g., severity of disease, progression/nonprogression/improvement, etc.). While the present disclosure may provide exemplary predetermined levels, it is well-known that cutoff values may vary depending on the nature of the immunoassay (e.g., antibodies employed, etc.). It further is well within the ordinary skill of one in the art to adapt the disclosure herein for other immunoassays to obtain immunoassay-specific cutoff values for those other immunoassays based on this disclosure. Whereas the precise value of the predetermined cutoff/level may vary between assays, correlations as described herein (if any) may be generally applicable.

“Pretreatment reagent,” e.g., lysis, precipitation and/or solubilization reagent, as used in a diagnostic assay as described herein refers to one that lyses any cells and/or solubilizes any analyte that is/are present in a test sample. Pretreatment is not necessary for all samples, as described further herein. Among other things, solubilizing the analyte (e.g., polypeptide of interest) may entail release of the analyte from any endogenous binding proteins present in the sample. A pretreatment reagent may be homogeneous (not requiring a separation step) or heterogeneous (requiring a separation step). With use of a heterogeneous pretreatment reagent there is removal of any precipitated analyte binding proteins from the test sample prior to proceeding to the next step of the assay.

“Quality control reagents” in the context of immunoassays and kits described herein, include, but are not limited to, calibrators, controls, and sensitivity panels. A “calibrator” or “standard” typically is used (e.g., one or more, such as a plurality) in order to establish calibration (standard) curves for interpolation of the concentration of an analyte, such as an antibody or an analyte. Alternatively, a single calibrator, which is near a predetermined positive/negative cutoff, can be used. Multiple calibrators (i.e., more than one calibrator or a varying amount of calibrator(s)) can be used in conjunction so as to comprise a “sensitivity panel.”

The term “specific binding partner” refers to a member of a specific binding pair. A specific binding pair comprises two different molecules that specifically bind to each other through chemical or physical means. Therefore, in addition to antigen and antibody specific binding, other specific binding pairs can include biotin and avidin (or streptavidin), carbohydrates and lectins, complementary nucleotide sequences, effector and receptor molecules, cofactors and enzymes, enzyme inhibitors and enzymes, and the like. Furthermore, specific binding pairs can include members that are analogs of the original specific binding members, for example, an analyte-analog. Immunoreactive specific binding members include antigens, antigen fragments, and antibodies, including monoclonal and polyclonal antibodies as well as complexes, fragments, and variants (including fragments of variants) thereof, whether isolated or recombinantly produced.

The term “Fc region” refers to the C-terminal region of an immunoglobulin heavy chain, which may be generated by papain digestion of an intact antibody or binding protein. The Fc region may be a native sequence Fc region or a variant Fc region. The Fc region of an immunoglobulin generally comprises two constant domains, a CH2 domain and a CH3 domain, and optionally comprises a CH4 domain. Replacements of amino acid residues in the Fc portion to alter effector function are known in the art (e.g., U.S. Pat. Nos. 5,648,260 and 5,624,821). The Fc region mediates several important effector functions, e.g., cytokine induction, antibody dependent cell mediated cytotoxicity (ADCC), phagocytosis, complement dependent cytotoxicity (CDC), and half-life/clearance rate of antibody or binding protein and antigen-antibody or antigen-binding protein complexes. In some cases these effector functions are desirable for a therapeutic immunoglobulin but in other cases might be unnecessary or even deleterious, depending on the therapeutic objectives.

The term “antigen-binding portion” of a binding protein refers to one or more fragments of a binding protein that retain the ability to specifically bind to an antigen. The antigen-binding function of a binding protein may be performed by fragments of a full-length binding protein, including bispecific, dual specific, or multi-specific formats; for instance, binding to two or more different antigens. Examples of binding fragments encompassed within the term “antigen-binding portion” of an binding protein include (i) an Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) an F(ab′)₂fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody or binding protein, (v) a dAb fragment, which comprises a single variable domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they may be joined, e.g., using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv). Such single chain antibodies or binding proteins are also intended to be encompassed within the term “antigen-binding portion” of an antibody or binding protein. Other forms of single chain antibodies, such as diabodies are also encompassed. In addition, single chain antibodies or binding protein also include “linear” antibodies or binding protein comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen binding regions.

The term “multivalent binding protein” refers to a binding protein comprising two or more antigen binding sites. In an embodiment, the multivalent binding protein is engineered to have three or more antigen binding sites, and may not be a naturally occurring antibody. The term “multispecific binding protein” refers to a binding protein capable of binding two or more related or unrelated targets. In an embodiment, the dual variable domain (DVD) binding proteins provided herein comprise two or more antigen binding sites and are tetravalent or multivalent binding proteins.

The term “linker” refers to an amino acid residue or a polypeptide comprising two or more amino acid residues joined by peptide bonds that are used to link two polypeptides (e.g., two VH or two VL domains) Such linker polypeptides are well known in the art (see, e.g., Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al. (1994) Structure 2:1121-1123). A number of suitable linkers for use in the binding proteins described herein are set out in Table 55. In some embodiments, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10(dR) linker. In some embodiments, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10 linker. In some embodiments, the X1 linker on the heavy chain is an HG-short linker and the X1 linker on the light chain is an LK-long linker.

The terms “Kabat numbering”, “Kabat definitions” and “Kabat labeling” are used interchangeably herein. These terms, which are recognized in the art, refer to a system of numbering amino acid residues which are more variable (i.e., hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody or binding protein, or an antigen binding portion thereof (Kabat et al. (1971) Ann. NY Acad. Sci. 190:382-391 and, Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3. For the light chain variable region, the hypervariable region ranges from amino acid positions 24 to 34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3. In some embodiments, the CDR sequences, framework sequences, and or constant region sequences are identified using Kabat numbering.

The term “CDR” refers to a complementarity determining region within an immunoglobulin variable region sequence. There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the heavy and light chain variable regions. The term “CDR set” refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody or binding protein, but also provides precise residue boundaries defining the three CDRs in each heavy or light chain sequence. These CDRs may be referred to as Kabat CDRs. Chothia and coworkers (Chothia and Lesk (1987) J. Mol. Biol. 196:901-917; Chothia et al. (1989) Nature 342:877-883) found that certain sub-portions within Kabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub-portions were designated as L1, L2 and L3 or H1, H2 and H3 where the “L” and the “H” designates the light chain and the heavy chain regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan (1995) FASEB J. 9:133-139 and MacCallum (1996) J. Mol. Biol. 262(5):732-45). Still other CDR boundary definitions may not strictly follow one of the herein systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, although certain embodiments use Kabat or Chothia defined CDRs.

The term “epitope” refers to a region of an antigen that is specifically bound by a binding protein disclosed herein. In certain embodiments, epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl, and, in certain embodiments, may have specific three dimensional structural characteristics, and/or specific charge characteristics. An antigen or fragment can contain more than one epitope. An epitope may be determined by obtaining an X-ray crystal structure of an antibody:antigen complex and determining which residues on the antigen (e.g., VEGF or PDGF or a receptor) are within a specified distance of residues on the antibody of interest, wherein the specified distance is, 5 Å or less, e.g., 5 Å, 4 Å, 3 Å, 2 Å, 1 Å or less, or any distance in between. In some embodiments, the epitope is defined as a stretch of 8 or more contiguous amino acid residues along the antigen sequence in which at least 50%, 70% or 85% of the residues are within the specified distance of the antibody or binding protein in the X-ray crystal structure.

In certain embodiments, a binding protein specifically binds an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macromolecules. Binding proteins that bind to the same or similar epitopes will likely cross-compete (one prevents the binding or modulating effect of the other). Cross-competition, however, can occur even without partial or complete epitope overlap, e.g., if epitopes are adjacent in three-dimensional space and/or due to steric hindrance.

The term “pharmacokinetic(s)” refers to the process by which a drug is absorbed, distributed, metabolized, and excreted by an organism. To generate a multivalent binding protein molecule with a desired pharmacokinetic profile, parent monoclonal antibodies with similarly desired pharmacokinetic profiles are selected. The PK profiles of the selected parental monoclonal antibodies can be easily determined in rodents using methods known to one skilled in the art (see, e.g., U.S. Pat. No. 7,612,181).

The term “bioavailability” refers to the degree and rate at which a drug is absorbed into a living system or is made available at the site of physiological activity. Bioavailability can be a function of several of the previously described properties, including stability, solubility, immunogenicity and pharmacokinetics, and can be assessed using methods known to one skilled in the art (see, e.g., U.S. Pat. No. 7,612,181).

The term “surface plasmon resonance” refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIAcore® system (BIAcore International AB, a GE Healthcare company, Uppsala, Sweden and Piscataway, N.J.). For further descriptions, see Jönsson et al. (1993) Ann. Biol. Clin. 51:19-26. The term “K_on” refers to the on rate constant for association of a binding protein (e.g., an antibody or DVD-Ig) to the antigen to form the, e.g., DVD-Ig/antigen complex. The term “K_on” also refers to “association rate constant”, or “ka”, as is used interchangeably herein. This value indicating the binding rate of a binding protein to its target antigen or the rate of complex formation between a binding protein, e.g., an antibody, and antigen also is shown by the equation below:

Antibody (“Ab”)+Antigen (“Ag”)→Ab-Ag

The term “K_off” refers to the off rate constant for dissociation, or “dissociation rate constant”, of a binding protein (e.g., an antibody or DVD-Ig) from the, e.g., DVD-Ig/antigen complex as is known in the art. This value indicates the dissociation rate of a binding protein, e.g., an antibody, from its target antigen or separation of Ab-Ag complex over time into free antibody and antigen as shown by the equation below:

Ab+Ag←Ab-Ag

The terms “K_d” and “equilibrium dissociation constant” may refer to the value obtained in a titration measurement at equilibrium, or by dividing the dissociation rate constant (K_off) by the association rate constant (K_on). The association rate constant, the dissociation rate constant and the equilibrium dissociation constant, are used to represent the binding affinity of a binding protein (e.g., an antibody or DVD-Ig) to an antigen. Methods for determining association and dissociation rate constants are well known in the art. Using fluorescence-based techniques offers high sensitivity and the ability to examine samples in physiological buffers at equilibrium. Other experimental approaches and instruments such as a BIAcore® (biomolecular interaction analysis) assay, can be used (e.g., instrument available from BIAcore International AB, a GE Healthcare company, Uppsala, Sweden). Additionally, a KinExA® (Kinetic Exclusion Assay) assay, available from Sapidyne Instruments (Boise, Id.), can also be used.

The term “variant” refers to a polypeptide that differs from a given polypeptide in amino acid sequence by the addition (e.g., insertion), deletion, or conservative substitution of amino acids, but that retains the biological activity of the given polypeptide (e.g., a variant VEGF antibody can compete with anti-VEGF antibody for binding to VEGF). A conservative substitution of an amino acid, i.e., replacing an amino acid with a different amino acid of similar properties (e.g., hydrophilicity and degree and distribution of charged regions) is recognized in the art as typically involving a minor change. These minor changes can be identified, in part, by considering the hydropathic index of amino acids, as understood in the art (see, e.g., Kyte et al. (1982) J. Mol. Biol. 157: 105-132). The hydropathic index of an amino acid is based on a consideration of its hydrophobicity and charge. It is known in the art that amino acids of similar hydropathic indexes in a protein can be substituted and the protein still retains protein function. In one aspect, amino acids having hydropathic indexes of ±2 are substituted. The hydrophilicity of amino acids also can be used to reveal substitutions that would result in proteins retaining biological function. A consideration of the hydrophilicity of amino acids in the context of a peptide permits calculation of the greatest local average hydrophilicity of that peptide, a useful measure that has been reported to correlate well with antigenicity and immunogenicity (see, e.g., U.S. Pat. No. 4,554,101). Substitution of amino acids having similar hydrophilicity values can result in peptides retaining biological activity, for example immunogenicity, as is understood in the art. In one aspect, substitutions are performed with amino acids having hydrophilicity values within ±2 of each other. Both the hydrophobicity index and the hydrophilicity value of amino acids are influenced by the particular side chain of that amino acid. Consistent with that observation, amino acid substitutions that are compatible with biological function are understood to depend on the relative similarity of the amino acids, and particularly the side chains of those amino acids, as revealed by the hydrophobicity, hydrophilicity, charge, size, and other properties. The term “variant” also includes polypeptide or fragment thereof that has been differentially processed, such as by proteolysis, phosphorylation, or other post-translational modification, yet retains its biological activity or antigen reactivity, e.g., the ability to bind to VEGF. The term “variant” encompasses fragments of a variant unless otherwise defined. A variant may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, or 75% identical to the wild type sequence.

Use of Disclosed Binding Proteins in Treating Various Diseases

The binding protein molecules provided herein are useful as therapeutic molecules to treat various diseases, e.g., wherein the targets that are recognized by the binding proteins are detrimental. Such binding proteins may bind one or more targets involved in a specific disease.

Without limiting the disclosure, further information on certain disease conditions is provided.

1. Age-Related Macular Degeneration (AMD)

In various embodiments, one or more of the binding proteins disclosed herein that are capable of binding to VEGF and PDGF and/or their cognate receptors (e.g., a combination of an anti-VEGF and an anti-PDGF binding protein, or a multispecific binding protein capable of targeting both VEGF and PDGF) can be used to treat AMD. In some embodiments, any of the binding proteins disclosed herein can be used to treat AMD, or a binding protein comprising the CDR and/or variable domain sequences from any of the binding disclosed herein. In certain embodiments, the binding protein used to treat AMD is one or more of the binding proteins listed in Tables 27-30, 38-42, 46-50, or 55-58. In certain embodiments, the binding protein used to treat AMD is one or more of the binding proteins listed in Tables 56-58. In certain embodiments, the binding protein is PR-1572102, PR-1572105, or PR-1610561.

Age-Related Macular Degeneration (AMD) is the leading cause of irreversible vision loss in individuals over the age of 50 in the United States and a major cause of blindness worldwide. Globally more than 160 million people suffer from AMD. AMD is an age-related ocular disease that results in blindness due to damage to the macula; the region of the retina responsible for sharp central vision. It is associated with the degeneration of the macula and in particular the retinal pigmented epithelium (RPE).

The disease occurs in two forms, the dry or non-exudative AMD form and the wet or exudative form. The most common form of macular degeneration, dry AMD (non-neovascular), is an early stage of the disease and may result from aging and thinning of macular tissues, deposition of pigment in the macula, or a combination of both processes. Dry AMD is diagnosed when yellowish spots known as drusen accumulate in and around the macula. Drusen are thought to be deposits or debris from nearby deteriorating tissue. The onset of dry AMD is usually associated with age-related changes in Bruch's membrane, a highly specialized matrix for adhesion of retinal pigment epithelial (RPE) cells. These alterations in Bruch's membrane can result in death of RPE cells in the macula, accumulation of drusen, and damage to photoreceptor cells. Gradual central loss of vision may occur with dry AMD, but the symptoms are typically not nearly as severe as with the wet form of the disease. Dry AMD can slowly progress to late-stage geographic atrophy (GA) resulting in a gradual deterioration of retinal cells that can cause severe vision loss. Dry AMD (both early and late stage) is the most common form of AMD representing more than 85% of all diagnosed cases.

The wet or exudative form of the disease usually results in more severe vision loss. Wet macular degeneration mainly affects central vision, causing “blind spots” in the central line of vision. Approximately 10-15% of dry AMD cases progress to wet AMD. Wet AMD is characterized by new blood vessel growth beneath the retina. Clinically, this is referred to as choroidal neovascularization (CNV). Wet AMD accounts for about 10-15% of all cases of AMD. Progression of dry AMD to wet AMD is marked by the development of neovascularization within Bruch's membrane, as well as in the subretinal space. Wet AMD occurs when abnormal blood vessels behind the retina grow under the macula. These new blood vessels tend to be fragile and often leak blood and fluid. The blood and fluid result in macula inflammation and thickening and disrupts the connection between the photoreceptors and the RPE, leading to vision loss. In wet AMD, neovascularization is stimulated by many angiogenic factors; including vascular endothelial growth factor (VEGF), which appears to be the primary angiogenic factor in patients with wet AMD (Miller et al. (1994) Am. J. Pathol. 145(3):574-584). Additionally, VEGF can act as a powerful endothelial cell mitogen, increasing vascular permeability. The primary goals of current AMD treatment are to block or inhibit choroidal neovascularization (CNV) and macular edema following retinal vein occlusion (RVO), stabilize or improve vision, and to reduce the occurrence of adverse effects.

Anti-VEGF agents may reduce choroidal neovascularization (CNV) and leakage, but do not lead to regression of CNV itself. Emerging evidence indicates the important role of pericytes on the maturation of new blood vessels. Anti-PDGF agents can directly block pericyte recruitment and prevent the maturation and stabilization of choroidal neovascularization. If pericytes can be stripped away from new blood vessels, vascular endothelial cells may become more susceptible to VEGF blockade, ultimately leading to a regression of angiogenesis.

Among other functions, VEGF stimulates endothelial cell proliferation/growth, increases vascular permeability, and promotes leukocyte activity capable of damaging retinal endothelial cells (Leung et al. (1989) Science 246(4935):1306-9). In wet AMD, retinal tissues produce and release angiogenic growth factors such as VEGF that bind to specific receptors located on the endothelial cells of nearby preexisting blood vessels. Activation of endothelial cells can result in the release of enzymes targeting tight junctions. These enzymes act on the basement membrane surrounding all existing blood vessels and lead to the formation of holes in the membrane. The endothelial cells proliferate and migrate out through these holes toward the diseased tissue. Specialized adhesion molecules such as integrins promote formation of new blood vessel sprouts, and matrix metalloproteinases (MMPs) dissolve the tissue in front of the sprouting vessel tip in order to accommodate it. Finally, smooth muscle cells (pericytes) provide structural support to these newly formed blood vessel loops and blood flow begins in these new immature vessels. Thus, VEGF may serve as a rate-limiting step in angiogenesis. VEGF also increases vascular permeability by leukocyte-mediated endothelial cell injury, formation of fenestrations, and the dissolution of tight junctions. This leads to intra-retinal fluid accumulation and a detrimental effect on visual acuity. Moreover, VEGF can also cause the release of inflammatory cytokines that further reinforce the cycle of inflammation and angiogenesis.

In some embodiments, treatments inhibiting VEGF, PDGF, and/or the receptors (in a combination therapy or in one molecule) using the binding proteins disclosed herein may offer improved options for patients with wet AMD, while reducing the number of injections, reducing the safety concerns associated with multiple injections, and reducing cost.

2. Diabetic Retinopathy

Diabetic retinopathy is the most common diabetic eye disease and a leading cause of blindness in American adults. It is caused by changes in the blood vessels of the retina. In some people with diabetic retinopathy, blood vessels may swell and leak fluid. In other people, abnormal new blood vessels grow on the surface of the retina. The retina is the light-sensitive tissue at the back of the eye. A healthy retina is necessary for good vision.

Diabetic retinopathy has four stages: (1) Mild Nonproliferative Retinopathy. At this earliest stage, microaneurysms occur. They are small areas of balloon-like swelling in the retina's tiny blood vessels. (2) Moderate Nonproliferative Retinopathy. As the disease progresses, some blood vessels that nourish the retina are blocked. (3) Severe Nonproliferative Retinopathy. Many more blood vessels are blocked, depriving several areas of the retina with their blood supply. These areas of the retina send signals to the body to grow new blood vessels for nourishment. (4) Proliferative Retinopathy. At this advanced stage, the signals sent by the retina for nourishment trigger the growth of new blood vessels. This condition is called proliferative retinopathy. These new blood vessels are abnormal and fragile. They grow along the retina and along the surface of the clear, vitreous gel that fills the inside of the eye. By themselves, these blood vessels do not cause symptoms or vision loss. However, they have thin, fragile walls. If they leak blood, severe vision loss and even blindness can result.

Blood vessels damaged from diabetic retinopathy can cause vision loss in two ways: (1) Fragile, abnormal blood vessels can develop and leak blood into the center of the eye, blurring vision. This is proliferative retinopathy and is the fourth and most advanced stage of the disease. (2) Fluid can leak into the center of the macula, the part of the eye where sharp, straight-ahead vision occurs. The fluid makes the macula swell, blurring vision. This condition is called macular edema. It can occur at any stage of diabetic retinopathy, although it is more likely to occur as the disease progresses. About half of the people with proliferative retinopathy also have macular edema.

In some embodiments, the binding proteins disclosed herein may be used to inhibit VEGF, PDGF, and/or the receptors (in a combination therapy or in one molecule) to treat diabetic retinopathy.

In various embodiments, other diseases may be treated using the binding proteins disclosed herein, including but not limited to other eye disorders, cancers, fibrosis, renal disease, pathologic angiogenesis, wound healing, bone formation, or other diseases associated with aberrant (e.g., elevated) PDGF and/or VEGF expression.

Pharmaceutical Compositions

In various embodiments, pharmaceutical compositions comprising one or more of the binding proteins disclosed herein, either alone or in combination with other prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers, are provided. The pharmaceutical compositions comprising binding proteins provided herein are for use in, but not limited to, diagnosing, detecting, or monitoring a disorder, in preventing, treating, managing, or ameliorating a disorder or one or more symptoms thereof, and/or in research. The formulation of pharmaceutical compositions, either alone or in combination with prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers, are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).

Methods of administering a pharmaceutical composition or a prophylactic or therapeutic agent provided herein include, but are not limited to, parenteral administration (e.g., intradermal, intramuscular, intraperitoneal, intravitreous, intravenous and subcutaneous), epidural administration, intratumoral administration, mucosal administration (e.g., intranasal and oral routes) and pulmonary administration (e.g., aerosolized compounds administered with an inhaler or nebulizer). In an embodiment, the methods of administering a pharmaceutical composition or a prophylactic or therapeutic agent provided herein include topical eye drops, gels, or creams. The formulation of pharmaceutical compositions for specific routes of administration, and the materials and techniques necessary for the various methods of administration are available and known to one skilled in the art (U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).

Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic 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. The term “dosage unit form” refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing 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 provided herein are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic or prophylactic 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 binding protein provided herein is 0.1-20 mg/kg, for example, 1-10 mg/kg. 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 may 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.

Combination Therapy

In various embodiments, a binding protein provided herein may also be administered with one or more additional therapeutic agents useful in the treatment of various diseases, the additional agent being selected by the skilled artisan for its intended purpose. For example, the additional agent can be a therapeutic agent art-recognized as being useful to treat the disease or condition being treated by the antibody provided herein, such as AMD. The combination can also include more than one additional agent, e.g., two or three additional agents.

Combination therapy agents include, but are not limited to imaging agents, cytotoxic agents, angiogenesis inhibitors, kinase inhibitors, tyrosine kinase inhibitors, tyrosine kinase receptor inhibitors, co-stimulation molecule blockers, adhesion molecule blockers, anti-cytokine antibodies or functional fragments thereof, methotrexate, cyclosporin, rapamycin, FK506, detectable labels or reporters, TNF antagonists, antirheumatics, muscle relaxants, narcotics, non-steroid anti-inflammatory drugs (NSAIDs), analgesics, anesthetics, local anesthetics, sedatives, a hyaluronidase enzyme, neuromuscular blockers, antimicrobials, antipsoriatics, corticosteriods, anabolic steroids, erythropoietin, immunizations, immunoglobulins, immunosuppressives, growth hormones, hormone replacement drugs, radiopharmaceuticals, antidepressants, antipsychotics, stimulants, asthma medications, beta agonists, inhaled steroids, epinephrine or analogs, cytokines, or cytokine antagonists.

Diagnostics

The disclosure herein also provides, in various embodiments, diagnostic applications including, but not limited to, diagnostic assay methods, diagnostic kits containing one or more binding proteins, and adaptation of the methods and kits for use in automated and/or semi-automated systems. The methods, kits, and adaptations provided may be employed in the detection, monitoring, and/or treatment of a disease or disorder in an individual. This is further elucidated below.

The present disclosure also provides a method for determining the presence, amount or concentration of an analyte, or fragment thereof, in a test sample using at least one binding protein as described herein. Any suitable assay as is known in the art can be used in the method. Examples include, but are not limited to, immunoassays and/or methods employing mass spectrometry.

Immunoassays provided by the present disclosure may include sandwich immunoassays, radioimmunoassay (RIA), enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), competitive-inhibition immunoassays, fluorescence polarization immunoassay (FPIA), enzyme multiplied immunoassay technique (EMIT), bioluminescence resonance energy transfer (BRET), and homogenous chemiluminescent assays, among others.

A chemiluminescent microparticle immunoassay, in particular one employing the ARCHITECT® automated analyzer (Abbott Laboratories, Abbott Park, Ill.), is an example of an immunoassay.

Methods employing mass spectrometry are provided by the present disclosure and include, but are not limited to MALDI (matrix-assisted laser desorption/ionization) or by SELDI (surface-enhanced laser desorption/ionization).

Methods for collecting, handling, processing, and analyzing biological test samples using immunoassays and mass spectrometry would be well-known to one skilled in the art, are provided for in the practice of the present disclosure (see, e.g., U.S. Pat. No. 7,612,181).

Kits

In various embodiments, a kit for assaying a test sample for the presence, amount or concentration of an analyte, or fragment thereof, in a test sample is also provided. The kit comprises at least one component for assaying the test sample for the analyte, or fragment thereof, and instructions for assaying the test sample for the analyte, or fragment thereof. The at least one component for assaying the test sample for the analyte, or fragment thereof, can include a composition comprising a binding protein, as disclosed herein, and/or an anti-analyte binding protein (or a fragment, a variant, or a fragment of a variant thereof), which is optionally immobilized on a solid phase.

Optionally, the kit may comprise a calibrator or control, which may comprise isolated or purified analyte. The kit can comprise at least one component for assaying the test sample for an analyte by immunoassay and/or mass spectrometry. The kit components, including the analyte, binding protein, and/or anti-analyte binding protein, or fragments thereof, may be optionally labeled using any art-known detectable label. The materials and methods for the creation provided for in the practice of the present disclosure would be known to one skilled in the art (see, e.g., U.S. Pat. No. 7,612,181).

The kit (or components thereof), as well as the method of determining the presence, amount or concentration of an analyte in a test sample by an assay, such as an immunoassay as described herein, can be adapted for use in a variety of automated and semi-automated systems (including those wherein the solid phase comprises a microparticle), as described, for example, in U.S. Pat. Nos. 5,089,424 and 5,006,309, and as commercially marketed, for example, by Abbott Laboratories (Abbott Park, Ill.) as ARCHITECT®.

Other platforms available from Abbott Laboratories include, but are not limited to, AxSYM®, IMx® (see, for example, U.S. Pat. No. 5,294,404, PRISM®, EIA (bead), and Quantum™ II, as well as other platforms. Additionally, the assays, kits and kit components can be employed in other formats, for example, on electrochemical or other hand-held or point-of-care assay systems. The present disclosure is, for example, applicable to the commercial Abbott Point of Care (i-STATED, Abbott Laboratories) electrochemical immunoassay system that performs sandwich immunoassays Immunosensors and their methods of manufacture and operation in single-use test devices are described, for example in, U.S. Pat. Nos. 5,063,081, 7,419,821, 7,682,833, 7,723,099, and 9,035,027; and U.S. Publication No. 20040018577.

Sequences

Table 1 discloses amino acid and nucleotide sequences encoding VEGF-A from different human isoforms and different species. Table 2 discloses amino acid and nucleotide sequences encoding PDGF-BB from different human isoforms and different species. Table 3 discloses human IgG heavy chain and light chain constant domains, including sequences with the indicated amino acid modifications relative to the wild-type sequence. In various embodiments, the constant domains listed in Table 3 can be used with any of the binding proteins disclosed herein. The variable domains of the binding proteins disclosed herein may be attached to constant regions of any immunoglobulin species, isotypes, or mutants. Exemplary modifications in constant domain mutants include those with amino acid mutations intended to increase or reduce constant domain interactions with Fc-gamma receptors, C1q and FcRn, and/or mutations intended to modulate protein stability or valency (full-length and half molecule, heterodimer molecule, etc.). Tables 4 and 5 disclose exemplary heavy and light chain acceptor framework sequences that can be used with any of the CDR sets disclosed herein (i.e., heavy chain acceptor sequences paired with any of the heavy chain CDRs 1-3 disclosed herein, and/or light chain acceptor sequences paired with any of the light chain CDRs 1-3 disclosed herein) to form functional binding sites for PDGF, VEGF, and/or their cognate receptors.

TABLE 1

Amino Acid and Nucleotide Sequences for VEGF-A

Sequence
Sequence

Kind of Sequence
Identifier
123456789012345678901234567890

Human VEGF-A 165
SEQ ID NO:
APMAEGGGQNHHEVVKFMDVYQRSYCHPIE

Amino Acid Sequence
253
TLVDIFQEYPDEIEYIFKPSCVPLMRCGGC

CNDEGLECVPTEESNITMQIMRIKPHQGQH

IGEMSFLQHNKCECRPKKDRARQENPCGPC

SERRKHLFVQDPQTCKCSCKNTDSRCKARQ

LELNERTCRCDKPRR

Human VEGF-A 121
SEQ ID NO:
APMAEGGGQNHHEVVKFMDVYQRSYCHPIE

Amino Acid Sequence
254
TLVDIFQEYPDEIEYIFKPSCVPLMRCGGC

CNDEGLECVPTEESNITMQIMRIKPHQGQH

IGEMSFLQHNKCECRPKKDRARQEKCDKPR

R

Human VEGF-A 110
SEQ ID NO:
APMAEGGGQNHHEVVKFMDVYQRSYCHPIE

Amino Acid Sequence
255
TLVDIFQEYPDEIEYIFKPSCVPLMRCGGC

CNDEGLECVPTEESNITMQIMRIKPHQGQH

IGEMSFLQHNKCECRCDKPRR

Cynomolgus monkey
SEQ ID NO:
APMAEGGGQNHHEVVKFMDVYQRSYCHPIE

VEGF-A 165 Amino Acid
256
TLVDIFQEYPDEIEYIFKPSCVPLMRCGGC

Sequence

CNDEGLECVPTEESNITMQIMRIKPHQGQH

IGEMSFLQHNKCECRPKKDRARQENPCGPC

SERRKHLFVQDPQTCKCSCKNTDSRCKARQ

LELNERTCRCDKPRR

Mouse VEGF-A 164
SEQ ID NO:
APTTEGEQKSHEVIKFMDVYQRSYCRPIET

Amino Acid Sequence
257
LVDIFQEYPDEIEYIFKPSCVPLMRCAGCC

NDEALECVPTSESNITMQIMRIKPHQSQHI

ERMSFLQHSRCECRPKKDRTKPENHCEPCS

ERRKHLFVQDPQTCKCSCKNTDSRCKARQL

ELNERTCRCDKPRR

Rat VEGF-A 164 Amino
SEQ ID NO:
APTTEGEQKAHEVVKFMDVYQRSYCRPIET

Acid Sequence
258
LVDIFQEYPDEIEYIFKPSCVPLMRCAGCC

NDEALECVPTSESNVTMQIMRIKPHQSQHI

GEMSFLQHSRCECRPKKDRTKPENHCEPCS

ERRKHLFVQDPQTCKCSCKNTDSRCKARQL

ELNERTCRCDKPRR

Rabbit VEGF-A Amino
SEQ ID NO:
MNFLLSWVHWSLALLLYLHHAKWSQAAPMA

Acid Sequence
259
EEGDNKPHEVVKFMEVYRRSYCQPIETLVD

IFQEYPDEIEYIFKPSCVPLVRCGGCCNDE

SLECVPTEEFNVTMQIMRIKPHQGQHIGEM

SFLQHNKCECRPKKDRARQENPCGPCSERR

KHLFVQDPQTCKCSCKNTDSRCKARQLELN

ERTCRCDKPRR

TABLE 2

Amino Acid and Nucleotide Sequences for PDGF-BB

Sequence
Sequence

Kind of Sequence
Identifier
123456789012345678901234567890

Human PDGF-BB Amino
SEQ ID NO:
SLGSLTIAEPAMIAECKTRTEVFEISRRLI

Acid Sequence
260
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC

RPTQVQLRPVQVRKIEIVRKKPIFKKATVT

LEDHLACKCETVAAARPVT

Human PDGF-BB-RM
SEQ ID NO:
MNRCWALFLSLCCYLRLVSAEGDPIPEELY

(Retention Motif) Amino
261
EMLSDHSIRSFDDLQRLLHGDPGEEDGAEL

Acid Sequence

DLNMTRSHSGGELESLARGRRSLGSLTIAE

PAMIAECKTRTEVFEISRRLIDRTNANFLV

WPPCVEVQRCSGCCNNRNVQCRPTQVQLRP

VQVRKIEIVRKKPIFKKATVTLEDHLACKC

ETVAAARPVTRSPGGSQEQRAKTPQTRVTI

RTVRVRRPPKGKHRKFKHTHDKTALKETLG

A

Cynomolgus monkey
SEQ ID NO:
SLGSLTVAEPAMIAECKTRTEVFEISRRLI

PDGF-BB Amino Acid
262
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC

Sequence

RPTQVQLRPVQVRKIEIVRKKPIFKKATVT

LEDHLACKCETVAAARPVT

Mouse PDGF-BB Amino
SEQ ID NO:
SLGSLAAAEPAVIAECKTRTEVFQISRNLI

Acid Sequence
263
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC

RASQVQMRPVQVRKIEIVRKKPIFKKATVT

LEDHLACKCETIVTPRPVT

Rat PDGF-BB Amino
SEQ ID NO:
SLGSLAAAEPAVIAECKTRTEVFQISRNLI

Acid Sequence
264
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC

RASQVQMRPVQVRKIEIVRKKPVFKKATVT

LEDHLACKCETVVTPRPVT

Rabbit PDGF-BBA Amino
SEQ ID NO:
SLGSLAAAEPAVIAECKTRTEVFQISRNLI

Acid Sequence
265
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC

RASQVQMRPVQVRKIEIVRKKPVFKKATVT

LEDHLACKCETVVTPRPVT

TABLE 3

Amino Acid Sequences of Human IgG Heavy Chain and

Light Chain Constant Domains

Sequence
Sequence

Protein
Identifier
123456789012345678901234567890

Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK

region
266
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS

GLYSLSSVVTVPSSSLGTQTYICNVNHKPS

NTKVDKKVEPKSCDKTHTCPPCPAPELLGG

PSVFLFPPKPKDTLMISRTPEVTCVVVDVS

HEDPEVKFNWYVDGVEVHNAKTKPREEQYN

STYRVVSVLTVLHQDWLNGKEYKCKVSNKA

LPAPIEKTISKAKGQPREPQVYTLPPSREE

MTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYKTTPPVLDSDGSFFLYSKLTVDKSRW

QQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK

region L234A, L235A
267
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS

GLYSLSSVVTVPSSSLGTQTYICNVNHKPS

NTKVDKKVEPKSCDKTHTCPPCPAPEAAGG

PSVFLFPPKPKDTLMISRTPEVTCVVVDVS

HEDPEVKFNWYVDGVEVHNAKTKPREEQYN

STYRVVSVLTVLHQDWLNGKEYKCKVSNKA

LPAPIEKTISKAKGQPREPQVYTLPPSREE

MTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYKTTPPVLDSDGSFFLYSKLTVDKSRW

QQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK

region L234A, L235A,
268
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS

H435A

GLYSLSSVVTVPSSSLGTQTYICNVNHKPS

NTKVDKKVEPKSCDKTHTCPPCPAPEAAGG

PSVFLFPPKPKDTLMISRTPEVTCVVVDVS

HEDPEVKFNWYVDGVEVHNAKTKPREEQYN

STYRVVSVLTVLHQDWLNGKEYKCKVSNKA

LPAPIEKTISKAKGQPREPQVYTLPPSREE

MTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYKTTPPVLDSDGSFFLYSKLTVDKSRW

QQGNVFSCSVMHEALHNAYTQKSLSLSPGK

Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK

region L234A, L235A,
269
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS

H435R

GLYSLSSVVTVPSSSLGTQTYICNVNHKPS

NTKVDKKVEPKSCDKTHTCPPCPAPEAAGG

PSVFLFPPKPKDTLMISRTPEVTCVVVDVS

HEDPEVKFNWYVDGVEVHNAKTKPREEQYN

STYRVVSVLTVLHQDWLNGKEYKCKVSNKA

LPAPIEKTISKAKGQPREPQVYTLPPSREE

MTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYKTTPPVLDSDGSFFLYSKLTVDKSRW

QQGNVFSCSVMHEALHNRYTQKSLSLSPGK

Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK

region C226A, C229A,
270
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS

N297A, F405R (Half

GLYSLSSVVTVPSSSLGTQTYICNVNHKPS

body)

NTKVDKKVEPKSCDKTHTAPPAPAPELLGG

PSVFLFPPKPKDTLMISRTPEVTCVVVDVS

HEDPEVKFNWYVDGVEVHNAKTKPREEQYA

STYRVVSVLTVLHQDWLNGKEYKCKVSNKA

LPAPIEKTISKAKGQPREPQVYTLPPSREE

MTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYKTTPPVLDSDGSFRLYSKLTVDKSRW

QQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Ig Kappa constant region
SEQ ID NO:
RTVAAPSVFIFPPSDEQLKSGTASVVCLLN

271
NFYPREAKVQWKVDNALQSGNSQESVTEQD

SKDSTYSLSSTLTLSKADYEKHKVYACEVT

HQGLSSPVTKSFNRGEC

Ig Lambda constant region
SEQ ID NO:
GQPKAAPSVTLFPPSSEELQANKATLVCLI

272
SDFYPGAVTVAWKADSSPVKAGVETTTPSK

QSNNKYAASSYLSLTPEQWKSHRSYSCQVT

HEGSTVEKTVAPTECS

TABLE 4

Amino Acid Sequences of Heavy Chain Acceptor Frameworks

Protein region/

SEQ ID
Closest
Amino Acid Sequence

NO:
Germline Family
12345678901234567890123456789012

273
VH3-7 FR1
EVQLVESGGGLVQPGGSLRLSCAASGFTFS

274
VH3-7 FR2
WVRQAPGKGLEWVA

275
VH3-7 FR3
RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR

276
JH4 FR4
WGQGTLVTVSS

277
VH3 CONSENUSUS FR1
EVQLVESGGGLVQPGGSLRLSCAASGFTFS

278
VH3 CONSENUSUS FR2
WVRQAPGKGLEWVS

279
VH3 CONSENUSUS FR3
RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

280
JH4 FR4
WGQGTLVTVSS

281
VH1-46 FR1
QVQLVQSGAEVKKPGASVKVSCKASGYTFT

282
VH1-46 FR2
WVRQAPGQGLEWMG

283
VH1-46 FR3
RVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR

284
JH4 FR4
WGQGTLVTVSS

285
VH3-30 FR1
QVQLVESGGGVVQPGRSLRLSCAASGFTFS

286
VH3-30 FR2
WVRQAPGKGLEWVA

287
VH3-30 FR3
RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

288
JH3 FR4
WGQGTMVTVSS

289
VH3 CONSENUSUS FR1
EVQLVESGGGLVQPGGSLRLSCAASGFTFS

290
VH3 CONSENUSUS FR2
WVRQAPGKGLEWVS

291
VH3 CONSENUSUS FR3
RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR

292
JH3 FR4
WGQGTMVTVSS

293
VH2-70/JH6 FR1
EVTLRESGPALVKPTQTLTLTCTFSGFSLS

294
VH2-70/JH6 FR2
WIRQPPGKALEWLA

295
VH2-70/JH6 FR3
RLTISKDTSKNQVVLTMTNMDPVDTATYYCAR

296
VH2-70/JH6 FR4
WGQGTTVTVSS

297
VH2-26/JH6 FR1
EVTLKESGPVLVKPTETLTLTCTVSGFSLS

298
VH2-26/JH6 FR2
WIRQPPGKALEWLA

299
VH2-26/JH6 FR3
RLTISKDTSKSQVVLTMTNMDPVDTATYYCAR

300
VH2-26/JH6 FR4
WGQGTTVTVSS

301
VH3-72/JH6 FR1
EVQLVESGGGLVQPGGSLRLSCAASGFTFS

302
VH3-72/JH6 FR2
WVRQAPGKGLEWVG

303
VH3-72/JH6 FR3
RFTISRDDSKNSLYLQMNSLKTEDTAVYYCAR

304
VH3-72/JH6 FR4
WGQGTTVTVSS

305
VH3-21/JH6 FR1
EVQLVESGGGLVKPGGSLRLSCAASGFTFS

306
VH3-21/JH6 FR2
WVRQAPGKGLEWVS

307
VH3-21/JH6 FR3
RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR

308
VH3-21/JH6 FR4
WGQGTTVTVSS

309
VH1-69/JH6 FR1
EVQLVQSGAEVKKPGSSVKVSCKASGGTFS

310
VH1-69/JH6 FR2
WVRQAPGQGLEWMG

311
VH1-69/JH6 FR3
RVTITADKSTSTAYMELSSLRSEDTAVYYCAR

312
VH1-69/JH6 FR4
WGQGTTVTVSS

313
VH1-18/JH6 FR1
EVQLVQSGAEVKKPGASVKVSCKASGYTFT

314
VH1-18/JH6 FR2
WVRQAPGQGLEWMG

315
VH1-18/JH6 FR3
RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR

316
VH1-18/JH6 FR4
WGQGTTVTVSS

317
IGHV4-59 FR1
EVQLQESGPGLVKPSETLSLTCTVSGGSIS

318
IGHV4-59 FR2
WIRQPPGKGLEWIG

319
IGHV4-59 FR3
RVTISVDTSKNQFSLKLSSVTAADTAVYYCAR

320
IGHV4-59/JH FR4
WGQGTLVTVSS

321
IGHV3-66 FW1
EVQLVESGGGLVQPGGSLRLSCAVSGGSIS

322
IGHV3-66 FW2
WIRQAPGKGLEWIG

323
IGHV3-66 FW3
RVTISVDTSKNSFYLQMNSLRAEDTAVYYCAR

324
IGHV3-66/JH FW4
WGQGTLVTVSS

325
IGHV4-59 FR1
EVQLQESGPGLVKPGETLSLTCTVSGGSIS

326
IGHV4-59 FR2
WIRQAPGKGLEWIG

327
IGHV4-59 FR3
RVTISVDTSKNQFYLKLSSVRAEDTAVYYCAR

328
IGHV4-59/JH FR4
WGQGTLVTVSS

329
IGHV5-51 FR1
EVQLVQSGTEVKKPGESLKISCKVSGGSIS

330
IGHV5-51 FR2
WIRQMPGKGLEWIG

331
IGHV5-51 FR3
QVTISVDTSFNTFFLQWSSLKASDTAMYYCAR

332
IGHV5-51/JH FR4
WGQGTMVTVSS

333
IGHV2-70 FR1
EVTLRESGPALVKPTQTLTLTCTVSGGSIS

334
IGHV2-70 FR2
WIRQPPGKGLEWIG

335
IGHV2-70 FR3
RVTISVDTSKNQFVLTMTNMDPVDTATYYCAR

336
IGHV2-70/JH FR4
WGQGTTVTVSS

337
IGHV3-15 FR1
EVQLLESGGGLVKSGGSLRLSCAASGFTFR

338
IGHV3-15 FR2
WVRQAPGKGLEWVA

339
IGHV3-15 FR3
RFTISRDNSKNTLYLQLNSLRAEDTAVYYCAK

340
IGHV3-15/JH FR4
WGQGTMVTVSS

341
IGHV3-43 FR1
EVQLVESGGGVVQPGGSLRLSCAASGFTFG

342
IGHV3-43 FR2
WVRQAPGKGLEWVA

343
IGHV3-43 FR3
RFTISRDNSKNTLYLQLNSLRAEDTAVYYCAK

344
IGHV3-43/JH FR4
WGQGTMVTVSS

TABLE 5

Amino Acid Sequences

of Light Chain Acceptor Frameworks

Protein

region/

SEQ
Closest

ID
Germline
Sequence

NO:
Family
12345678901234567890123456789012

345
O2 FR1
DIQMTQSPSSLSASVGDRVTITC

346
O2 FR2
WYQQKPGKAPKLLIY

347
O2 FR3
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

348
JK2 FR4
FGQGTKLEIK

349
L2 FR1
EIVMTQSPATLSVSPGERATLSC

350
L2 FR2
WYQQKPGQAPRLLIY

351
L2 FR3
GIPARFSGSGSGTEFTLTISSLQSEDFAVYYC

352
JK2 FR4
FGQGTKLEIK

353
B3/JK4 FR1
DIVMTQSPDSLAVSLGERATINC

354
B3/JK4 FR2
WYQQKPGQPPKLLIY

355
B3/JK4 FR3
GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC

356
B3/JK4 FR4
FGGGTKVEIKR

357
L2/JK4 FR1
EIVMTQSPATLSVSPGERATLSC

358
L2/JK4 FR2
WYQQKPGQAPRLLIY

359
L2/JK4 FR3
GIPARFSGSGSGTEFTLTISSLQSEDFAVYYC

360
L2/JK4 FR4
FGGGTKVEIKR

361
L15/JK4 FR1
DIQMTQSPSSLSASVGDRVTITC

362
L15/JK4 FR2
WYQQKPEKAPKSLIY

363
L15/JK4 FR3
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

364
L15/JK4 FR4
FGGGTKVEIKR

365
L5/JK4 FR1
DIQMTQSPSSVSASVGDRVTITC

366
L5/JK4 FR2
WYQQKPGKAPKLLIY

367
L5/JK4 FR3
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

368
L5/JK4 FR4
FGGGTKVEIKR

369
IGLV3-1 FR1
SYELTQPPSVSVSPGQTASITC

370
IGLV3-1 FR2
WYQQKPGQSPVLVIY

371
IGLV3-1 FR3
GIPERFSGSNSGDTATLTISGTQPMDEADYYC

372
IGLV3-1/JL FR4
FGYGTKVTVL

373
IGLV3-1 FR1
SYELTQPPSVSVSPGQTASITC

374
IGLV3-1 FR2
WYQQKPGQSPVLVIY

375
IGLV3-1 FR3
GIPERFSGSNSGDTATLTISGTQPMDEADYYC

376
IGLV3-1/JL FR4
GGGTKLTVLG

377
IGLV3-1 FR1
YELTQPPSVSVSPGQTASITC

378
IGLV3-1 FR2
WYQQKPGQSPVLVIY

379
IGLV3-1 FR3
GIPERFSGSNSGDTATLTISGTQPMDEADYYC

380
IGLV3-1/JL FR4
GGGTKLTVLG

381
IGLV3-1 FR1
LYVLTQPPSVSVSPGQTASITC

382
IGLV3-1 FR2
WYQQKPGQSPVLVIY

383
IGLV3-1 FR3
GIPERFSGSNSGDTATLTISGTQTMDEADYLC

384
IGLV3-1/JL FR4
FGGGTKVTVLG

385
IGKV6D-21 FR1
EYVLTQSPDFQSVTPKEKVTITC

386
IGKV6D-21 FR2
WYQQKPDQSPKLVIY

387
IGKV6D-21 FR3
GVPSRFSGSNSGDDATLTINSLEAEDAATYYC

388
IGKV6D-21/JK
FGQGTKVEIKR

FR4

389
IGKV3D-15 FR1
EYVLTQSPATLSVSPGERATLSC

390
IGKV3D-15 FR2
WYQQKPGQSPRLVIY

391
IGKV3D-15 FR3
DIPARFSGSNSGDEATLTISSLQSEDFAVYYC

392
IGKV3D-15/JK
FGQGTRLEIKR

FR4

393
IGKV4-1 FR1
DYVLTQSPDSLAVSLGERATINC

394
IGKV4-1 FR2
WYQQKPGQSPKLVIY

395
IGKV4-1 FR3
GIPDRFSGSNSGDDATLTISSLQAEDVAVYYC

396
IGKV4-1/JK FR4
FGGGTKVEIKR

397
IGLV3-1 FR1
LPVLTQPPSVSVSPGQTASITC

398
IGLV3-1 FR2
WYQQKPGQSPVLVIY

399
IGLV3-1 FR3
GIPERFSGSNSGNTATLTISGTQTMDEADYLC

400
IGLV3-1/JL FR4
FGGGTKVTVL

401
IGLV3-1 FR1
SYELTQPPSVSVSPGQTASITC

402
IGLV3-1 FR2
WYQQKPGQSPVLVIY

403
IGLV3-1 FR3
GIPERFSGSNSGNTATLTISGTQTMDEADYLC

404
IGLV3-1/JL FR4
FGGGTKLTVL

TABLE A

Select Heavy Chain and Light Chain Variable Domain Sequences

(CDRs in bold)

SEQ

Sequence

ID NO
VD name
12345678901234567890123456789012

1
hBDI-9E8.4 VH
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEW

(PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCA

RIESIGTTYSFDYWGQGTMVTVSS

2
hBDI-9E8.4 VL
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLV

(PDGF)
IYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINID

IVFGGGTKVEIK

3
hBDI-5H1.9
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIRQPPGKALEW

VH (PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCA

RISTGISSYYVMDAWGQGTTVTVSS

4
hBDI-5H1.9 VL
DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVSWYQQKPGQPPKNV

(PDGF)
IYGNDQRPSGVPDRFSGSGSGNSATLTISSLQAEDVAVYFCQSYDSDID

IVFGGGTKVEIK

5
hBDI-9E8.12
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTYGMGVGWIRQAPGKGLEW

VH (PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCA

RIESIGTTYSFDYWGQGTLVTVSS

6
hBDI-9E8.12
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAPKNV

VL (PDGF)
IYADDQRPSGVPSRFSGSGSGNSASLTISSLQPEDFATYYCQSYDINID

IVFGQGTKVEIK

7
hBDI-9E8.9 VH
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEW

(PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCA

RIESIGTTYSFDYWGQGTTVTVSS

8
hBDI-9E8.9 VL
DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVSWYQQKPGQPPKNV

(PDGF)
IYADDQRPSGVPDRFSGSGSGNSASLTISSLQAEDVAVYFCQSYDINID

IVFGGGTKVEIK

9
hBDI-9E8.12
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTYGMGVGWIRQAPGKGLEW

VH (PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCA

RIESIGTTYSFDYWGQGTLVTVSS

10
hBDI-9E8.12
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAPKNV

VL (PDGF)
IYADDQRPSGVPSRFSGSGSGNSASLTISSLQPEDFATYYCQSYDINID

IVFGQGTKVEIK

11
hBDI-9E8.4E
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEW

VH (PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCA

RIESIGTTYSFDYWGQGTMVTVSS

12
hBDI-9E8.4E
EFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLV

VL (PDGF)
IYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINID

IVFGGGTKVEIK

13
hBFU-3E2.1
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIG

VH (PDGF)

RIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCAR

FGARSYFYPMDAWGQGTTVTVSS

14
hBFU-3E2.1 VL
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIY

(PDGF)

GASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTF

GGGTKVEIK

15
CL-33675 VH
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEW

(PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCA

RIESSGPKYSFDYWGQGTMVTVSS

16
CL-33675 VL
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLL

(PDGF)
IYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINID

VVFGGGTKVEIK

17
hBDB-4G8.3
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMG

VH (VEGF)

WINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCAR

TNYYYRSYIFYFDYWGQGTMVTVSS

18
hBDB-4G8.3
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIY

VL (VEGF)

GASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTF

GQGTKLEIK

19
hBDB-4G8.13
EIQLVQSGTEVKKPGESLKISCKASGYTFTNYGMYWVKQMPGKGLEYMG

VH (VEGF)

WINTETGKPTYADDFKGRFTFSLDKSFNTAFLQWSSLKASDTAMYFCAR

TNYYYRSYIFYFDYWGQGTMVTVSS

20
hBDB-4G8.13
ETVLTQSPATLSVSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIY

VL (VEGF)

GASNLESGVPARFSGSGSGTDFTLTISSLQSEDFAVYFCQQSWNDPFTF

GQGTRLEIK

21
hBDB-4G8.14
EIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQAPGKGLEYMG

VH (VEGF)

WINTETGKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFCAR

TNYYYRSYIFYFDYWGQGTLVTVSS

22
hBDB-4G8.14
DTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIY

VL (VEGF)

GASNLESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTF

GQGTKVEIK

23
hBDB-4G8.15
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQAPGKGLEYMG

VH (VEGF)

WINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYFCAR

TNYYYRSYIFYFDYWGQGTLVTVSS

24
hBDB-4G8.15
DTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIY

VL (VEGF)

GASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTF

GQGTKVEIK

25
hBEW-9A8.12
EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMG

VH (VEGF)

WINTETGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR

VDYDGSFWFAYWGQGTLVTVSS

26
hBEW-9A8.12
DTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIH

VL (VEGF)

GASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTF

GQGTKLEIK

27
hBDB-4G8.2
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMG

VH (VEGF)

WINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCAR

TNYYYRSYIFYFDYWGQGTMVTVSS

28
hBDB-4G8.2
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYG

VL (VEGF)

ASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFG

QGTKLEIK

29
hBDB-4G8.4
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMG

VH (VEGF)

WINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCAR

TNYYYRSYIFYFDYWGQGTMVTVSS

30
hBDB-4G8.4
AIQLTQSPSSLSASVGDRVTITCRASESVSTHMHWYQQKPGKAPKLLIY

VL (VEGF)

GASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSWNDPFTF

GQGTKLEIK

31
hBDB-4G8.5
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMG

VH (VEGF)

WINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCAR

TNYYYRSYIFYFDYWGQGTMVTVSS

32
hBDB-4G8.5
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYG

VL (VEGF)

ASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFG

QGTKLEIK

33
hBDB-4G8.12
EIQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMG

VH (VEGF)

WINTETGKPTYADDFKGRFTFTLDTSTSTAYMELRSLRSDDTAVYFCAR

TNYYYRSYIFYFDYWGQGTMVTVSS

34
hBDB-4G8.12
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIY

VL (VEGF)

GASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTF

GQGTKLEIK

35
hBEW-9E10.1
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMG

VH (VEGF)

WIDTETGRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCAR

WSGDTTGIRGPWFAYWGQGTLVTVSS

36
hBEW-9E10.1
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIY

VL (VEGF)

NANGLQNGVPSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTF

GQGTKLEIK

37
hBEW-9E10.6
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMG

VH (VEGF)

WIDTETGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDTAVYYCAR

WSGDTTGIRGPWFAYWGQGTLVTVSS

38
hBEW-9E10.6
DIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIY

VL (VEGF)

NANGLQNGVPSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTF

GQGTKLEIK

39
hBEW-1B10.1
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVA

VH (VEGF)

SITTSGVGTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCAR

GYGAMDAWGQGTTVTVSS

40
hBEW-1B10.1
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIY

VL (VEGF)

AATRLADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTF

GGGTKVEIK

41
hBEW-1E3.4
EIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMYWVKQAPGQGLEYMG

VH (VEGF)

WINTEAGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCAR

WGYISDNSYGWFDYWGQGTLVTVSS

42
hBEW-1E3.4
ATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIY

VL (VEGF)

KASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTF

GQGTKLEIK

43
CL-34565 VH
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGLEWMG

(VEGF)

WIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCAR

TNYYYRNYMFYFDYWGQGTMVTVSS

44
CL-34565 VL
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIY

(VEGF)

GASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITF

GQGTKLEIK

211
hBDI-5H1.12
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTFGMGVGWIRQAPGKGLEW

VH (PDGF)
LANIWWDDDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCA

RISTGISSYYVMDAWGQGTLVTVSS

212
hBDI-5H1.12
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAPKNV

VL (PDGF)
IYGNDQRPSGVPSRFSGSGSGNSATLTISSLQPEDFATYFCQSYDSDID

IVFGQGTKVEIK

It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the methods described herein are obvious and may be made using suitable equivalents without departing from the scope of the embodiments disclosed herein. Having now described certain embodiments in detail, the same will be more clearly understood by reference to the following examples, which are included for purposes of illustration only and are not intended to be limiting.

EXAMPLES
Example 1
In Vitro Assays Used to Determine the Functional Activity of Anti-VEGF-A Antibodies, Anti-PDGF-BB Antibodies, Anti-VEGFR Antibodies, Anti-PDGFR-B Antibodies, and DVD-Ig Proteins
Example 1.1
Affinity Determination Using BIACORE® Surface Plasmon Resonance Technology for Antigen Binding

The BIACORE® surface plasmon resonance assay (Biacore, Inc., Piscataway, N.J.) determines the affinity of antibodies with kinetic measurements of on-rate and off-rate constants. Binding of anti-VEGF-A antibodies, anti-PDGF-BB antibodies, anti-VEGFR antibodies, anti-PDGFR-B antibodies, or anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules, to a purified recombinant VEGF-A, PDGF-BB, VEGFR extracellular domain (ECD), PDGFR-B ECD or their Fc fusion proteins was determined by surface plasmon resonance-based measurements with a Biacore® instrument (either a Biacore 2000, Biacore 3000, or Biacore T100; GE Healthcare, Piscataway, N.J.) using running buffer HBS-EPB (10 mM HEPES [pH 7.4], 150 mM NaCl, 3 mM EDTA, 0.1 mg/ml BSA and 0.005% surfactant P20) at 25° C. For example, approximately 9000 RU of goat anti-human Fc specific polyclonal antibody (Thermo Fisher Scientific Inc., Rockford, Ill.) diluted in 10 mM sodium acetate (pH 4.5) is directly immobilized across a CM5 research grade biosensor chip using a standard amine coupling kit according to manufacturer's instructions and procedures at 25 μg/ml. Unreacted moieties on the biosensor surface were blocked with ethanolamine. For kinetic analysis, rate equations derived from the 1:1 Langmuir binding model were fitted simultaneously to multiple antigen injections (using global fit analysis) with the use of Scrubber 2 (BioLogic Software), Biacore Biaevaluation 4.0.1 software or Biacore T100 Evaluation software. Purified antibodies or DVD-Ig molecules were diluted in running buffer for capture across goat anti-human Fc reaction surfaces. Antibodies or DVD-Ig molecules to be captured as a ligand (1 μg/ml) were injected over reaction matrices at a flow rate of 10 μl/minute. During the assay, all measurements were referenced against the capture surface alone (i.e., with no captured antibody or DVD-Ig molecule). The association and dissociation rate constants, K_on(M⁻¹s⁻¹) and K_off(s⁻¹) were determined under a continuous flow rate of 80 μl/minute. Rate constants were derived by making kinetic binding measurements at different antigen concentrations ranging from 1.23-900 nM, as a 3-fold dilution series, and included buffer-only injections (to be used for double referencing). The equilibrium dissociation constant K_D(M) of the reaction between antibodies and the target antigen was then calculated from the kinetic rate constants by the following formula: K_D=K_off/K_on. Binding was recorded as a function of time and kinetic rate constants were calculated. In this assay, on-rates as fast as 10⁶M⁻¹s⁻¹and off-rates as slow as 10⁻⁶s⁻¹could be measured.

In some experiments, the conditions below were used for affinity determination:

Chip surface: CM5 chip with goat anti human Fc IgG (5000 RU).

Reference: Goat IgG (capture 5000 RU).

Running buffer: HBS-EP, 0.1 mg/ml BSA

DVD-Ig or mAbs were captured at 1 μg/ml, at 70-200 RU.

Recombinant ECD proteins were serially diluted 1:5 at 0.016-50 nM.

Association time was 5 min and dissociation time was observed for 10 and 30 min.

Flow rate was 50 ul/min.

Surface regeneration: two 30s pulses of 10 mM Glycine, pH 1.5, at 50 μl/min.

Example 1.2
Surface Resonance FcγRIIa, FcγRIIb, FcγRIIIa, and FcRn Binding Assay

The binding of VEGF/PDGF DVD-Ig molecules to recombinant FcγRs captured via 6×His-tag (SEQ ID NO: 405) was assessed using a Biacore T200 (GE Healthcare) instrument. A CM5 chip (GE Healthcare, Pittsburgh, Pa.) with mouse anti-6×His antibodies (“6×His” disclosed as SEQ ID NO: 405) that were directly immobilized on the chip via amine coupling according to the GE Healthcare protocol to the density of 10000RU (all flow cells) was used for experiments. Human FcγRs were captured on flow cells 2, 3 and 4. Flow cell 1 was used as a reference surface. HBS-EP+ was used as the running buffer. Anti VEGF/PDGF DVD-Igs were injected over all the flow cells at a flow rate of 50 μL/minute for 1-2 minutes at concentrations of 31.25; 62.5, 125, 250, 500, 1000, 2000 and 4000 nM, followed by 1-3 minutes of dissociation. The chip surfaces were regenerated with an injection of 10 mM glycine pH 1.5 at a flow rate of 100 μL/minute over all four flow cells after each cycle.

For FcRn binding analysis, VEGF/PDGF DVD-Igs were directly immobilized on a CM5 chip by amine coupling according to the manufacturer's (GE Healthcare) protocol to a density of approximately 750 RU. Flow cell 1, where blank immobilization was performed, did not contain DVD-Igs and was used as a reference surface. Human, cynomolgus, mouse, rat and rabbit recombinant FcRns were injected over all the flow cells at a flow rate of 50 μL/minute for 1 minute at a concentrations range of from 2.7 to 6000 nM (three fold serial dilution), followed by a 2 minute dissociation time. The surfaces were regenerated with an injection of 10 mM HCl at 100 μL/minute for 2 seconds followed by an injection of HBS-EP+, pH 7.4, at a flow rate of 50 μL/minute for 30 seconds over all four flow cells. Samples were prepared and run in two running buffer systems, pH 6.0 MES-EP+, and pH 7.4 HBS-EP-EP+. Recombinant human FcγRIIIa V158 and rat and mouse FcRn data were fitted to 1:1 kinetic model. Recombinant human FcγRIIa R131 and FcγRIIa H131, FcγRIIIa F158, and recombinant human, cynomolgus and rabbit FcRn binding data were fitted to a steady state affinity model. Biacore T200 Evaluation Software version 2.0 was used to fit all the data.

Example 1.3
VEGF-A Binding Activity Determined by Capture ELISA

To identify molecules that could bind hVEGF₁₆₅, a direct binding ELISA was performed. 96-well high binding neutravidin plates (Thermo Scientific cat#15507) were coated with 0.25 μg/mL/6.51E-9 M biotinylated recombinant human VEGF₁₆₅(AP PR-1361002, 50 μL/well in D-PBS), and shaken for 1.5 hours at 25° C. During the coating step, supernatant, antibodies, benchmark compounds or DVD-Ig were diluted in 10% Superblock (Thermo Scientific, cat#37535) and an eight point titration of each sample molecule was performed. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20). The sample molecule titration was added to the coated plate at 50 μL in duplicate and incubated for one hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The appropriate anti-species-IgG HRP conjugate was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for forty-five minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, Lexington, Ky. cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, Radnor, Pa. cat#BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in optical density indicates the binding of the test molecule to biotinylated recombinant human VEGF₁₆₅. Data was analyzed using Softmax Pro 4.8 software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.4
VEGF-A Blocking Activity Determined by Inhibition of VEGF-R2 Interaction with Human VEGF₁₆₅

To identify molecules that could block the binding of hVEGF₁₆₅to the hVEGF-R2 (KDR/Flk-1) receptor, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.27E-9 M recombinant human VEGF-R2-Fc (R&D Systems cat#357-KD), 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatant, antibodies, benchmark compounds or DVD-Ig were diluted in 1% Blocker BSA (Thermo Scientific cat#37525) and an eight point titration of each sample molecule was performed. The biotinylated human VEGF₁₆₅(AP, PR-1361002) was diluted in 1% Blocker BSA at 35 ng/mL. The sample molecule titration was added to the biotinylated human VEGF₁₆₅(17.5 ng/mL/4.56E-10 M final concentration) and pre-incubated for 45 minutes at 25° C. with shaking. The pre-incubated sample/hVEGF₁₆₅complex was added to the coated plate at 50 μL in duplicate and incubated for 30 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Streptavidin-polyHRP-40 (Fitzgerald cal#65r-s104phrp) was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the hVEGF₁₆₅binding to the hVEGF-R2-Fc. Data was analyzed using Softmax Pro 4.8 software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.5
Mouse VEGF-A Blocking Activity Determined by Inhibition of Mouse VEGF-R2 Interaction with Mouse VEGF₁₆₄

To identify molecules that could block the binding of mVEGF₁₆₄to the mVEGF-R2, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 2 μg/mL anti-human IgG-Fc (Thermo-Scientific, cat 31125) shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were washed four times with wash buffer (TBS, 0.05% Tween-20) and 1 μg/mL/4.55E-9 M recombinant mouse VEGF-R2-Fc (R&D Systems cat#443-KD)(50 μL/well in D-PBS) was added to wells and incubated for 1.5 hour at 25° C. with shaking. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, hybridoma supernatants were diluted in 1% Blocker BSA (Thermo Scientific cat#37525). The mouse VEGF₁₆₄(R&D Systems cat#493-MV-005) was diluted in 1% Blocker BSA to 20 ng/mL. The diluted sample was added to the mouse VEGF₁₆₄(10 ng/mL/5.15E-10 M final concentration) and pre-incubated for 45 minutes at 25° C. with shaking. The pre-incubated sample/mVEGF₁₆₄complex was added to the coated plate at 50 μL and incubated for 30 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The detection reagent biotinylated goat anti-mVEGF₁₆₄(R&D Systems cat#BAF-493) was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates for 1 hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Streptavidin-polyHRP-40 (Fitzgerald cat#65r-s104phrp) was diluted in assay diluent and added to plates (50 μK) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the mVEGF₁₆₄binding to the mouse VEGF-R2-Fc. Data was analyzed using Softmax Pro 4.8 software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.6
VEGF-A Blocking Activity Determined by VEGFR2 (Tyr1054) Phosphorylation

To test candidate molecules for the ability to neutralize hVEGF-A activity, a cell based human VEGF-R2 (KDR/Flk-1) phosphorylation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, 400 μg/mL geneticin and 10% FBS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 6 hours at 37° C., 5% CO₂. Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO₂. The following day, the MSD anti-VEGFR2-phospho assay plate (Mesoscale VEGFR2-Tyr1054 phospho-MSD kit cat# K151DJD-2) was blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in growth media and pre-incubated with recombinant human VEGF₁₆₅(AP, PR-1350437) (50 ng/ml/1.3E-9 M final concentration), hVEGF₁₁₁(R&DSystems, cat#5336-VE-10/CF) (50 ng/mL/1.9E-9 M final concentration) or rabbit VEGF₁₆₅(AbbVie, PR-1563693.0) (50 ng/mL/1.24E-9 M final concentration) for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO₂Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. Ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL) on ice. Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated for 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr1054-IgG-sulfotag reagent was diluted in detection solution (K151DJD-2 components) and 25 μL added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K151DJD-2 component) added to wells and plates read on MSD Sector Imager 6000. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF-A mediated activation. Data was analyzed using Graphpad Prism software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.7
VEGF-A Blocking Activity Determined by Inhibition of Human VEGF₁₆₅Stimulated VEGFR2-3T3 Cell Proliferation/Survival

To screen candidate molecules for the ability to neutralize hVEGF₁₆₅activity, a cell based proliferation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 8.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 4,250 cells/well (50 μL) on black 96-well plates and incubated for 24 hours at 37° C., 5% CO₂. The following day, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant human VEGF₁₆₅(AP, PR-1350437) (40 ng/ml/1.04E-9 M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% C0₂for 72 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using an ATPlite kit (Perkin Elmer, Waltham, Mass.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF₁₆₅induced proliferation. Data was analyzed and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.8
VEGF-A Blocking Activity Determined by Inhibition of HumanVEGF₁₁₁and HumanVEGF₁₂₁Stimulated VEGFR2-3T3 Cell Proliferation/Survival

To test the ability of candidate molecules to neutralize hVEGF₁₁₁and hVEGF₁₂₁activity, a cell based proliferation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 8.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 4,250 cells/well (50 μL) on black 96-well plates and incubated for 24 hours at 37° C., 5% CO₂. The following day, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with either recombinant human VEGF₁₁₁(R&D Systems, cat#5336-VE) (10 ng/ml/3.85E-10 M final concentration) or human VEGF₁₂₁(R&D Systems, cat#4644-VS) (10 ng/ml/3.57E-10 M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO₂for 72 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using an ATPlite kit (Perkin Elmer, Waltham, Mass.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF₁₁₁or hVEGF₁₂₁induced proliferation. Data was analyzed and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.9
VEGF-A Blocking Activity Determined by Inhibition of Rabbit VEGF₁₆₅Stimulated VEGFR2-3T3 Cell Proliferation/Survival

To screen candidates for the ability to neutralize rabbitVEGF₁₆₅, a cell based proliferation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 8.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 4,250 cells/well (50 μL) on black 96-well plates and incubated for 24 hours at 37° C., 5% CO₂. The following day, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant rabbit VEGF₁₆₅(AbbVie, PR-1563693.0) (40 ng/ml/9.92E-10M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO₂for 72 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using an ATPlite kit (Perkin Elmer, Waltham, Mass.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the rabbitVEGF₁₆₅induced proliferation. Data was analyzed and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.10
VEGF-A Blocking Activity Determined by Inhibition of Human VEGF₁₆₅Stimulated Endothelial Cell Proliferation/Survival

To test for the ability to neutralize hVEGF₁₆₅, a cell based proliferation assay was performed. Human microvascular endothelial cells (Lonza, cat#CC-2516) were maintained in EBM-2 (Lonza cat#CC3156) supplemented with EGM-2V singlequots (Lonza cat#3202). The day of the assay, the cells (passage 2-7) were trypsinized, washed in D-PBS and resuspended at 1E5 cells/mL in assay media (M199, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 10 mM HEPES and 10% FBS). Cells were plated at 5,000 cells/well (50 μL) on 96-well gelatin coated plates (BD Biocoat cat#354689) and incubated at 37° C., 5% CO₂. The anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant human VEGF₁₆₅(AP, PR-1350437) (5 ng/ml/1.3E-10 M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO₂for 72 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF₁₆₅induced proliferation. Data was analyzed and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.11
Generation of Naturally Derived Human VEGF-A and Reactivity to the Anti-VEGF Antibodies or Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Proteins

To identify molecules that could bind naturally derived human VEGF-A, a sandwich ELISA was performed. Native human VEGF-A was obtained from the supernatant of Y-79 cells (ATCC, cat#HTB-18) grown in the presence of dimethyloxalylglycine (Sigma-Aldrich, cat#D3695). The naturally derived material was quantified using the R&D Systems VEGF Duoset kit (cat#DY293B). 96-well Costar high binding plates (#3369) were coated with 13.3E-8 M antibodies, benchmark compounds or DVD-Ig in D-PBS, shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were blocked with Superblock blocking buffer (Thermo Scientific, cat#37535) followed by four washes with wash buffer (TBS, 0.05% Tween-20). The naturally derived human VEGF-A supernatant was serially diluted in assay diluent (1% Blocker BSA; Pierce, cat#37525) for final test concentrations of 2900 ng/mL-11.88 ng/mL. The dilutions were added to the plates (50 μL) and incubated for 2 hours at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Detection antibody from the R&D Systems Duoset kit (Part 840163, cat#DY293B) was diluted in assay diluent and added to plates (50 μL) for 2 hours at 25° C. with shaking. Plates were then washed four times with wash buffer. The streptavidin-HRP from the R&D Systems Duoset kit (Part 890803, cat#DY293B) was diluted in assay diluent and added to plates (50 μL) for 35 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in optical density indicates binding of the test molecule to the naturally derived human VEGF-A. Data was analyzed using Softmax Pro 4.8 software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.12
PDGF-BB Binding Activity Determined by Capture ELISA

To identify molecules that could bind hPDGF-BB, a direct binding ELISA was performed. 96-well high binding neutravidin plates (Thermo Scientific cat#15507) were coated with 0.5 μg/mL/1.99E-8 M recombinant human PDGF-BB-biotin (CST cat#8912BF; labeled at AbbVie, 50 μL/well in D-PBS), shaken for 2 hours at 25° C. During the coating step, supernatants, benchmark compounds or DVD-Ig were diluted in 10% Superblock (Thermo Scientific, cat#37525) and an eight point titration of each sample molecule was performed. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20). The sample molecule titration was added to the coated plate at 50 μL in duplicate and incubated for one hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The appropriate anti-species-IgG HRP conjugate was in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for one hour at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in optical density indicates binding of the test molecule to biotinylated recombinant human PDGF-BB. Data was analyzed using Softmax Pro 4.8 software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.13
PDGF-BB Blocking Activity Determined by Inhibition of PDGF-Rβ Interaction with Human PDGF-BB

To identify molecules that could block the binding of hPDGF-BB to the hPDGF-Rβ, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.98E-9 M recombinant human PDGF-Rβ-Fc (R&D Systems #385-PR, 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatants, antibodies, benchmark compounds or DVD-Ig were diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and an eight point titration of each sample molecule was performed. The recombinant human PDGF-BB-biotin (CST cat#8912BF; labeled at AbbVie) was diluted in assay diluent at 20 ng/mL. The sample molecule titration was added to the human PDGF-BB-biotin (10 ng/mL/3.97E-10 M final concentration) and pre-incubated for 45 minutes at 25° C. with shaking. The pre-incubated sample/PDGF-BB complex was added to the coated plate at 50 μL in duplicate and incubated for 35 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Detection reagent Streptavidin-polyHRP-40 (Fitzgerald, cat#65r-s104phrp) was diluted in assay diluent and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the hPDGF-BB binding to the human PDGF-Rβ-Fc. Data was analyzed using Softmax Pro 4.8 software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.14
PDGF-BB Blocking Activity Determined by PDGFRβ (Tyr751) Phosphorylation

To test candidate molecules for the ability to neutralize hPDGF-BB activity, a cell based PDGF-Rβ phosphorylation assay was performed. Balb-3T3 cells (ATCC cat# CCL-163) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, and 10% FCS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 20 hours at 37° C., 5% CO₂. Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO₂. The following day, the MSD anti-PDGF-Rβ phospho-assay plate (Mesoscale PDGF-Rβ-Tyr751 phospho-MSD kit cat# K150DVD-2) was blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, anti-PDGF-BB supernatants, monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in growth media and pre-incubated with recombinant human PDGF-BB (CST, cat#8912BF) (20 ng/ml/7.94E-10 M final concentration) and rat PDGF-BB (R&D Systems,cat#520-BB) (70 ng/ml/1.4E-9 M final concentration) for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO₂. Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. On ice, ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL). Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr751-IgG-sulfotag reagent was diluted in detection solution (K150DVD-2 components) and 25 μl added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K150DVD-2 component) added to wells and plates read on MSD Sector Imager 6000. A decrease in observed reporter signal indicates the test molecule is neutralizing the hPDGF-BB mediated activation. Data was analyzed using Graphpad Prism software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.15
PDGF-BB Blocking Activity Determined by Inhibition of Human PDGF-BB Stimulated NIH-3T3 Cell Proliferation/Survival

To screen candidate molecules for the ability to neutralize hPDGF-BB activity, a cell based proliferation assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO₂. During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant human PDGF-BB (CST, cat#8912BF) (1.67 ng/ml/6.63E-11 M final concentration) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO₂for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hPDGF-BB induced proliferation. Data was analyzed and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.16
PDGF-BB Blocking Activity Determined by Inhibition of Cynomolgus PDGF-BB Stimulated NIH-3T3 Cell Proliferation/Survival

To screen candidate molecules for the ability to neutralize cynomolgus PDGF-BB activity, a cell based proliferation assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO₂. During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant cynomolgus PDGF-BB (AP, PR-1575400) (4 ng/ml/1.61E-10 M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO₂for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the cynoPDGF-BB induced proliferation. Data was analyzed and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.17
PDGF-BB Blocking Activity Determined by Inhibition of Murine PDGF-BB Stimulated NIH-3T3 Cell Proliferation/Survival

To test candidate molecules for the ability to neutralize mouse PDGF-BB activity, a cell based assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO₂. During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant murine PDGF-BB (Abnova, cat#0309-200-58-S) (2 ng/ml/8.13E-11 M final concentration) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO₂for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the murine PDGF-BB induced proliferation. Data was analyzed and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.18
PDGF-BB Blocking Activity Determined by Inhibition of Rat PDGF-BB Stimulated NIH-3T3 Cell Proliferation/Survival

To test candidate molecules for the ability to neutralize rat PDGF-BB activity, a cell based assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO₂. During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant rat PDGF-BB (R&D Systems,cat#520-BB) (2 ng/ml/8.0E-11 M final concentration) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% C0₂for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the rat PDGF-BB induced proliferation. Data was analyzed and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.19
Generation of Naturally Derived Human PDGF-BB and Reactivity to the Anti-PDGF-BB Antibodies or Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Proteins

The native form of human PDGF was purified from platelets by a modified protocol from Antoniades et al. (Antoniades et al. (1979) Proc. Natl. Acad. Sci. USA 76(4): 1809-1813. In the modified protocol, ten units of platelets (Bioreclamation Inc.) were thawed, washed with 12 ml of Platelet Wash Buffer (HBSS—Gibco #14175/0.3% BSA/10 mM EDTA) and centrifuged. The platelets were then suspended in 25 ml of Buffer A (20 mM NaHPO4, pH 7.4, 80 mM NaCl in a 50 ml tube). From here the platelet wash (50 ml tube) and the suspended platelets were worked up in parallel using the same protocol.

Both the suspended platelets and platelets wash tubes were placed into a boiling water bath for 10 minutes, after which the contents of the tubes were cooled on ice. The supernatant was separated from the pellet by centrifugation. The supernatant was placed aside at 4° C. and the pellet was extracted with 30 ml Buffer B (20 mM NaHPO4, pH 7.4, 1M NaCl) by stirring overnight at 4° C. The supernatant was separated from the pellet by centrifugation. The supernatant was placed aside (4° C.) and the pellet was extracted with 30 ml Buffer B by stirring overnight at 4° C. This was repeated two more times. All the supernatants were then dialyzed separately against Buffer A. After removal from dialysis, they were all analyzed for protein content and PDGF-BB (ELISA) (See Table 6).

TABLE 6

Native PDGF Extraction from Human Platelets

Total

Volume
PDGF-BB
PDGF-BB
Protein
Total Protein
ng PDGF-BB

Sample
(ml)
(ng/mL)
(ng)
(mg/mL)
(mg)
per mg Protein

Boiled platelet

Supernatant
50
4.52
226.18
0.63
31.50
7.18

Pellet

Extraction 1
35
8.77
306.95
0.31
10.85
28.29

Extraction 2
35
3.79
132.76
0.25
8.58
15.48

Extraction 3
35
1.26
44.03
0.10
3.43
12.83

Extraction 4
37
1.53
56.65
0.19
7.03
8.05

Platelet Wash

Boiled

Supernatant
27
7.49
202.12
0.64
17.28
11.70

Extracted Pellet
37
10.89
402.75
0.90
33.15
12.15

Total
256
5.36
1371.32
0.44
111.82
12.26

TABLE 7

Native PDGF Purification from Human Platelets

Specific

Total

Activity

PDGF-

PDGF-
Total
ng
Endotoxin Levels

Platelet
BB
Volume
BB
Protein
PDGF/mg

EU/mg

Purification
(ng/mL)
(mL)
(ng)
(mg)
Protein
EU/ml
protein
EU/μg PDGF

Eluate 1
214.94
6.74
1449
0.443
3266.49
2.36
35.87
10.98

Flow
1.17
500
585
110.5
5.29

Thru 1

Due to low specific activity (ng PDGF-BB per mg protein), the supernatants were subjected to further purification by CM sepharose. The supernatants were applied (with washing Buffer A) to a 20 ml CM sepharose column (GE Healthcare cat#17-0719-01) and the PDGF was eluted with Buffer B. Subsequently the eluted protein was dialyzed against Buffer A. From here the protein that was eluted and subsequently dialyzed as well as the flow through were all analyzed for protein content and PDGF-BB (ELISA). At this point the specific activity (eluate 1) was high enough to be queried in the assay.

To identify molecules that could bind naturally derived human PDGF-BB, a sandwich ELISA was performed. The native human PDGF-BB was isolated and purified from human platelets (AbbVie, PR-1566692). This material was quantified using the R&D Systems PDGF-BB Duoset kit (cat#DY220). 96-well Costar high binding plates (#3369) were coated with 13.3E-8 M antibodies, benchmark compounds or DVD-Ig in D-PBS, shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were blocked with Superblock blocking buffer (Thermo Scientific, cat#37535) followed by four washes with wash buffer (TBS, 0.05% Tween-20). The native human PDGF-BB was serially diluted in assay diluent (1% Blocker BSA; Pierce, cat#37525) for final test concentrations of 2000 ng/mL-2.74 ng/mL (5.4E-8 M-7.5E-11 M). The dilutions were added to the plates (50 μL) and incubated for 2 hours at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Detection antibody from the R&D Systems Duoset kit (Part 840926, cat#DY220) was diluted in assay diluent and added to plates (50 μL) for 2 hours at 25° C. with shaking. Plates were then washed four times with wash buffer. The streptavidin-HRP from the R&D Systems Duoset kit (Part 890803, cat#DY220) was diluted in assay diluent and added to plates (50 μL) for 35 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in optical density indicates binding of the test molecule to the naturally derived human PDGF-BB. Data was analyzed using Softmax Pro 4.8 software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.20
hVEGF-A Neutralization Potency of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Proteins when Pre-Incubated with hPDGF-BB

To test candidate molecules for the ability to neutralize hVEGF-A activity in the presence of hPDGF-BB, a cell based VEGF-R2 (KDR/Flk-1) phosphorylation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, 400 μg/mL geneticin and 10% FBS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 6 hours at 37° C., 5% CO₂Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO₂. The following day, the MSD anti-VEGFR2-phospho assay plate (Mesoscale VEGFR2-Tyr1054 phospho-MSD kit, cat#K151DJD-2) was blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in growth media and pre-incubated with recombinant human PDGF-BB (CST cat#8912BF) (0.992 μg/ml/3.94E-8 M final concentration) for 30 minutes at 25° C. with shaking. Following the first pre-incubation step, recombinant human VEGF₁₆₅(AP, PR-1350437) was added to the samples for a final concentration of human VEGF₁₆₅of 50 ng/ml/1.3E-9 M and of hPDGF-BB of 0.496 μg/ml/1.97E-8 M final concentration for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO₂. Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. Ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL) on ice. Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr1054-IgG-sulfotag reagent was diluted in detection solution (K151DJD-2 components) and 25 L added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K151DJD-2 component) added to wells and plates read on MSD Sector Imager 6000. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF₁₆₅mediated activation in the presence of hPDGF-BB. Data was analyzed using Graphpad Prism software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.21
PDGF Neutralization Potency of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Proteins when Pre-Incubated with VEGF

To test candidate molecules for the ability to neutralize hPDGF-BB activity in the presence of hVEGF-A, a cell based proliferation assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO₂. During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media containing hVEGF₁₆₅(4 μg/mL/104.2 nM). The samples were pre-incubated with recombinant human PDGF-BB in assay media (CST, cat#8912BF) (3.34 ng/ml/1.33E-10 M final concentration in well) for 1 hour at 25° C. with gentle shaking. The final concentrations of ligand in assay wells were hVEGF₁₆₅2.6E-8 M and hPDGF-BB 6.63E-11 M. The pre-incubated samples were added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% C0₂for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hPDGF-BB induced proliferation in the presence of hVEGF₁₆₅. Data was analyzed and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.22
Human VEGF-R2 Binding Activity of the Anti-VEGF-R2 Antibodies

To identify molecules which could bind VEGF-R2 (KDR/Flk-1), a direct binding ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.27E-9 M recombinant human VEGF-R2-Fc (R&D Systems cat#357-KD), 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatant, antibodies or benchmark compounds were diluted in 1% Blocker BSA (Thermo Scientific cat#37525) and an eight point titration of each sample molecule was performed. The samples were added to wells and incubated for one hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The appropriate anti-species-IgG HRP conjugate was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for forty-five minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in observed optical density indicates the test molecule is binding the human VEGF-R2-Fc. Data was analyzed using Softmax Pro 4.8 software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.23
Human VEGF-R2 Blocking Activity of the Anti-VEGF-R2 Antibodies as Determined by Inhibition of Human VEGF-R2 Interaction with Human VEGF₁₆₅

To identify molecules which could block the binding of VEGF-R2 (KDR/Flk-1) to hVEGF₁₆₅, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.27E-9 M recombinant human VEGF-R2-Fc (R&D Systems cat#357-KD), 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatant, antibodies or benchmark compounds were diluted in 1% Blocker BSA (Thermo Scientific cat#37525) and an eight point titration of each sample molecule was performed. The samples were added to wells and incubated for 30 minutes at 25° C. with shaking. The biotinylated human VEGF₁₆₅(AP, PR-1361002) was diluted in 1% BSA at 35 ng/mL. This was added to wells (17.5 ng/mL/4.56E-10 M final concentration) and incubation was continued for 30 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Streptavidin-polyHRP-40 (Fitzgerald cat#65r-s104phrp) was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the human VEGF-R2-Fc binding to hVEGF₁₆₅. Data was analyzed using Softmax Pro 4.8 software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.24
VEGF-A Blocking Activity of the Anti-VEGF-R2 Antibodies as Determined by VEGFR2 (Tyr1054) Phosphorylation

To test candidate molecules for the ability to neutralize hVEGF-R2 activity, a cell based VEGF-R2 (KDR/Flk-1) phosphorylation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, 400 μg/mL geneticin and 10% FBS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 6 hours at 37° C., 5% CO₂. Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO₂. The following day, the MSD anti-VEGR2-phospho assay plate (Mesoscale VEGFR2-Tyr1054 phospho-MSD #kit cat K151DJD-2) was blocked with MSD Blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, anti-VEGF-R2 supernatant, monoclonal antibodies and benchmark compounds were serially diluted in growth media and pre-incubated with recombinant human VEGFR2-Fc (R&D Systems, cat#357-KD) (500 ng/ml/2.27E-9 M final concentration) for 30 minutes at 25° C. with shaking. Recombinant human VEGF₁₆₅(AP, PR-1350437) (50 ng/ml/1.3E-9 M final concentration) was added to the wells and incubation was continued for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO₂. Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. Ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL) on ice. Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr1054-IgG-sulfotag reagent was diluted in detection solution (K151DJD-2 components) and 25 μL added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K151DJD-2 component) added to wells and plates read on MSD Sector Imager 6000. An increase in observed signal indicates the test molecule is neutralizing the exogeneous hVEGFR2 and allowing for hVEGF₁₆₅mediated activation. Data was analyzed using Graphpad Prism software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.25
Mouse VEGF-R2 Blocking Activity of the Anti-VEGF-R2

Antibodies as Determined by Inhibition of Mouse VEGF-R2 Interaction with Mouse VEGF₁₆₄

To identify molecules which could block the binding of mVEGF₁₆₄to the mVEGF-R2, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 1 μg/mL/4.55E-9 M recombinant mouse VEGF-R2-Fc (R&D Systems cat#443-KD)(50 μL/well in D-PBS) shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were washed four times with wash buffer (TBS, 0.05% Tween-20). Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, hybridoma supernatants and rat IgG were diluted in 1% Blocker BSA (Thermo Scientific cat#37525). The sample was added to the plates (50 μL) and incubated for 45 minutes at 25° C. with shaking. The mouse VEGF₁₆₄(R&D Systems cat#493-MV-005) was diluted in 1% Blocker BSA to 20 ng/mL and added to wells for a final concentration of 10 ng/mL/5.15E-10 M final concentration. Incubation was continued for 30 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The detection reagent biotinylated goat anti-mVEGF₁₆₄(R&D Systems cat#BAF-493) was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates for 1 hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Streptavidin-polyHRP-40 (Fitzgerald cat#65r-s104phrp) was diluted in assay diluent and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the mouse VEGF-R2-Fc binding to the mVEGF₁₆₄. Data was analyzed using Softmax Pro 4.8 software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.26
PDGF-Rβ Binding Activity of the Anti-PDGF-Rβ Antibodies

To identify molecules which bind hPDGF-Rβ, a direct ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.98E-9 M recombinant human PDGF-Rβ-Fc (R&D Systems #385-PR, 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatants, antibodies and benchmark compounds were diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and an eight point titration of each sample molecule was performed. The samples were added to wells and incubated for one hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The appropriate anti-species-IgG HRP conjugate was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for forty-five minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in observed optical density indicates the test molecule is binding the human PDGF-Rβ-Fc. Data was analyzed using Softmax Pro 4.8 software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.27
PDGF-Rβ Blocking Activity of the Anti-PDGF-Rβ Antibodies as Determined by Inhibition of PDGF-Rβ Interaction with Human PDGF-BB

To identify molecules which could block the binding of hPDGF-Rβ to hPDGF-BB, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.98E-9 M recombinant human PDGF-Rβ-Fc (R&D Systems #385-PR, 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatants, antibodies and benchmark compounds were diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and an eight point titration of each sample molecule was performed. The samples were added to wells and incubated for 30 minutes at 25° C. with shaking. The recombinant human PDGF-BB-biotin (CST cat#8912BF; labeled at ABC) was diluted in assay diluent at 20 ng/mL. This was added to wells (10 ng/mL/3.97E-10 M final concentration) and incubation was continued for 35 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Detection reagent Streptavidin-polyHRP-40 (Fitzgerald, cat#65r-s104phrp) was diluted in assay diluent and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the human PDGF-Rβ-Fc binding to hPDGF-BB. Data was analyzed using Softmax Pro 4.8 software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.28
PDGF-Rβ Blocking Activity of the Anti-PDGF-Rβ Antibodies as Determined by PDGFRβ (Tyr751) Phosphorylation

To test candidate molecules for the ability to neutralize hPDGF-Rβ activity, a cell based PDGF-Rβ phosphorylation assay was performed. Balb-3T3 cells (ATCC cat# CCL-163) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, and 10% FCS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 20 hours at 37° C., 5% CO₂. Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO₂. The following day, the MSD anti-PDGFRβ-phospho-assay plate (Mesoscale PDGF-Rβ-Tyr751 phospho-MSD kit cat# K150DVD-2) was blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, supernatants, antibodies or benchmark compounds were serially diluted in growth media and pre-incubated with 500 ng/mL/2.98E-9 M hPDGF-Rβ (R&D System, cat 385-PR) for 30 minutes at 25° C. Recombinant human PDGF-BB (CST, cat#8912BF) (20 ng/ml/7.94E-10 nM final concentration) was added to the wells and incubation was continued for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO₂. Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. Ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL) on ice. Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr751-IgG-sulfotag reagent was diluted in detection solution (K150DVD—2 components) and 25 μL added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K150DVD-2 components) added to wells and plates read on MSD Sector Imager 6000. An increase in observed signal indicates the test molecule is neutralizing the exogeneous hPDGF-Rβ and allowing for hPDGF-BB mediated activation. Data was analyzed using Graphpad Prism software and IC₅₀values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.

Example 1.29
Reactivity of Anti-PDGF-BB Antibodies and Anti-VEGF-A/anti-PDGF-BB DVD-Ig Molecules to ECM-associated PDGF-BB

Both recombinant cell line HEK293 cells over-expressing PDGFBB-RM and HUVEC naturally expressing ECM-associated PDGF-BB cells were used for staining.

HEK293 Cell Staining:

PDGFB-RM transient transfected HEK 293 cells and parental HEK293 cells were re-suspended at 1E6 cells/mL in PBS and fixed in 4% paraformaldehyde at RT for 10 minutes, washed with PBS and 2E5 cells/tube were incubated in blocking buffer (10% goat serum in PBS) for one hour on ice. Cells were washed with PBS and incubated with primary antibodies or DVD-Ig molecules at 33 nM in antibody dilution buffer (5% goat serum in PBS) for one hour on ice. Cells were washed three times with PBS and incubated with Alexa Fluo 488 conjugated Goat anti-Human IgG (Jackson Immune, code: 109-546-098; lot: 108427) 1:400 dilution in antibody dilution buffer, incubated on ice for 45 minutes, cells were washed three times with PBS and cytospin onto glass slides and mounted with mounting media with DAPI. Pictures were taken by fluorescent microscopy.

HUVEC Staining:

The anti-VEGF/anti-PDGF DVD-Ig was further assessed for its staining on naturally derived ECM-associated PDGF-BB on HUVEC cells. HUVECs (Lonza, cat#: C2519A lot: 181607) were trypsinized, resuspended at 2E4 cells/mL in culture media (Lonza, EGM2 MV Bulletkit: CC-3202). Cells were plated at 10,000 cells/500 μl/well in 8-chamber glass slide and incubated for 16 hours at 37° C., 5% CO₂. After incubation, cells were fixed with 200 μl 4% paraformaldehyde at RT for 10 minutes, washed with PBS and incubated in blocking buffer (10% goat serum in PBS) for one hour on ice. Cells were washed with PBS 3× and incubated with primary antibodies or DVD-Ig molecules at 33 nM in antibody dilution buffer (5% goat serum in PBS) for one hour on ice. Cells were washed three times with PBS and incubated with Alexa Fluo 488 conjugated Goat anti-Human IgG (JacksonImmune, code: 109-546-098; lot: 108427) 1:400 dilution in antibody dilution buffer, incubate on ice for 45 minutes, cells were washed three times with PBS and mounted with mounting media with DAPI. Pictures were taken by fluorescent microscopy.

A. Example 1.30
Inhibition of Sprouting in HUVEC/MSC Co-culture Sprouting Assay by Anti-VEGF-A/anti-PDGF-BB DVD-Ig Molecules

In early therapeutic treatment mode, Cytodex-3 beads (Sigma-Aldrich, cat# C3275) were coated with HUVEC cells (Lonza) overnight, and then embedded (100 beads/well) with human mesenchymal stem cells (Lonza, 20,000 cells/well) in fibrin gel in 24-well tissue culture plates. A 1:1 mixture of fresh EGM-2 complete media (Lonza) and fibroblast (Lonza) conditioned EGM-2 media were added on top of the fibrin gel along with 2 ng/mL of recombinant human HGF. Medium was replaced every 2-3 days till the end of the experiment. After EC sprouts and pericyte covering were formed usually on day 4, anti-VEGF-A (4G8.4), anti-PDGFBB (9E8.) or anti-PDGFBB/VEGF-A DVD-Ig, were added to the culture medium at 10 nM starting. 10 days later cells were fixed in 4% PFA overnight at 4° C. Endothelial cells were stained with anti-PECAM (Abcam, ab32457), followed by fluorescence-conjugated secondary antibody, and pericytes were labeled with anti-aSMA-Cy3 (Sigma, C6198). Cells were then viewed by an inverted fluorescence microscope and 5× images were captured (FIGS. 2 and 3).

Example 2
Analytical Methods and Techniques for Physicochemical Property Characterizations of DVD-Ig Proteins
Example 2.1
Size Exclusion Chromatography Technique

Size exclusion chromatography (SEC) is used to separate proteins based on size. Proteins are carried in an aqueous mobile phase and through a porous stationary phase resin packed in a column. The retention time in the column is a function of the hydrodynamic size of the protein and the size of the pores in the packed resin bed. Smaller molecules can penetrate into smaller pores in the resin and are retained longer than larger molecules. Samples at 1 mg/ml, or diluted with formulation buffer to this concentration, are injected onto the SEC column at a volume of 10 μl. Upon elution from the column, the proteins are detected by UV absorbance. The SEC method uses a TSK gel guard (TOSOH Biosciences, Montgomeryville, Pa., cat. no. 08543) and a TSK gel G3000SWxL (TOSOH Biosciences, Montgomeryville, Pa., cat. no. 08541). The mobile phase was 100 mM Na₂HPO₄, 100 mM Na₂SO₄, pH 6.8. The flow rate is 0.25 ml/minute. The column temperature is room temperature. The autosampler temperature is 2-8° C. The total run time is 55 minutes. The detection is based on UV absorbance at 214 nm wavelength, with band width set at 8 nm, using reference wavelength at 360 nm with band width 100 nm. The resulting chromatogram is analysed for the distribution of different size species (aggregate, monomer, and fragment) by the percentage of the total area of the signal.

Example 2.2
Differential Scanning Calorimetry Technique

The thermal stability of the protein samples was assessed using a differential scanning calorimetry (DSC) instrument. The DSC instrument used was an automated VP-DSC equipment with Capillary Cell (Microcal, GE Healthcare Ltd./Microcal, Buckinghamshire, UK). Unfolding of molecules was studied applying a 1° C./minute scan rate over a 25° C.-95° C. temperature range for samples at 1 mg/mL. Additional measurement parameters applied were a fitting period of 16 seconds, a pre-scan wait time of 10 minutes, and measurements were performed in none-feedback mode. For each measurement, 420 μL of sample or blank buffer was filled into the designated receptacle within the DSC instrument. The thermograms obtained (heat capacity versus temperature) were fitted to a non-two state model to obtain the midpoint temperatures and enthalpies of the different transitions.

Example 2.3
Sample Preparation

The antibodies and DVD-Ig molecules were initially obtained as a solution and diluted below 10 mg/ml with the formulation buffer. Each sample was then inserted into a separate dialysis cartridge (Slide-a-lyzer cassette, 10,000 MWCO, 3-12 mL capacity, Thermo Scientific, USA, Cat. No. 66810) and dialyzed against 2 L of the formulation buffer with continuous stirring via a magnetic stir bar for 18-24 hours. The samples were then retrieved from the cartridge and briefly spun down in a centrifuge and/or passed through 0.45 μm PVDF filters to remove any precipitation or particles. This was followed by up-concentration of the DVD-Ig solutions with centrifuge spin filters (Amicon Ultra 30,000 MWCO Regenerated Cellulose) to reach the desired protein concentration which was confirmed by UV measurements at 280 nm. If the solutions were above the desired concentration, they were diluted to that concentration with the formulation buffer.

Example 2.4
Storage Stability Analysis Method

The antibodies and DVD-Ig molecule solutions prepared according to Example 2.3 were analyzed for their physical stability during storage at 40° C., 25° C., and/or 5° C. Both 25° C. (room temperature) and 5° C. (storage temperature) are typical temperatures at which the samples would be subjected either during preparation and storage for manufacture or as part of the final drug product presentation. Storage at 40° C. is considered an accelerated stability condition which provides an indication of long-term stability prospects. The samples were aliquoted into low volume containers (<0.1 ml), tightly sealed, and placed at the designated temperatures (sometimes in a water bath). The samples were then pulled at periodic intervals and a small portion was removed for analysis by SEC (Example 2.1).

Example 2.5
Freeze-Thaw Analysis Method

The antibody and DVD-Ig molecule solutions prepared according to Example 2.3 were analyzed for their physical stability during freeze/thaw stress. Samples were aliquoted into low volume containers (<1 ml) and tightly sealed. The samples were then placed at −80° C. for at least 6 hours and then thawed at 30° C. in a water bath. This was repeated three more times. After the second and fourth thaws, a small portion of each sample was removed for analysis by SEC (Example 2.1).

DVD-Ig solutions are typically frozen at −80° C. for long term storage as well as shipping to remote manufacturing sites. The samples are then thawed in order to complete the drug product manufacturing process. Stability due to freeze-thawing was assessed at low concentration in order to evaluate greater exposure of protein molecules to the denaturing ice-water interfaces. At higher concentrations, proportionally less protein encounters the ice-water interface, instead interacting with other protein molecules.

Example 2.6
Viscosity Determination Method

The antibody and DVD-Ig molecule solutions prepared according to Example 2.3 were analyzed for their viscosity at room temperature (˜23° C.) with a Malvern Viscosizer 200 instrument. The viscosity serves as an indication of the ease of delivery of the sample through a small diameter needle attached to a syringe, a likely drug product presentation. A higher viscosity requires a greater force for delivery, and vice-versa.

Example 2.7
Intact and Reduced Molecular Weight Determination

The intact molecular weights of the three samples shown in Table 8 were acquired. Each sample was diluted to 1 mg/mL with Milli-Q water. 1.0 μL of the 1 mg/mL sample was injected onto an Agilent 6510 Q-Tof LC/MS system with a C4 MicroTrap column. Table 9 shows the HPLC gradient for intact molecular weight analysis. Buffer A was 0.02% TFA, 0.08% FA in water. Buffer B was 0.02% TFA, 0.08% FA in acetonitrile. The flow rate was 50 μL/minute. The column temperature was set at 60° C. The mass spectrometer was operated at 5 kvolts spray voltage and the scan range was from 600 to 3200 mass to charge ratio. The deglycosylated intact molecular weights of all three samples were measured by Agilent 6510 Q-Tof LC/MS system after the samples were deglycosylated. 100 μL of 1 mg/mL sample was mixed with 5 μL of 10% N-octylglucoside and 2 μL of PNGase F enzyme. The sample was incubated at 37° C. for 18 hours. 1.0 μg of the deglycosylated sample was injected onto an Agilent 6510 Q-Tof LC/MS system with a C4 MicroTrap for deglycosylated intact molecular weight analysis.

The reduced molecular weights of all three samples were obtained. Each sample was diluted to 1 mg/mL with Milli-Q water. 1.0 μL of 1M DTT was added to 100 μL of a 1 mg/mL sample and incubated at 37° C. for 30 minutes. 2.0 μL of the reduced sample was injected onto an Agilent 6510 Q-Tof LC/MS system with a diphenyl column. The HPLC gradient for reduced molecular weight analysis is shown in Table 9. The mass spectrometer was operated at 5 kvolts spray voltage and the scan range was from 600 to 3200 mass to charge ratio.

TABLE 8

VEGF/PDGF DVD-Ig Formulations

Concentration

Sample ID
Lot
Detailed name
(mg/mL)
Formulation

PR-1572102
Lot 2211502
hu VEGF 4G8.3-GS-hu PDGF
6.5
30 mM histidine,

9E8.4 (germline) [hu IgG1/k]

8% sucrose pH

LALA H435A

5.2

PR-1572105
Lot 2211597
hu VEGF 4G8.3-SL-hu PDGF
1.5
30 mM Histidine,

9E8.4 (germline) [hu IgG1/k]

8% Sucrose pH

LALA H435A

5.2

PR-1610561
Lot 2213329
hu VEGF 9E10.1-GS-hu PDGF
5
30 mM Histidine,

33675 [hu IgG1/k] LALA H435A

8% sucrose, pH

5.2

TABLE 9

PLC Operating Conditions For Intact And Reduced Molecular Weight

Intact/C4

Reduced/Diphenyl

Time (min)
% Buffer B
Time (min)
% Buffer B

0
5
0
5

5
5
5
30

5.5
95
30
40

10
95
32
90

10.5
5
37
90

15
5
39
5

44
5

Example 2.8
Oligosaccharide Profiles Determined by Fc Molecular Weight Measurement

Samples were partially digested with Lys-C enzyme, reduced and analyzed by LC/MS. Different oligosaccharide species were quantitated based on the peak intensity detected by mass spectrometry and the relative percentage of different oligosaccharide species was reported. Samples were diluted to 1 mg/mL with Milli-Q water. 100 μL of each sample was mixed with 2 μL of 0.005 mg/mL Lys-C enzyme and incubated at 37° C. for 30 minutes. 1 μL of 1 M DTT was added and incubated at 37° C. for 30 minutes for reduction. 2 μL of sample was injected onto an Agilent 6510 Q-Tof LC/MS system with a diphenyl column and a reduced HPLC gradient was used. The column temperature was set at 60° C. The mass spectrometer was operated at 5 kvolts spray voltage and the scan range was from 600 to 3200 mass to charge ratio.

Example 2.9
Charge Heterogeneity by Weak Cation Exchange Chromatography and Imaged Isoelectric Focusing (icIEF)

Charge heterogeneity was studied using a Propac WCX-10 column for weak cation exchange chromatography analysis. Mobile phase A was 20 mM MES, pH 5.5. Mobile phase B was 20 mM MES, 500 mM NaCl, pH 5.5. Each sample was diluted to 1 mg/mL in mobile phase A. 50 μg of each sample was loaded, and the HPLC gradient is shown in Table 10. The flow rate was 1 mL/minute flow rate and the UV detector was monitored at 280 nm.

TABLE 10

Gradient Used For Weak Cation Exchange Chromatography

Time (minutes)
Mobile phase B

0
20

5
20

25
40

27
100

32
100

34
20

38
20

Imaged isoelectric focusing was performed on an iCE instrument from ProteinSimple. All three samples were diluted to 1 mg/mL with Milli-Q water before mixing with amphalyte and other components as shown in Table 11. Each sample was vortexed briefly and centrifuged for 5 minutes at 10 k RPM before being transferred to glass inserts for analysis. Each sample was pre-focused at 1500 V for 1 minute and focused at 3000 V for 8 minutes.

TABLE 11

Sample Preparation for icIEF

Component
Volume (μL)

1% Methyl cellulose
70

Pharmalyte 3-10
4

Pharmalyte 5-8
4

Diluted pI 5.1 marker
8

Diluted pI 8.2 marker
8

1 mg/mL test sample
50

Water
6

8M Urea
50

Example 3
Generation of Rat Anti-VEGF-A, Anti-VEGFRII, Rat-Anti-PDGF-BB, Anti-PDGFR-B Monoclonal Antibodies by DNA Immunization and Rat Hybridoma Technology
Example 3.1
DNA Immunization, Hybridoma Fusion and Screening

Genetic immunization enables the development of antibodies against any protein target directly from a cDNA. A cDNA encoding the soluble human VEGFA-165, soluble human PDGF-BB, human VEGFR-II ECD (extracellular domain) or human PDGFR-BB ECD was cloned into a eukaryotic expression vector (Aldevron GmbH, Freiburg, Germany). Wistar rats were immunized by intradermal application of DNA-coated gold-particles using a hand-held device for particle-bombardment (“gene gun”). Antibody-producing splenocytes or lymph node cells were isolated and fused with fusion partner myeloma cells using polyethylene glycol (PEG) according to standard procedures. To help identify positive antisera and hybridomas, screening is done with the use of either cells transfected with screening vector encoding GPI anchored human VEGF-A165, human PDGF-BB, human VEGFR-II ECD or human PDGFR-BB ECD proteins, soluble recombinant human VEGF-A165 and human PDGF-BB protein or peptides. The tables below are the lists of antibodies generated using the rat DNA immunization approach.

Anti-VEGF-A antibodies derived from rat hybridomas were characterized for binding, function and cross-reactivity in a panel of assays. Supernatants were tested for the ability to bind hVEGF₁₆₅(Example 1.3) and block binding of hVEGF₁₆₅to hVEGFR2 in a competition ELISA format (Example 1.4). Select hybridomas were assessed for cross-reactivity by testing for the ability to block human VEGF₁₁₁and rabbit VEGF₁₆₅in a Tyr1054 phosphorylation assay (Example 1.6) and blocking of murine VEGF₁₆₄binding to mVEGFR2 (Example 1.5). Candidate rat IgG was then examined for potency in the hVEGF₁₆₅-induced cell proliferation assay (Example 1.7), reactivity to native hVEGF₁₆₅(Example 1.11) and binding affinity measurement by Biacore analysis (Example 1.1). The data is summarized in Tables 12 and 13 below.

TABLE 12

A List of Anti-VEGF-A Antibodies Generated Using DNA Immunization and Rat

Hybridoma Technology

huVEGF-

Receptor
A₁₆₅

Competition
Neutralization

Phospho-
ELISA
ELISA
Potency in
ELISA
ELISA
Phospho-

ELISA
ELISA
Tyr1054/
Binding to
huVEGF-
hVEGF-
Mouse
Rat
Tyr1054/

huVEGF-
huVEGF-
huVEGF-
Naturally
A₁₆₅/
R2 Over-
VEGF-
VEGF-
Rabbit

Hybridoma

A 165
A₁₂₁
A₁₁₁
Derived
huVEGF-
expressing
A₁₆₄
A₁₆₄
VEGF-A₁₆₅

Clones
Isotype
Binding
Binding
Neutralization
huVEGF-A
R2 (nM)
Cells (nM)
Binding
Binding
Neutralization

BEW-
IgG2b/κ
+
NT
+
+
0.18
0.09
−
NT
+

164-

C4

BEW-
IgG2b/κ
+
NT
+
+
0.62
0.39
−
NT
+

1E3-

D6

BEW-
IgG2b/κ
+
NT
+
+
0.156
0.88
−
NT
+

5C3-

E7

BEW-
IgG2b/κ
+
NT
+
+
0.197
<0.1
−
NT
+

6C2-

C8

BEW-
IgG2a/κ
+
NT
+
+
0.342
0.41
−
NT
+

8E6-

E4

BEW-
IgG2a/κ
+
NT
+
+
0.249
0.16
−
NT
+

9A8-

E2

BEW-
IgG2a/κ
+
NT
+
+
0.274
0.17
−
NT
+

9E10-

E7

BEW-
IgG2b/κ
+
NT
+
+
0.42
0.42
−
NT
+

10H2-

B9

BEW-
IgG2a/κ
+
NT
+
+
0.124
<0.1
−
NT
+

9E3--

B9

BEW-
IgG2b/κ
+
NT
+
+
0.207
0.14
−
NT
+

9E7-

B4

BEW-
IgG1/κ
+
NT
+
+
0.584
1.46
−
NT
+

1G1-

C2

BEW-
IgG2b/κ
+
NT
+
+
0.155
<0.1
−
NT
+

9C2-

D6

BEW-
IgG2a/κ
+
NT
+
+
0.127
0.09
−
NT
+

9D2-

E8

BEW-
IgG2a/κ
+
NT
+
+
0.326
2.8
−
NT
+

1B10-

B9-C3

BEW-
IgG2b/κ
+
NT
+
+
0.124
0.96
−
NT
+

3A1-

D10-

G9

BED-
IgG2b/κ
+
NT
+
+
0.13
0.38
−
NT
+

4G10-

C8

BDB-
IgG2b/κ
+
NT
+
+
0.13
0.617
−
NT
+

4G8-

D4

NT = not tested

TABLE 13

Biacore Binding of Rat Anti-VEGF Antibodies

Antibody
k_on(M−1 s−1)
k_off(M−1)
K_D(M)

BDB-4G8-D4
≧1.0E+07
8.1E−06
≦8.1E−13

BDB-4G8-D4
1.4E+07
1.6E−05
1.2E−12

BED-4G10-C8
1.8E+07
1.1E−03
6.0E−11

BEW-1B4-C4
1.8E+07
1.3E−04
7.4E−12

BEW-1B10-B9-C3
4.4E+06
7.2E−05
1.6E−11

BEW-1E3-D6
1.4E+07
1.4E−04
1.0E−11

BEW-1G1-C2
1.6E+07
3.0E−05
1.9E−12

BEW-3A1-D10-G9
1.0E+07
1.4E−03
1.4E−10

BEW-5C3-E7
1.2E+07
4.8E−05
3.9E−12

BEW-6C2-C8
6.9E+06
8.4E−05
1.2E−11

BEW-8E6-E4
6.9E+06
1.2E−04
1.7E−11

BEW-9A8-E2
7.4E+06
7.1E−06
9.6E−13

BEW-9C2-D6
5.5E+06
≦1.0E−06
≦1.8E−13

BEW-9D2-E8
7.0E+06
9.8E−05
1.4E−11

BEW-9E10-E7
1.3E+07
3.9E−05
3.1E−12

BEW-9E3-B9
6.7E+06
9.5E−05
1.4E−11

BEW-9E7-B4
5.9E+06
2.5E−05
4.3E−12

BEW-10H2-B9
2.4E+07
2.7E−04
1.1E−11

Anti-PDGF-BB antibodies derived from rat hybridomas were characterized for binding, function and cross-reactivity in a panel of assays. Supernatants were tested for the ability to bind hPDGF-BB (Example 1.12) and block binding of hPDGF-BB to hPDGF-R in a competition ELISA format (Example 1.13). Select hybridomas were assessed for the ability to block human and rat PDGF-BB in a Tyr751 phosphorylation assay (Example 1.14). Candidate rat IgG was then examined for potency in the human, mouse and cynomolgus PDGF-BB-induced cell proliferation assay (Examples 1.15-1.17), reactivity to native hPDGF-BB (Example 1.19) and binding affinity measurement by Biacore analysis (Example 1.1). The data is summarized in Tables 14 and 15 below.

TABLE 14

A List of Anti-PDGF-BB Antibodies Generated using DNA Immunization and Rat

Hybridoma Technology

ELISA
Receptor

huPDGF-

mPDGF-
cynoPDGF-

Binding
Competition

BB
Phospho-
BB
BB

to
ELISA
Phospho-
Neutralization
Tyr751/
Neutralization
Neutralization

ELISA
Naturally
huPDGF-
Tyr751/hPDGF-
Potency
ratPDGF-
Potency
Potency

huPDGF-
Derived
BB/
BB
(nM) in
BB
(nM) in
(nM) in

Hybridoma

BB
huPDGF-
huPDGF
Neutralization
NIH-3T3
Neutralization
NIH-3T3
NIH-3T3

Clones
Isotype
Binding
BB
Rβ (nM)
(nM)
Cells
(nM)
Cells
Cells

BDI-
IgG2b/κ
+
+
1.121
0.629
0.195
0.333
0.026
0.194

9E8-E7

BDI-
IgG2b/κ
+
+
0.528
0.884
0.371
0.319
NT
NT

5H1-F6

BDI-
IgG2b
+
+
>10
>10
>5
>5
NT
NT

7H10-

D8

BDI-
IgG2b/κ
+
NT
>10
1.057
>5
+
NT
NT

1E1-D5

BDI-
IgG2b/λ
+
NT
1.065
0.923
0.741
+
NT
NT

5G2-F9

BDI-
IgG2b/λ
+
NT
3.228
1.618
>5
−
NT
NT

6A3-A9

BDI-
IgG2b
+
NT
>10
>10
>5
−
NT
NT

7F6-D3

BDI-
IgG2b/λ
+
NT
1.035
2.53
>5
−
NT
NT

10E7-

F9

BDI-
IgG2b/λ
+
NT
1.086
3.159
>5
−
NT
NT

8B8-F2

BFF-
IgG2b/κ
+
NT
>50
0.753
>5
NT
NT
NT

5C9-C7-

B5

BFF-
IgG2b/λ
+
NT
>50
1.745
>10
NT
NT
NT

7D7-D3-

E4

BFF-
IgG2b/κ
+
NT
>50
>10
>10
NT
NT
NT

7E9-C3-

B6

BFF-
IgG2b/λ
+
NT
>50
1.896
>10
NT
NT
NT

4G8-B4

BFF-
IgG2b/λ
+
NT
>50
0.739
>10
NT
NT
NT

4E8-E5

BFU-
IgG2b/κ
+
NT
>50
0.642
0.247
NT
NT
NT

3E2-B9-

B8

BFU-
IgG2b/κ
+
NT
7.095
0.736
0.344
NT
NT
NT

11A8-

D6-C3

BFU-
IgG2b
+
NT
2.287
0.639
>10
NT
NT
NT

3H6-D2

TABLE 15

Biacore Binding of Rat Anti-PDGF Antibodies

Antibody
k_on(M−1 s−1)
k_off(M−1)
K_D(M)

BDI-1E1-D5
≧1.0E+07
3.7E−04**
≦3.7E−11**

BDI-5G2-F9
≧1.0E+07
≦1.0E−06
≦1.0E−13

BDI-5H1-F6
≧1.0E+07
≦1.0E−06
≦1.0E−13

BDI-6A3-A9
≧1.0E+07
6.7E−03**
≦6.7E−10**

BDI-7F6-D3
≧1.0E+07
6.0E−03
≦6.0E−10

BDI-7H10-D8
≧1.0E+07
≦1.3E−02**
≦1.3E−09**

BDI-8B8-F2
≧1.0E+07*
≦1.0E−06*
≦1.0E−13*

BDI-9E8-E7
≧1.7E+07
≦1.0E−06
≦5.8E−14

BDI-9E8-E7
≧1.0E+07
≦1.0E−06
≦1.0E−13

BDI-10E7-F9
≧1.0E+07*
1.3E−04*
≦1.3E−11*

BFF-4E8-E5
≧1.0E+07
8.3E−03***
≦8.3E−10***

BFF-4G4-B8
≧1.0E+07
8.3E−03**
≦8.3E−10**

BFF-5C9-C7-B5
≧1.0E+07
5.8E−05
≦5.8E−12

BFF-7D7-D3-E4
≧1.0E+07
2.1E−02**
≦2.1E−09**

BFF-7E9-C3-B6
≧1.0E+07
1.2E−03**
≦1.2E−10**

BFU-3E2-B9-B8
≧1.0E+07
1.5E−06
≦1.5E−13

BFU-3H6-D2
≧1.0E+07
2.7E−04**
≦2.7E−11**

BFU-11A8-D6-C3
2.1E+07
≦1.0E−06
≦4.7E−14

*Low Ag response

**Heterogeneous off-rate

***Low Ag response and Heterogeneous off-rate

Anti-VEGFR2 antibodies derived from rat hybridomas were characterized for binding, function and cross-reactivity in a panel of assays. The subcloned rat antibodies were tested for the ability to bind hVEGFR2 (Example 1.22), block binding of hVEGF-R2 to hVEGF₁₆₅in a competition ELISA format (Example 1.23), and a hVEGF₁₆₅Tyr1054 phosphorylation assay (Example 1.24). Candidate molecules were then characterized for species cross-reactivity by testing their ability to block binding of mVEGFR2 to mVEGF₁₆₄in a competition ELISA format (Example 1.25). The data is summarized in Table 16 below.

TABLE 16

A List of Anti-VEGFR II Antibodies Generated Using

DNA Immunization and Rat Hybridoma Technology

Potency (nM)

hVEGF₁₆₅/
mVEGF₁₆₄/
Tyr1054

Hybridoma

hVEGFR2-
hVEGFR2-Fc
mVEGFR2-Fc
phospho-

Clones
Isotype
Fc Binding
Competition
Competition
assay

BCU-3D6-C9

+
NT
NT
NT

BCU-6B1-G6
IgG2a/κ
+
4.850
1.350
+

BCU-7A6-C2
IgG2b/κ
+
−
−
+

Anti-PDGF-Rβ antibodies derived from rat hybridomas were characterized for binding and function in a panel of assays. The subcloned rat antibodies were tested for the ability to bind hPDGF-Rβ (Example 1.26). Candidate IgG was also characterized for the ability to block binding of hPDGF-Rβ to hPDGF-BB in a competition ELISA format (Example 1.27) and an hPDGF-BB Tyr751 phosphorylation assay (Example 1.28). The data is summarized in Table 17 below.

TABLE 17

A List of Anti-PDGFR-B Antibodies Generated Using

DNA Immunization and Rat Hybridoma Technology

Potency (nM)

hPDGF-BB/
hPDGF-BB/

Hybridoma

hPDGFRβ-
hPDGFRβ-Fc
Tyr751

Clones
Isotype
Fc Binding
Competition
phospho-assay

BDE-3C9-G4
IgG2b/κ
+
0.832
4.696

BDE-4F2-D4
IgG2a/κ
+
0.527
+

BDE-8H6-F7

+
+
−

Example 4
Deduction of Variable Region Protein Sequences of Monoclonal Antibodies by DNA Cloning and Sequencing

Total RNA was extracted from hybridoma cell pellets using RNeasy mini kit (Qiagen, catalog #74104) using the following protocol. 600 μl of buffer RLT were added to disrupt cells by pipetting up and down several times. The cell lysate was homogenized by passing it 10 times through a 20-gauge needle fitted to an RNase-free syringe. One volume of 70% ethanol was added to the homogenized lysate and mixed well by pipetting. Up to 700 μl at a time of the sample were added to an RNeasy spin column and spun for 15 seconds at 10,000 rpm, discarding flow through. 700 μl of buffer RW1 were added to the column and spun for 15 seconds at 10,000 rpm, discarding flow through. 500 μl of buffer RPE were added to wash the column membrane and spun for 15 seconds at 10,000 rpm, discarding flow through. The same step was repeated one more time, but the column was centrifuged for 2 minutes. Sample was then centrifuged for 1 minute at 10,000 rpm to eliminate any carryover of buffer RPE. RNA was eluted with 30 μl of RNase-free water by centrifuging for 1 minute at 10,000 rpm. Subsequently, 2 μg of total RNA were used to synthesize first-strand cDNA using SuperScript First-Strand Synthesis System for RT-PCR (Invitrogen, catalog #11904-018) according to following protocol: 2 tag of RNA+2 μl dNTP+2 μl Oligo (dT)+DEPC-H₂O (to 20 μl) were incubated at 65° C. for 5 minutes, then transferred to ice for at least 1 minute. The sample was then added to the following mixture: 4 μl of 10×RT buffer+8 μl 25 mM MgCl₂+4 μl 0.1 M DTT+2 μl RNase OUT and incubated at 42° C. for 2 minutes. Then, 2 μl of SuperScript II RT were added to the sample and incubated at 42° C. for 50 minutes. Sample was then incubated at 70° C. for 15 minutes and chilled on ice. 2 μl of RNase H were then added and the sample was incubated at 37° C. for 20 minutes. cDNA was then used as template for PCR amplification of variable regions of antibodies. PCR was performed using first-strand cDNA, primers from Mouse Ig-Primer Set (Novagen, catalog #69831-3) and Platinum Super Mix High Fidelity (Invitrogen, catalog #12532-016). To amplify heavy chain variable regions, PCR samples were assembled as follows: 22.5 μl PCR Super Mix+0.25 μl reverse primer MuIgG V_H3′-2+1 μl cDNA+1.25 μl of one the forward primers (VH-A, VH-B) or 0.5 μl of one of the forward primers (VH-C, VH-D, VH-E, VH-F). To amplify light chain variable regions, PCR samples were assembled as follows: 22.5 μl PCR Super Mix+0.25 μl reverse primer MuIgKV_L-3′-1+1 μl cDNA+1.25 μl of one the forward primers (VL-A, VL-B) or 0.5 μl of one of the forward primers (VL-C, VL-D, VL-E, VL-F, VL-G).

For samples with primers VH-A, VH-B, VL-A and VL-B, the following PCR cycles were used (40-45 cycles, steps 2 through 4):

1—Denature 94° C. 2 minutes.

2—Denature 94° C. 30 seconds.

3—Anneal 50° C. 30 seconds.

4—Extend 68° C. 1 minute.

5—Final extension 68° C. 5 minutes.

6—Cool 4° C. forever

For samples with primers VH-C through VH-F, and VL-C through VL-G, the following PCR cycles were used (40-45 cycles, steps 2 through 4):

1—Denature 94° C. 2 minutes.

2—Denature 94° ° C. 30 seconds.

3—Anneal 60° C. 30 seconds.

4—Extend 68° C. 1 minute.

5—Final extension 68° C. 5 minutes.

6—Cool 4° C. forever

PCR products were run on a 1.2% agarose gel, and bands migrating at the expected size (400-500 bp) were excised for DNA extraction. DNA was purified using QIAquick Gel Extraction Kit (Qiagen, catalog #28704) according to the following protocol: gel slices were weighed. 3 volumes of buffer QG to 1 volume of gel were added to each gel slice. Samples were incubated at 50° C. for 10 minutes until gel slices were completely dissolved, mixing every 2-3 minutes. One gel volume of isopropanol was then added to each sample and mixed. Samples were then applied to QIAquick column and centrifuged for 1 minute at 13000 rpm. To wash, 750 μl of buffer PE were added to samples and spun for 1 minute at 13000 rpm. Columns were then centrifuged for an additional minute at 13,000 rpm to completely remove residual ethanol DNA was eluted by adding 30 μl of H₂O to each column and by spinning 1 minute at 13,000 rpm. Purified PCR products were then sequenced to identify variable region sequences (see Tables below).

TABLE 18

VH and VL Amino Acid Sequences of Rat

Anti-Human VEGFA Monoclonal Antibodies

SEQ ID

Protein
V Region

NO:
Clone
Region
123456789012345678901234567

406
BDB-4G8-D4 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGMYW

VKQAPGQGLQYMGWINTETGKPTYADDFKGRFVFFL

ETSASTAYLQINNLKNEDMATYFCARTNYYYRSYIF

YFDYWGQGTMVTVSS

407
BDB-4G8-D4
CDR-H1

GYTFTNYGMY

408
BDB-4G8-D4
CDR-H2

WINTETGKPTYADDFKG

409
BDB-4G8-D4
CDR-H3

TNYYYRSYIFYFDY

410
BDB-4G8-D4 VL

DTVLTQSPALAVSPGERVSISCRASESVSTHMHWYQ

QKPGQQPKLLIYGASNLESGVPARFSGSGSGTDFTL

TIDPVEADDTATYFCQQSWNDPFTFGAVTKLELK

411
BDB-4G8-D4
CDR-L1

RASESVSTHMH

412
BDB-4G8-D4
CDR-L2

GASNLES

413
BDB-4G8-D4
CDR-L3

QQSWNDPFT

414
BED-4G10-C8 VH

QVQLQQSGTELVKPGSSVKISCKASGYTFTSNYMHW

IRQQPGNGLEWIGWIYPGDGDTNYNHNFNGKATLTA

DKSSSTAYMQLSSLTSEDFAVYFCASSTRAIPGWFT

YWGQGTLVTVSS

415
BED-4G10-C8
CDR-H1

GYTFTSNYMH

416
BED-4G10-C8
CDR-H2

WIYPGDGDTNYNHNFNG

417
BED-4G10-C8
CDR-H3

STRAIPGWFTY

418
BED-4G10-C8 VL

DTVLTQSPALAVSPGERVSISCWASESVSTLMHWYQ

QKLGQQPKLLIYGASNLESGVPARFRGSGSGTDFTL

TIDPVEADDTATYFCQQSWSDPYTFGAGTKLELK

419
BED-4G10-C8
CDR-L1

WASESVSTLMH

420
BED-4G10-C8
CDR-L2

GASNLES

421
BED-4G10-C8
CDR-L3

QQSWSDPYT

422
BEW-10H2-B9 VH

QIQLVQSGPELKKPGESVKISCKASGYSFTNFGLYW

VKQAPGQGLQYMGWIDTETGKPTYADDFRGRFVFFL

ETSASTAYLQINNLKNEDMATYFCARVYGYPSWYFD

FWGPGTMVTVSS

423
BEW-10H2-B9
CDR-H1

GYSFTNFGLY

424
BEW-10H2-B9
CDR-H2

WIDTETGKPTYADDFRG

425
BEW-10H2-B9
CDR-H3

VYGYPSWYFDF

426
BEW-10H2-B9 VL

DIQMTQSPASLSTSLEEIVTITCQASQDIDNYLSWY

QQKPGKSPQLLIHSATSLADGVPSRFSGSRSGTQFS

LKIHRLQVEDTGIYYCLQHFFPPWTFGGGTKLELK

427
BEW-10H2-B9
CDR-L1

QASQDIDNYLS

428
BEW-10H2-B9
CDR-L2

SATSLAD

429
BEW-10H2-B9
CDR-L3

LQHFFPPWT

430
BEW-1B10-B9-C3 VH

EVQLVESGGGLVQPGRSLKLSCAASGFSFSKYDMAW

FRQTPTKGLEWVASITTSGVGTYYRDSVKGRFTVSR

DNAKSTLYLQMDSLRSEDTATYYCARGYGAMDAWGQ

GTSVTVSS

431
BEW-1B10-B9-C3
CDR-H1

GFSFSKYDMA

432
BEW-1B10-B9-C3
CDR-H2

SITTSGVGTYYRDSVKG

433
BEW-1B10-B9-C3
CDR-H3

GYGAMDA

434
BEW-1B10-B9-C3 VL

DIQMTQSPASLSASLEEIVTITCKASQDIDDYLSWY

QQKPGKSPQLVIYAATRLADGVPSRFSGSGSGTQYS

LKISRLQVDDSGIYYCLQSSSTPWTFGGGTNLELK

435
BEW-1B10-B9-C3
CDR-L1

KASQDIDDYLS

436
BEW-1B10-B9-C3
CDR-L2

AATRLAD

437
BEW-1B10-B9-C3
CDR-L3

LQSSSTPWT

438
BEW-1B4-C4 VH

QIQLVQSGPELKKPGESVKISCKASGYSFTNYGMYW

VKQAPGQGLQYMGWIDTETGKPTYTDDFKGRFVFFL

ETSASTAYLQINNLKNEDMATYFCARWSGDTAGIRG

PWFAYWGQGTLVTVSS

439
BEW-1B4-C4
CDR-H1

GYSFTNYGMY

440
BEW-1B4-C4
CDR-H2

WIDTETGKPTYTDDFKG

441
BEW-1B4-C4
CDR-H3

WSGDTAGIRGPWFAY

442
BEW-1B4-C4 VL

DIRMTQSPASLSASLGETVNIECLASEDIYSDLAWY

QQKPGKSPQLLIYNANDLQKGVPSRFSGSGSGTQYS

LKINSLQSEDVATYFCQQYNYYPGTFGAGTKLELK

443
BEW-1B4-C4
CDR-L1

LASEDIYSDLA

444
BEW-1B4-C4
CDR-L2

NANDLQK

445
BEW-1B4-C4
CDR-L3

QQYNYYPGT

446
BEW-1C6-D2 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGMYW

VKQAPGQGLQYMGWINTETGKPTYADDFKGRFVFFL

ETSASTAYFQINNLKNEDLATYFCARPSDYYDGFWF

PYWGQGTLVTVSS

447
BEW-1C6-D2
CDR-H1

GYTFTNYGMY

448
BEW-1C6-D2
CDR-H2

WINTETGKPTYADDFKG

449
BEW-1C6-D2
CDR-H3

PSDYYDGFWFPY

450
BEW-1C6-D2 VL

DTALTQSPALAVSPGERVSISCRASEGVNSYMHWYQ

QSPGQQPKLLIYKASNLASGVPARFSGSGSGTDFTL

TIDPVEADDTATYFCQQSWYDPLTFGSGTKLEIK

451
BEW-1C6-D2
CDR-L1

RASEGVNSYMH

452
BEW-1C6-D2
CDR-L2

KASNLAS

453
BEW-1C6-D2
CDR-L3

QQSWYDPLT

454
BEW-1E3-D6 VH

QIQLVQSGPELKKPGESVKISCKASGYPFTNSGMYW

VKQAPGQGLQYMGWINTEAGKPTYADDFKGRFVFFL

ETSASTAYLQINNLKNEDMATYFCARWGYISDNSYG

WFDYWGQGTLVTVSS

455
BEW-1E3-D6
CDR-H1

GYPFTNSGMY

456
BEW-1E3-D6
CDR-H2

WINTEAGKPTYADDFKG

457
BEW-1E3-D6
CDR-H3

WGYISDNSYGWFDY

458
BEW-1E3-D6 VL

DTVLTQSPALAVSPGERVSISCRASEGVYSYMHWYQ

QNPGQQPKLLIYKASNLASGVPARFSGSGSGTDFTL

TIDPVEADDTATYFCHQNWNDPLTFGSGTKLEIK

459
BEW-1E3-D6
CDR-L1

RASEGVYSYMH

460
BEW-1E3-D6
CDR-L2

KASNLAS

461
BEW-1E3-D6
CDR-L3

HQNWNDPLT

462
BEW-3A1-D10-G9 VH

QVQLEQSGAELVKPGTSVKLSCMASGYTSSSNHMNW

MKQTTGQGLEWIGIINPGSGGTRYNVKFEGKATLTV

DKSSSTAFMQLNSLTPEDSAVYYCARAGFPGPFSYY

AMGAWGQGTSVTVSS

463
BEW-3A1-D10-G9
CDR-H1

GYTSSSNHMN

464
BEW-3A1-D10-G9
CDR-H2

IINPGSGGTRYNVKFEG

465
BEW-3A1-D10-G9
CDR-H3

AGFPGPFSYYAMGA

466
BEW-3A1-D10-G9 VL

DIQMTQSPPVLSASVGDRVTLSCKASQNIHNNLDWY

QQKHGEAPKLLIFYTNNLQTGIPSRFSGSGSGTDYT

LTISSLQPEDVATYYCYQYNSGYTFGAGTKLELK

467
BEW-3A1-D10-G9
CDR-L1

KASQNIHNNLD

468
BEW-3A1-D10-G9
CDR-L2

YTNNLQT

469
BEW-3A1-D10-G9
CDR-L3

YQYNSGYT

470
BEW-5C3-E7 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGVYW

VKQAPGQGLQYMGWINTETGKPTYADDFKGRFVFFL

ETSTNTAYLQINNLKNEDMATFFCARARQLDWFVYW

GQGTLVTVSS

471
BEW-5C3-E7
CDR-H1

GYTFTNYGVY

472
BEW-5C3-E7
CDR-H2

WINTETGKPTYADDFKG

473
BEW-5C3-E7
CDR-H3

ARQLDWFVY

474
BEW-5C3-E7 VL

DTVLTQSPALTVSPGERVSISCRARESLTTSLCWFQ

QKPGQQPKLLIYGASKLESGVPARFSGSGSGTDFTL

TIDPVEADDTATYFCQQSWYDPPTFGGGTKLELK

475
BEW-5C3-E7
CDR-L1

RARESLTTSLC

476
BEW-5C3-E7
CDR-L2

GASKLES

477
BEW-5C3-E7
CDR-L3

QQSWYDPPT

478
BEW-6C2-C8 VH

EVQLVESGGGLVQPGSSLKLSCAASGFTFSYYGMHW

IRQAPKKGLEWMALIYYDSSKMYYADSVKGRFTISR

DNSKNTLYLEMNSLRSEDTAMYYCAAGGTAPVYWGQ

GVMVTVSS

479
BEW-6C2-C8
CDR-H1

GFTFSYYGMH

480
BEW-6C2-C8
CDR-H2

LIYYDSSKMYYADSVKG

481
BEW-6C2-C8
CDR-H3

GGTAPVY

482
BEW-6C2-C8 VL

NIQLTQSPSLLSASVGDRVTLSCKGSQNIANYLAWY

QQKLGEAPKLLIYNTDSLQTGIPSRFSGSGSGTDYT

LTISSLQPEDVATYFCYQSNNGYTFGAGTKLELR

483
BEW-6C2-C8
CDR-L1

KGSQNIANYLA

484
BEW-6C2-C8
CDR-L2

NTDSLQT

485
BEW-6C2-C8
CDR-L3

YQSNNGYT

486
BEW-8E6-E4 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTDYAMHW

VKQAPGKVLKWMGWINTFTGKPTYIDDFKGRFVFSL

EASASTANLQISDLKNEDTATYFCARGNYYSGYWYF

DFWGPGTMVTMSS

487
BEW-8E6-E4
CDR-H1

GYTFTDYAMH

488
BEW-8E6-E4
CDR-H2

WINTFTGKPTYIDDFKG

489
BEW-8E6-E4
CDR-H3

GNYYSGYWYFDF

490
BEW-8E6-E4 VL

DIQMTQSPASLSASLGETISIECRASEDISSNLAWY

QQKSGKSPQLLIFAANRLQDGVPSRFSGSGSGTQFS

LKISGMQPEDEGDYFCLQGSKFYTFGAGTKLELK

491
BEW-8E6-E4
CDR-L1

RASEDISSNLA

492
BEW-8E6-E4
CDR-L2

AANRLQD

493
BEW-8E6-E4
CDR-L3

LQGSKFYT

494
BEW-9A8-E2 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGMYW

VKQAPGQGLQYMGWINTETGKPIYADDFKGRFVFFL

ETSASTAYLQINNLKNEDMATFFCARVDYDGSFWFA

YWGQGTLVTVSS

495
BEW-9A8-E2
CDR-H1

GYTFTNYGMY

496
BEW-9A8-E2
CDR-H2

WINTETGKPIYADDFKG

497
BEW-9A8-E2
CDR-H3

VDYDGSFWFAY

498
BEW-9A8-E2 VL

DTVLTQSPALAVSPGERVSISCRASESVSTVIHWYQ

QKPGQQPKLLIHGASNLESGVPARFSGSGSGTDFTL

TIDPVEADDTATYFCQQHWNDPPTFGAGTKLEMK

499
BEW-9A8-E2
CDR-L1

RASESVSTVIH

500
BEW-9A8-E2
CDR-L2

GASNLES

501
BEW-9A8-E2
CDR-L3

QQHWNDPPT

502
BEW-9C2-D6 VH

QIQLVQSGPELKKPGESVKVSCKASGYTFTNYGIHW

VKQAPGQGLQYVGWINTETGRPTYADDFKGRFVFFL

ETSASTAYLQINNLKNEDMATYFCARPLYYGYAHYF

DYWGQGVMVTVSS

503
BEW-9C2-D6
CDR-H1

GYTFTNYGIH

504
BEW-9C2-D6
CDR-H2

WINTETGRPTYADDFKG

505
BEW-9C2-D6
CDR-H3

PLYYGYAHYFDY

506
BEW-9C2-D6 VL

DIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWY

QQKPGKSPQLLIYGATSLADGVPSRFSGSRSGTQYS

LKISRLQVEDIGIYYCQQASSVTYTFGAGTKLELK

507
BEW-9C2-D6
CDR-L1

QASQDIGNWLA

508
BEW-9C2-D6
CDR-L2

GATSLAD

509
BEW-9C2-D6
CDR-L3

QQASSVTYT

510
BEW-9D2-E8 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGMYW

VKLAPGQGLQYLGWINTETGKPTYADDFKGRFVFFL

ETSASTAYLQINNLRNEDMATYFCARPSDYYDGFWF

AYWGQGTLVTVSS

511
BEW-9D2-E8
CDR-H1

GYTFTNYGMY

512
BEW-9D2-E8
CDR-H2

WINTETGKPTYADDFKG

513
BEW-9D2-E8
CDR-H3

PSDYYDGFWFAY

514
BEW-9D2-E8 VL

DTVLTQSPALTVSPGERVSISCRASEWVNSYMHWYQ

QNPGQQPKLLIYKASNLASGVPARFSGSGSGTDFTL

TLDPVEADDTATYFCQQSWNDPLTFGSGTKLEIK

515
BEW-9D2-E8
CDR-L1

RASEWVNSYMH

516
BEW-9D2-E8
CDR-L2

KASNLAS

517
BEW-9D2-E8
CDR-L3

QQSWNDPLT

518
BEW-9E10-E7 VH

QIQLLQSGPELKKPGESVKISCKASGYTFTNYGMYW

VKQAPGQGLQYMGWIDTETGRPTYADDFKGRFVFFL

ETSASTAYLQINNLKNEDMATYFCARWSGDTTGIRG

PWFAYWGQGTLVTVSS

519
BEW-9E10-E7
CDR-H1

GYTFTNYGMY

520
BEW-9E10-E7
CDR-H2

WIDTETGRPTYADDFKG

521
BEW-9E10-E7
CDR-H3

WSGDTTGIRGPWFAY

522
BEW-9E10-E7 VL

DIRMTQSPASLSASLGETVNIECLASEDIYSDLAWY

QQKPGRSPQLLIYNANGLQNGVPSRFGGSGSGTQYS

LKINSLQSEDVATYFCQQYNYFPGTFGAGTKLELK

523
BEW-9E10-E7
CDR-L1

LASEDIYSDLA

524
BEW-9E10-E7
CDR-L2

NANGLQN

525
BEW-9E10-E7
CDR-L3

QQYNYFPGT

526
BEW-9E3-B9 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGMYW

VKQAPGQGLQYMGWINTETGKPTYADDFKGRFVFFL

ETSASTAFLQINNLKNEDMATYFCARPSDYYDGFWF

PYWGQGALVTVSS

527
BEW-9E3-B9
CDR-H1

GYTFTNYGMY

528
BEW-9E3-B9
CDR-H2

WINTETGKPTYADDFKG

529
BEW-9E3-B9
CDR-H3

PSDYYDGFWFPY

530
BEW-9E3-B9 VL

DTILTQSPALAVSPGERISISCRASEGVNSYMHWYQ

QNPGQQPKLLIYKASNLASGVPARFSGSGSGTDFTL

TIDPVEADDTATYFCQQSWNDPLTFGSGTKLEIK

531
BEW-9E3-B9
CDR-L1

RASEGVNSYMH

532
BEW-9E3-B9
CDR-L2

KASNLAS

533
BEW-9E3-B9
CDR-L3

QQSWNDPLT

534
BEW-9E7-B4 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGMYW

VKQAPGQGLQYMGWIDTETGKPTYADDFKGRFVFFL

ETSASTAYLQINNLRNEDMATYFCARWGYTSDYYYG

WFPDWGQGTLVTVST

535
BEW-9E7-B4
CDR-H1

GYTFTNYGMY

536
BEW-9E7-B4
CDR-H2

WIDTETGKPTYADDFKG

537
BEW-9E7-B4
CDR-H3

WGYTSDYYYGWFPD

538
BEW-9E7-B4 VL

DTVLTQSPALAVSPGERVSISCRASEGVNSYMHWYQ

QNPGQQPKLLIYKASNLASGVPARFSGSGSGTDFTL

NIHPVEADDTATYFCQQNWNVPLTFGSGTKLEIK

539
BEW-9E7-B4
CDR-L1

RASEGVNSYMH

540
BEW-9E7-B4
CDR-L2

KASNLAS

541
BEW-9E7-B4
CDR-L3

QQNWNVPLT

TABLE 19

VH and VL Amino Acid Sequences of Rat Anti-Human PDGF-BB Monoclonal

Antibodies

SEQ ID

Protein
V Region

NO:
Clone
Region
12345678901234567890123456

542
BDI-1E1-D5 VH

EVKLQQSGDELVRPGASVKMSCKASGYTFTDYVMHW

VKQSPGQGLEWIGTIIPLIDTTSYNQKFKGKATLTA

DKSSNTAYMELSRLTSEDSAVYYCARTSPYYYSSYD

VMDAWGQGASVTVSS

543
BDI-1E1-D5
CDR-H1

GYTFTDYVMH

544
BDI-1E1-D5
CDR-H2

TIIPLIDTTSYNQKFKG

545
BDI-1E1-D5
CDR-H3

TSPYYYSSYDVMDA

546
BDI-1E1-D5 VL

NIQLTQSPSLLSASVGDRVTLSCKGSQNINNYLAWY

QQKLGEAPKLLIYKTNNLQTGIPSRFSGCGSGTDYT

LTISSLHSEDLATYYCYQYDNGYTFGAGTKLELK

547
BDI-1E1-D5
CDR-L1

KGSQNINNYLA

548
BDI-1E1-D5
CDR-L2

KTNNLQT

549
BDI-1E1-D5
CDR-L3

YQYDNGYT

550
BDI-5G2-F9 VH

QVTLKESGPGILQPSQTLSLTCTFSGFSLSTFGMGV

GWIRQPSGKGLEWLANIWWDDDKYYNPSLKNRLTIS

KDTSNSQAFLEITNVDTADTATYYCARISTGISSYY

VMDAWGQGASVTVSS

551
BDI-5G2-F9
CDR-H1

GFSLSTFGMGVG

552
BDI-5G2-F9
CDR-H2

NIWWDDDKYYNPSLKN

553
BDI-5G2-F9
CDR-H3

ISTGISSYYVMDA

554
BDI-5G2-F9 VL

QFTLTQPKSVSGSLRSTITIPCERSSGDIGDTYVSW

YQQHLGRPPINVIYGNDQRPSEVSDRFSGSIDSSSN

SASLTITNLQMDDEADYFCQSYDSDIDIVFGGGTKL

TVL

555
BDI-5G2-F9
CDR-L1

ERSSGDIGDTYVS

556
BDI-5G2-F9
CDR-L2

GNDQRPS

557
BDI-5G2-F9
CDR-L3

QSYDSDIDIV

558
BDI-5H1-F6 VH

QVTLKESGPGILQPSQTLSLTCTFSGFSLSTFGMGV

GWIRQPSGKGLEWLANIWWDDDKYYNPSLKNRLTIS

KDTSNSQAFLEITNVDTADTATYYCARISTGISSYY

VMDAWGQGASVTVSS

559
BDI-5H1-F6
CDR-H1

GFSLSTFGMGVG

560
BDI-5H1-F6
CDR-H2

NIWWDDDKYYNPSLKN

561
BDI-5H1-F6
CDR-H3

ISTGISSYYVMDA

562
BDI-5H1-F6 VL

QFTLTQPKSVSGSLRSTITIPCERSSGDIGDTYVSW

YQQHLGRPPINVIYGNDQRPSEVSDRFSGSIDSSSN

SASLTITNLQMDDEADYFCQSYDSDIDIVFGGGTKL

TVL

563
BDI-5H1-F6
CDR-L1

ERSSGDIGDTYVS

564
BDI-5H1-F6
CDR-L2

GNDQRPS

565
BDI-5H1-F6
CDR-L3

QSYDSDIDIV

566
BDI-6A3-A9 VH

EVQLVESGGGLVQPGRSLKFSCAASGFSFSDSAMAW

VRQAPKKGLEWVATIIYDGSGTYYRDSVKGRFTISR

DNAKSTLYLQMDSLRSEDTATYYCARLGFNYGNYGY

YVMDAWGQGASVTVSS

567
BDI-6A3-A9
CDR-H1

GFSFSDSAMA

568
BDI-6A3-A9
CDR-H2

TIIYDGSGTYYRDSVKG

569
BDI-6A3-A9
CDR-H3

LGFNYGNYGYYVMDA

570
BDI-6A3-A9 VL

QFTLTQPKSVSGSLRNTITIPCERSSGDIGDSYVSW

YQQHLGRPPINVIFADDQRPSEVSDRFSGSIDSSSN

SASLTITNLQMDDEADYFCQSYDSNIDINIVFGGGT

KLTVL

571
BDI-6A3-A9
CDR-L1

ERSSGDIGDSYVS

572
BDI-6A3-A9
CDR-L2

ADDQRPS

573
BDI-6A3-A9
CDR-L3

QSYDSNIDINIV

574
BDI-7H10-D8 VH

EVKLQQSGDELVRPGASVKMSCKASGYTFTDYAMHW

VKQSPGQGLEWIGTIIPLIDTTSYNQKFKGKATLTA

DTSSNTAYMELSRLTSEDSAVYYCARDWDNNWGYFD

YWGQGVMVTVSS

575
BDI-7H10-D8
CDR-H1

GYTFTDYAMH

576
BDI-7H10-D8
CDR-H2

TIIPLIDTTSYNQKFKG

577
BDI-7H10-D8
CDR-H3

DWDNNWGYFDY

578
BDI-7H10-D8 VL

DVVLTQTPVSLSVTLGDQASISCRSSQSLEYSDGYT

YLEWYLQKPGQSPQLLIYGVSNRFSGVPDRFIGSGS

GTDFTLKISRVEPEDLGVYYCFQATHDPLTFGSGTK

LEIK

579
BDI-7H10-D8
CDR-L1

RSSQSLEYSDGYTYLE

580
BDI-7H10-D8
CDR-L2

GVSNRFS

581
BDI-7H10-D8
CDR-L3

FQATHDPLT

582
BDI-9E8-E7 VH

QVTLKESGPGILQPSQTLSLTCTFSGFSLSTYGMGV

GWIRQPSGKGLEWLANIWWDDDKYYNPSLKNRLTIS

KDTSNNQAFLKITNVDTADTATYYCARIESIGTTYS

FDYWGQGVMVTVSS

583
BDI-9E8-E7
CDR-H1

GFSLSTYGMGVG

584
BDI-9E8-E7
CDR-H2

NIWWDDDKYYNPSLKN

585
BDI-9E8-E7
CDR-H3

IESIGTTYSFDY

586
BDI-9E8-E7 VL

QFTLTQPKSVSGSLRSTITIPCERSSGDIGDSYVSW

YQQHLGRPPINVIYADDQRPSEVSDRFSGSIDSSSN

SASLTITNLQMDDEADYFCQSYDINIDIVFGGGTKL

TVL

587
BDI-9E8-E7
CDR-L1

ERSSGDIGDSYVS

588
BDI-9E8-E7
CDR-L2

ADDQRPS

589
BDI-9E8-E7
CDR-L3

QSYDINIDIV

590
BFU-11A8-D6-C3 VH

EVQLQQSGPELQRPGASVKLSCKASGYTFTESYIYW

VKQRPEQSLELIGRIDPEDGSTDYVEKFKNKATLTA

DTSSNTAYMQLSSLTSEDTATYFCARFGARSYFYPM

DAWGQGTSVTVSS

591
BFU-11A8-D6-C3
CDR-H1

GYTFTESYIY

592
BFU-11A8-D6-C3
CDR-H2

RIDPEDGSTDYVEKFKN

593
BFU-11A8-D6-C3
CDR-H3

FGARSYFYPMDA

594
BFU-11A8-D6-C3 VL

DTVLTQSPTLAVSPGERVSIPCRASESVSTLMHWYQ

QKPGQQPRLLIYGASNLESGVPARFSGSGSGTDFTL

TIDPVEADDTATYFCQQSWNDPWTFGGGTKLELK

595
BFU-11A8-D6-C3
CDR-L1

RASESVSTLMH

596
BFU-11A8-D6-C3
CDR-L2

GASNLES

597
BFU-11A8-D6-C3
CDR-L3

QQSWNDPWT

598
BFU-3E2-B9-B8 VH

EVQLQQSGPELQRPGASVKLSCKASGYTFTESYMYW

VKQRPEQSLELIGRIDPEDGSTDYVEKFKNKATLTA

DTSSNTAYMQLSSLTSEDSATYFCARFGARSYFYPM

DAWGQGTSVTVSS

599
BFU-3E2-B9-B8
CDR-H1

GYTFTESYMY

600
BFU-3E2-B9-B8
CDR-H2

RIDPEDGSTDYVEKFKN

601
BFU-3E2-B9-B8
CDR-H3

FGARSYFYPMDA

602
BFU-3E2-B9-B8 VL

DTVLTQPPALAVSPGERVSISCRASESVSTLMHWYQ

QKPGQQPRLLIYGASNLESGVPARFSGSGSGTDFTL

TIDPVEADDTATYFCQQSWNDPWTFGGGTKLELK

603
BFU-3E2-B9-B8
CDR-L1

RASESVSTLMH

604
BFU-3E2-B9-B8
CDR-L2

GASNLES

605
BFU-3E2-B9-B8
CDR-L3

QQSWNDPWT

TABLE 20

VH and VL Amino Acid Sequences of Rat Anti-Human VEGFR II

Monoclonal Antibodies

SEQ ID

Protein
V Region

NO:
Clone
Region
12345678901234567890123456

606
BCU-3D6-C9 VH

QIQLVQSGPELKKPGESVKISCKASEYTFTDYAIHW

VKQAPGKGLKWMGWINTYTGKPTYADDFKGRFVFSL

EASASTANLQISNLKNEDTATYFCARDYGGYGERRD

YFDYWGQGVMVTVSS

607
BCU-3D6-C9
CDR-H1

EYTFTDYAIH

608
BCU-3D6-C9
CDR-H2

WINTYTGKPTYADDFKG

609
BCU-3D6-C9
CDR-H3

DYGGYGERRDYFDY

610
BCU-3D6-C9 VL

DIQMTQSPASLSASLGETVTIECRVSEDIYNGLAWY

QQKPGKSPQFLIYNANRLHTGVPSRFSGSGSGTQFS

LKINSLQSEDVANYFCQQYYDYPLTFGSATKLEIK

611
BCU-3D6-C9
CDR-L1

RVSEDIYNGLA

612
BCU-3D6-C9
CDR-L2

NANRLHT

613
BCU-3D6-C9
CDR-L3

QQYYDYPLT

614
BCU-6B1-G6 VH

QIQLVQSGPELKKPGESVKISCKASGYTFTNYGMYW

VKQAPGQALQFMGWINTETGQPTYADDFKGRFVFFL

ETSASTAYLQINNLKNEDMATYFCARLGNNYGIWFA

YWGQGTLVTVSS

615
BCU-6B1-G6
CDR-H1

GYTFTNYGMY

616
BCU-6B1-G6
CDR-H2

WINTETGQPTYADDFKG

617
BCU-6B1-G6
CDR-H3

LGNNYGIWFAY

618
BCU-6B1-G6 VL

DIQMTQSPASLSASLGETVTIECRASDDLYSTLAWY

QQKPGDSPQLLIFDANRLAAGVPSRFSGSGSGTQYS

LKINSLQSEDVASYFCQQYNKFPWTFGGGTKLELK

619
BCU-6B1-G6
CDR-L1

RASDDLYSTLA

620
BCU-6B1-G6
CDR-L2

DANRLAA

621
BCU-6B1-G6
CDR-L3

QQYNKFPWT

622
BCU-7A6-C2 VH

EVQLVESGGGLVQPRGSLKLSCAASGFDFNSYGMSW

VRQAPGKGLDLVADISSKSYNYATYYADSVKDRFTI

SRDDSQSMVYLQMDNLKTEDTALYYCTESLELGGAY

WGQGTLVTVSS

623
BCU-7A6-C2
CDR-H1

GFDFNSYGMS

624
BCU-7A6-C2
CDR-H2

DISSKSYNYATYYADSVKD

625
BCU-7A6-C2
CDR-H3

SLELGGAY

626
BCU-7A6-C2 VL

DIQMTQSPPSLSASLGDEVTITCQASQNINKFIAWY

QQKPGKAPRLLIRYTSTLKSGTPSRFSGSGSGRDYS

FSISNVESEDIASYYCLQYDSLPWTFGGGTKLELK

627
BCU-7A6-C2
CDR-L1

QASQNINKFIA

628
BCU-7A6-C2
CDR-L2

YTSTLKS

629
BCU-7A6-C2
CDR-L3

LQYDSLPWT

TABLE 21

VH and VL Amino Acid Sequences of Rat Anti-Human PDGFR-B

Monoclonal Antibodies

SEQ ID

Protein
V Region

NO:
Clone
Region
12345678901234567890123456

630
BDE-3C9-G4 VH

EVQLVESGGGLVQPGRSLKLSCAASGFTFSNYGMA

WVRQAPTQGLEWVASITNSGGNTYYRDSVKGRFTI

SRDSAKNTQYLQMDSLRSEDTATYFCARHTPGANY

FDYWGQGLMVTVSS

631
BDE-3C9-G4
CDR-H1

GFTFSNYGMA

632
BDE-3C9-G4
CDR-H2

SITNSGGNTYYRDSVKG

633
BDE-3C9-G4
CDR-H3

HTPGANYFDY

634
BDE-3C9-G4 VL

DIQMTQSPPSLSASLGEKVTITCQASQSIKNYIAW

YQLKPGTAPRLLMRYTSTLESGTPSRFSGSGSGRD

YSFSISNVESEDIASYYCVQYANLYTFGGGTKLEL

K

635
BDE-3C9-G4
CDR-L1

QASQSIKNYIA

636
BDE-3C9-G4
CDR-L2

YTSTLES

637
BDE-3C9-G4
CDR-L3

VQYANLYT

638
BDE-4F2-D4 VH

QVQLKESGPGLMQPSQTLSLTCTVSGFSLTNYGVS

WVRQFPGKGLEWIAAISSGGSTYYNSALKSRLSIS

RDTSRSQVFLKMNSLLTEDTAFYFCTRVYYGSNYF

DYWGPGVMVTVSS

639
BDE-4F2-D4
CDR-H1

GFSLTNYGVS

640
BDE-4F2-D4
CDR-H2

AISSGGSTYYNSALKS

641
BDE-4F2-D4
CDR-H3

VYYGSNYFDY

642
BDE-4F2-D4 VL

DIVMTQTPSSQAVSAGEKVTMSCKSSQSLLYGGDQ

KNFLAWYQQKPGQSPKLLIYLASTRESGVPDRFIG

SGSGTDFTLTISSVQAEDLADYYCQQHYGYPFTFG

SGTKLEIK

643
BDE-4F2-D4
CDR-L1

KSSQSLLYGGDQKNFLA

644
BDE-4F2-D4
CDR-L2

LASTRES

645
BDE-4F2-D4
CDR-L3

QQHYGYPFT

646
BDE-8H6-F7 VH

EVQLVESGGGLVQPGSSLKLSCLASGFTFSNYNMY

WIRQAPKKGLEWIALIFYDNNNKYYADSVKGRFTI

SRDNSKNTLYLEMNSLRSEDTAMYYCLRDSGPFSY

WGQGTLVTVSS

647
BDE-8H6-F7
CDR-H1

GFTFSNYNMY

648
BDE-8H6-F7
CDR-H2

LIFYDNNNKYYADSVKG

649
BDE-8H6-F7
CDR-H3

DSGPFSY

650
BDE-8H6-F7 VL

DIQMTQSPPSLSASLGDKVTINCQAGQNIKKYIAW

YQQEPGKVPRLLIRYTSKLESDTPSRFSGSGSGRD

YSFSISNVESEDIASYYCLQYDNLPWTFGGGTKLE

LK

651
BDE-8H6-F7
CDR-L1

QAGQNIKKYIA

652
BDE-8H6-F7
CDR-L2

YTSKLES

653
BDE-8H6-F7
CDR-L3

LQYDNLPWT

Example 5
Generation of Chimeric Antibodies

The variable domains of the heavy and light chain of the rat mAbs were cloned in-frame to mutant human IgG1 (L234, 235A) heavy-chain and kappa light-chain constant regions, respectively. The activities of the resulting chimeric antibodies were confirmed in ELISA-based binding and competition assays or Biacore binding assay, and were comparable to their parental rat mAbs.

Chimeric anti-VEGF-A antibodies were characterized for binding, function and cross-reactivity in a panel of assays. Potency for all chimeric molecules was characterized in the hVEGF₁₆₅-induced cell proliferation assay (Example 1.7). Binding affinity of these molecules to hVEGF₁₆₅was measured by Biacore analysis (Example 1.1). Select chimeric molecules were tested for the ability to block binding of hVEGF₁₆₅to hVEGF-R2 in a competition ELISA format (Example 1.4) and a hVEGF₁₁₁Tyr1054 phosphorylation assay (Example 1.6). Candidate molecules were then examined for potency in the HMVEC-d hVEGF₁₆₅-induced proliferation assay (Example 1.10) and species cross-reactivity in the rabVEGF₁₆₅-induced cell proliferation assay (Example 1.9). The data is summarized in Tables 22 and 23 below.

TABLE 22

Characterization of Chimeric Anti-Human VEGF-A Monoclonal Antibodies

Receptor

huVEGF-

Competition

huVEGF-A₁₆₅
rabbitVEGF-A₁₆₅
A₁₆₅

ELISA
Phospho-
Neutralization
Neutralization
Neutralization

ELISA
huVEGF-
Tyr1054/
Potency in
Potency in
Potency

huVEGF-
A₁₆₅/
huVEGF-A₁₁₁
hVEGFR2
hVEGFR2
in

Chimeric
A₁₆₅
huVEGFR2
Neuterlization
Overexpressing
Overexpressing
HMVEC-d

Clones
Binding
(nM)
(nM)
Cells (nM)
Cells (nM)
cells (nM)

chBEW-1B4
NT
NT
NT
1.428
NT
NT

chBEW-1B4
NT
NT
NT
1.669
NT
NT

half-body

chBEW-1E3
NT
NT
NT
0.657
NT
NT

chBEW-1E3
NT
NT
NT
3.752
NT
NT

half-body

chBEW-5C3
NT
NT
NT
0.244
NT
NT

chBEW-5C3
NT
NT
NT
2.264
NT
NT

half-body

chBEW-6C2
NT
0.148
0.435
>10
0.58
0.031

chBEW-6C2
NT
NT
NT
>10
NT
NT

half-body

chBEW-8E6
NT
NT
NT
0.499
NT
NT

chBEW-8E6
NT
NT
NT
>10
NT
NT

half-body

chBEW-9A8
NT
0.097
0.260
0.416
0.510
0.026

chBEW-9A82
NT
NT
NT
1.584
NT
NT

half-body

chBEW-9E10
NT
NT
NT
0.448
NT
NT

chBEW-9E10
NT
NT
NT
0.598
NT
NT

half-body

chBEW-10H2
NT
NT
NT
0.912
NT
NT

chBEW-
NT
NT
NT
2.562
NT
NT

10H2-B9 half-

body

chBEW-9C2
NT
NT
NT
2.090
NT
NT

chBEW-9C2
NT
NT
NT
2.740
NT
NT

half-body

chBEW-9D2
NT
NT
NT
1.556
0.740
2.150

chBEW-9D2
NT
NT
NT
>10
NT
NT

half-body

chBEW-1B10
NT
NT
NT
0.377
NT
NT

chBEW-3A1
NT
NT
NT
0.680
NT
NT

chBEW-3A1
NT
NT
NT
>10
NT
NT

half-body

chBDB-4G8
NT
0.157
0.575
0.687
NT
0.195

chBEW-1C6
NT
NT
NT
3.595
NT
NT

half-body

NT—Not tested

TABLE 23

Biacore Binding of Rat and Rat-Human Chimera Anti-VEGF

Antibody
k_on(M−1 s−1)
k_off(M−1)
K_D(M)

chBDB-4G8
1.7E+07
2.4E−05
1.9E−12

chBDB-4G8
1.2E+07
4.7E−05
3.8E−12

chBED-4G10-C8
1.0E+07
5.9E−03
5.9E−10

chBEW-1B4-C4
1.1E+07
1.2E−04
1.1E−11

chBEW-1B10-B9-C3
5.5E+06
5.2E−05
9.4E−12

chBEW-1E3-D6
7.2E+06
8.0E−05
1.1E−11

chBEW-3A1-D10-G9
3.5E+07
8.0E−04
2.3E−11

chBEW-5C3-E7
6.8E+06
8.2E−05
1.2E−11

chBEW-6C2
4.9E+06
4.3E−05
8.8E−12

chBEW-8E6-E4
6.2E+06
1.0E−04
1.6E−11

chBEW-9A8
8.9E+06
≦1.0E−06
≦1.1E−13

chBEW-10H2-B9
2.8E+07
3.5E−04
1.3E−11

Chimeric anti-PDGF-BB antibodies were characterized for binding, function and cross-reactivity in a panel of assays. The chimeric molecules were first tested for the ability to bind hPDGF-BB in a direct binding ELISA (Example 1.12). Binding affinity of these molecules to hPDGF-BB was then measured by Biacore analysis (Example 1.1). Functional characterization of these molecules included testing of the ability to block binding of hPDGF-BB to hPDGF-Rβ in a competition ELISA format (Example 1.13) and an hPDGFRβ Tyr751 phosphorylation assay (Example 1.14). Potency was further characterized in the hPDGF-BB-induced cell proliferation assay (Example 1.15). Candidate molecules were advanced and cross-reactivity was determined for mouse and rat/rabbit PDGF-BB in the cell-based proliferation assay (Examples 1.17-1.18). The data is summarized in Tables 24 and 25 below.

TABLE 24

Characterization of Chimeric Anti-Human PDGF-BB Monoclonal Antibodies

Receptor
Phospho-
huPDGF-BB
ratPDGF-BB
mPDGF-BB

ELISA
Competition
Tyr751/hPDGF-
Neutralization
Neutralization
Neutralization

huPDGF-
ELISA
BB
Potency (nM)
Potency (nM)
Potency (nM)

Chimeric
BB
huPDGF-BB/
Neutralization
in NIH-3T3
in NIH-3T3
in NIH-3T3

Molecule
Binding
huPDGFR
(nM)
Cells
Cells B (nM)
Cells

chBDI-9E8
0.38
0.791
0.388
0.058
0.075
0.08

chBDI-9E8
NT
NT
NT
1.84
NT
NT

half-body

chBDI-5H1
0.12
1.039
1.602
0.275
0.17
NT

chBDI-5H1
NT
NT
NT
>10
NT
NT

half-body

chBDI-7H10
>10
10.1
2.476
>10
NT
NT

chBDI-5G2
NT
1.08
NT
0.181
0.118
NT

chBDI-1E1
NT
0.417
NT
>5
NT
NT

chBDI-1E1
NT
NT
NT
>10
NT
NT

half body

chBDI-8B8
NT
0.179
NT
>10
NT
NT

chBFU-3E2
NT
NT
NT
0.099
NT
NT

chBFU-3E2
NT
NT
NT
2.494
NT
NT

half-body

chBFU-11A8
NT
NT
NT
0.086
NT
NT

chBFU-11A8
NT
NT
NT
>10
NT
NT

half-body

NT—Not tested

TABLE 25

Biacore Binding Of Rat And Rat-Human Chimera Anti-PDGF

Antibody
k_on(M−1 s−1)
k_off(M−1)
K_D(M)

BFU-11A8-D6-C3
2.1E+07
≦1.0E−06
≦4.7E−14

chBDI-5H1
≧1.0E+07
1.5E−04
≦1.5E−11

chBDI-9E8
≧1.0E+07
1.2E−04
≦1.2E−11

chBFU-3E2-B9-B8
≧1.0E+07
1.9E−04
≦1.9E−11

chBFU-11A8-D6-C3
≧1.0E+07
1.5E−04
≦1.5E−11

Chimeric anti-VEGFR2 antibodies were tested for the ability to block binding of VEGFR2 to hVEGF₁₆₅in a competition ELISA format, as described in Example 1.22. The data is summarized in Table 26.

TABLE 26

Characterization of Chimeric Anti-Human

VEGFR II Monoclonal Antibodies

hVEGF₁₆₅/hVEGFR2-Fc

Chimeric Molecules
Competition

chBCU-6B1-G6
0.498

chBCU-7A6-C2
NT

Example 6
Humanization of Rat Monoclonal Antibodies

Below are the humanization designs for the rat monoclonal antibodies, followed by summaries of amino acid sequences and characterization of selected humanized antibodies.

Example 6.1
Humanization of PDGF-BB Antibodies
Example 6.1.1
Humanization Method

Antibody humanization is achieved by grafting CDRs of the rodent antibody onto a “similar” human framework (acceptor) and incorporating minimal number of key framework residues (back-mutation) from the rodent antibody that are selected to maintain the original CDR conformation in order to minimize the immunogenicity while retaining the optimal antigen binding.

Example 6.1.2
Human Germline Sequence Selections for Constructing CDR-Grafted, Humanized PDGF Antibodies

By applying the aforementioned method, the CDR sequences of VH and VL chains of monoclonal antibodies BDI-5H1-F6, BDI-9E8-E7, BDI-7H10-D8, BDI-1E1-D5, BDI-6A3-A9, BFU-3E2 and BFU-11A8 were grafted onto different human heavy and light chain acceptor sequences.

Example 6.1.2.1
BDI-5H1-F6

Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-5H1-F6 of the present invention, the following known human sequences are selected:

1. IGHV2-70*01 and IGHJ6*01 for constructing heavy chain acceptor sequences

2. IGHV2-70*04 and IGHJ6*01 as alternative acceptor sequence for constructing heavy chain

3. IGHV3-66*01 and IGHJ1*01 as alternative acceptor sequence for constructing heavy chain

4. IGLV6-57*01 and IGJL2*01 for constructing light chain acceptor sequences

5. IGKV3-20*01 and IGJK4*01 as alternative acceptor sequences for constructing light chain

6. IGKV4-1*01 and IGJK4*01 as alternative acceptor sequences for constructing light chain

7. IGKV1-39*01 and IGJK1*01 as alternative acceptor sequences for constructing light chain

By grafting the corresponding VH and VL CDRs of BDI-5H1-F6 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.1.2.2
BDI-9E8-E7

Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-9E8-E7 of the present invention, the following known human sequences are selected:

1. IGHV2-70*01 and IGHJ3*01 for constructing heavy chain acceptor sequences

2. IGHV2-70*04 and IGHJ6*01 as alternative acceptor sequence for constructing heavy chain

3. IGHV3-66*01 and IGHJ1*01 as alternative acceptor sequence for constructing heavy chain

4. IGLV6-57*01 and IGJL2*01 for constructing light chain acceptor sequences

5. IGKV3-20*01 and IGJK4*01 as alternative acceptor for constructing light chain sequences

6. IGKV4-1*01 and IGJK4*01 as alternative acceptor sequences for constructing light chain

7. IGKV1-39*01 and IGJK1*01 as alternative acceptor sequences for constructing light chain

By grafting the corresponding VH and VL CDRs of BDI-9E8-E7 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.1.2.3
BDI-7H10-D8

Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-7H10-D8 of the present invention, the following known human sequences are selected:

1. IGHV1-69*01 and IGHJ3*01 for constructing heavy chain acceptor sequences

2. IGKV2-29*02 and IGK2*01 for constructing light chain acceptor sequences

By grafting the corresponding VH and VL CDRs of BDI-7H10-D8 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.1.2.4
BDI-1E1-D5

Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-1E1-D5 of the present invention the following known human sequences are selected:

1. IGHV1-69*06 and IGHJ6*01 for constructing heavy chain acceptor sequences

2. IGKV1D-13*01 and IGKJ2*01 for constructing light chain acceptor sequences

3. IGKV3-11*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain

By grafting the corresponding VH and VL CDRs of BDI-1E1-D5 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.1.2.5
BDI-6A3-A9

Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-6A3-A9 of the present invention the following known human sequences are selected:

1. IGHV3-7*01 and IGHJ6*01 for constructing heavy chain acceptor sequences

2. IGHV1-3*01 and IGHJ6*01 as alternative acceptor sequence for constructing heavy chain

3. IGLV6-57*01 and IGJL2*01 for constructing light chain acceptor sequences

By grafting the corresponding VH and VL CDRs of BDI-6A3-A9 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.1.2.6
BFU-3E2

Based on the alignments with the VH and VL sequences of monoclonal antibody BFU-3E2 of the present invention, the following known human sequences are selected:

1. IGHV1-69*01 and IGHJ6*01 for constructing heavy chain acceptor sequences

2. IGKV3-11*01 and IGKJ4*01 for constructing light chain acceptor sequences

3. IGKV1-13*01 and IGKJ4*01 as alternative acceptor sequence for constructing light chain

By grafting the corresponding VH and VL CDRs of BFU-3E2 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.1.2.7
BFU-11A8

Based on the alignments with the VH and VL sequences of monoclonal antibody BFU-11A8 of the present invention, the following known human sequences are selected:

1. IGHV1-69*01 and IGHJ6*01 for constructing heavy chain acceptor sequences

2. IGKV3-11*01 and IGKJ4*01 for constructing light chain acceptor sequences

3. IGKV1-5*01 and IGKJ4*01 as alternative acceptor sequence for constructing light chain

By grafting the corresponding VH and VL CDRs of BFU-11A8 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.1.3
Introducing Potential Framework Back-Mutations in CDR-Grafted Antibodies

To generate humanized antibody with potential framework back-mutations, the mutations were identified and introduced into the CDR-grafted antibody sequences by de novo synthesis of the variable domain, or mutagenic oligonucleotide primers and polymerase chain reactions, or by methods well known in the art. Different combinations of back mutations and other mutations are constructed for each of the CDR-grafts as follows. Residue numbers for these mutations are based on the Kabat numbering system.

BDI-5H1-F6

When IGHV2-70*01 and IGHJ6*01 selected as BDI-5H1-F6 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, A44→G, K75→N, V78→A, M82→I with or without N65→T (CDR change).

When IGHV2-70*04 and IGHJ6*01 selected as BDI-5H1-F6 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q→1E, K5→R, K75→N, N76→S, V78→A and M82→I.

When IGHV3-66*01 and IGHJ1*01 selected as BDI-5H1-F6 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: A24→F, V37→I, V48→L, S49→A, F67→L, R71→K, N73→T, T77→Q, L78→A, and M82→I.

When IGLV6-57*01 and IGJL2*01 selected as BDI-5H1-F6 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: N1→Q, S22→P, S43→P, T464→N, G57→E, P59→S, and Y87→F.

When IGKV3-20*01 and IGJK4*01 selected as BDI-5H1-F6 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→F, A43→P, L46→N, L47→V, I58→V, G66→I, G68→S, T69→N, F71→A, Y87→F and with or without two residues insertion D66a, S66b and deletion of T10.

When IGKV4-1*01 and IGJK4*01 selected as BDI-5H1-F6 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→F, M4→L, L46→N, L47→V, T69→N, D70→S, F71→A, Y87→F.

When IGKV1-39*01 and IGJK1*01 selected as BDI-5H1-F6 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→F, M4→L, L46→N, L47→V, T69→N, D70→S, F71→A, and Y87→F.

BDI-9E8-E7

When IGHV2-70*01 and IGHJ6*01 selected as BDI-9E8-E7 heavy chain acceptor sequences, one or more of following residues could be back-mutated as follows: Q1→E, A44→G, V78→A M82→I with or without N65→T (CDR change).

When IGHV2-70*04 and IGHJ6*01 selected as BDI-9E8-E7 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, K5→R, V78→A, and M82→I.

When IGHV3-66*01 and IGHJ1*01 selected as BDI-9E8-E7 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: A24→F, V37→I, V48→L, S49→A, F67→L, R71→K, N73→T, T77→Q, L78→A, and M82→I.

When IGLV6-57*01 and IGJL2*01 selected as BDI-9E8-E7 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: S43→P, T46→N and Y87→F.

When IGKV3-20*01 and IGJK4*01 selected as BDI-9E8-E7 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→F, A43→P, L46→N, L47→V, I58→V, G66→I, T69→N, F71→A, Y87→F and W/WO two residues insertion (D66a, S66b) and deletion of T10.

When IGKV4-1*01 and IGJK4*01 selected as BDI-9E8-E7 light chain acceptor sequences, one or more of the following residues could be back mutated as follows: I2→F, M4→L, L46→N, L47→V, T69→N, D70→S, F71→A, T72→S, and Y87→F.

When IGKV1-39*01 and IGJK1*01 selected as BDI-9E8-E7 light chain acceptor sequences, one or more of the following residues could be back mutated as follows: I2→F, M4→L, L46→N, L47→V, T69→N, D70→S, F71→A, and T72→S.

BDI-7H10-D8

When IGHV1-69*01 and IGHJ3*01 selected as BDI-7H10-D8 heavy chain acceptor sequences, one or more of following residues could be back-mutated as follows: Q1→E, M48→I, V67→A, I69→L, E73→T, S76→N, with or without CDR changes Y27→G and T30→S.

When IGKV2-29*02 and IGKJ2*01 selected as BDI-7H10-D8 light chain acceptor sequences, one or more of following residues could be back-mutated as follows: I2→V and M4→L.

BDI-1E1-D5

When IGHV1-69*06 and IGHJ6*01 selected as BDI-1E1-D5 heavy chain acceptor sequence, one or more of the following residues could be back-mutated as follows: Q1→E M48→I, V67→A, I69→L and S76→N.

When IGKV1D-13*01 and IGKJ2*01 selected as BDI-1E1-D5 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V58→I and F71→Y.

When IGKV3-11*01 and IGKJ2*01 selected as BDI-1E1-D5 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: F71→Y and V85→T.

BDI-6A3-A9

When IGHV3-7*01 and IGHJ6*01 selected as BDI-6A3-A9 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: S28→T, R60→V, N76→S.

When IGHV1-3*01 and IGHJ6*01 selected as BDI-6A3-A9 heavy chains acceptor sequences, one or more of following residues could be back-mutated as follows: Q1→E, R44→G, M48→V, G49→A, V67→F, T73→N, A78→L and M80→L.

When IGLV6-57*01 and IGJL2*01 selected as BDI-6A3-A9 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: S43→P, T46→N, Y49→F and Y87→F.

BFU-3E2

When IGHV1-69*01 and IGHJ6*01 selected as BFU-3E2 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: R38-->K, G44-->S, W47-->L, M48-->I, R66-->K, V67-->A, 169-->L, S76-->N, Y91-->F.

When IGKV3-11*01 and IGKJ4*01 selected as BFU-3E2 light chain acceptor sequences, one or more of the following could be back-mutated as follows: I2-->T, A43-->Q, 158-->V, Y87-->F.

When IGKV1-13*01 and IGKJ4*01 selected as BFU-3E2 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2-->T, T22-->S, A43-->Q, K45-->R, Y87-->F.

BFU-11A8

When IGHV1-69*01 and IGHJ6*01 selected as BFU-11A8 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: R38-->K, W47-->L, M48-->I, R66-->K, V67-->A, 169-->L, S76-->N, and Y91-->F.

When IGKV3-11*01 and IGKJ4*01 selected as BFU-11A8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2-->T, S22-->P, A43-->Q, 158-->V, Y87-->F.

When IGKV1-5*01 and IGKJ4*01 selected as BFU-11A8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2-->T, M4-->L, T22-->P, A43-->Q, Y87-->F.

Example 6.1.4
Generation of Humanized Antibodies to PDGF Containing Framework Back-Mutations in CDR-Grafted Antibodies

The following humanized variable regions of the murine monoclonal PDGF antibodies were cloned into IgG expression vectors for functional characterization.

Example 6.1.4.1
BDI-5H1-F6

TABLE 1.4.1

Sequences of Humanized BDI-5H1-F6 Variable Regions

Sequence

SEQ ID

12345678901234567890123

NO:
Protein region
4567890

3882
hBDI-5H1-F6VH.1z
QVTLRESGPALVKPTQTLTLTCT

FSGFSLS

TFGMGVGWIRQPPGKALEWLANI

WWDDDKY

YNPSLKNRLTISKDTSKNQVVLT

MTNMDPV

DTATYYCARISTGISSYYVMDAW

GQGTTVT

VSS

3883
hBDI-5H1-F6VH.1
EVTLRESGPALVKPTQTLTLTCT

FSGFSLS

TFGMGVGWIRQPPGKALEWLANI

WWDDDKY

YNPSLKNRLTISKDTSKNQVVLT

MTNMDPV

DTATYYCARISTGISSYYVMDAW

GQGTTVT

VSS

3884
hBDI-5H1-F6VH.1a
EVTLRESGPALVKPTQTLTLTCT

FSGFSLS

TFGMGVGWIRQPPGKGLEWLANI

WWDDDKY

YNPSLKNRLTISKDTSNNQAVLT

ITNMDPV

DTATYYCARISTGISSYYVMDAW

GQGTTVT

VSS

3885
hBDI-5H1-F6VH.1b
EVTLRESGPALVKPTQTLTLTCT

FSGFSLS

TFGMGVGWIRQPPGKGLEWLANI

WWDDDKY

YNPSLKNRLTISKDTSKNQVVLT

ITNMDPV

DTATYYCARISTGISSYYVMDAW

GQGTTVT

VSS

3886
hBDI-5H1-F6VH.1c
EVTLRESGPALVKPTQTLTLTCT

FSGFSLS

TFGMGVGWIRQPPGKGLEWLANI

WWDDDKY

YNPSLKTRLTISKDTSKNQVVLT

ITNMDPV

DTATYYCARISTGISSYYVMDAW

GQGTTVT

VSS

3887
hBDI-5H1-F6VH.2z
QVTLKESGPALVKPTQTLTLTCT

FSGFSLS

TFGMGVGWIRQPPGKALEWLANI

WWDDDKY

YNPSLKNRLTISKDTSKNQVVLT

MTNMDPV

DTATYYCARISTGISSYYVMDAW

GQGTTVT

VSS

3888
hBDI-5H1-F6VH.2
EVTLKESGPALVKPTQTLTLTCT

FSGFSLS

TFGMGVGWIRQPPGKALEWLANI

WWDDDKY

YNPSLKNRLTISKDTSKNQVVLT

MTNMDPV

DTATYYCARISTGISSYYVMDAW

GQGTTVT

VSS

3889
hBDI-5H1-F6VH.2a
EVTLKESGPALVKPTQTLTLTCT

FSGFSLS

TFGMGVGWIRQPPGKGLEWLANI

WWDDDKY

YNPSLKNRLTISKDTSNSQAVLT

ITNMDPV

DTATYYCARISTGISSYYVMDAW

GQGTTVT

VSS

3890
hBDI-5H1-F6VH.2b
EVTLKESGPALVKPTQTLTLTCT

FSGFSLS

TFGMGVGWIRQPPGKALEWLANI

WWDDDKY

YNPSLKNRLTISKDTSKNQAVLT

ITNMDPV

DTATYYCARISTGISSYYVMDAW

GQGTTVT

VSS

3891
hBDI-5H1-F6VH.2c
EVTLRESGPALVKPTQTLTLTCT

FSGFSLS

TFGMGVGWIRQPPGKALEWLANI

WWDDDKY

YNPSLKNRLTISKDTSKNQAVLT

ITNMDPV

DTATYYCARISTGISSYYVMDAW

GQGTTVT

VSS

3892
hBDI-5H1-F6VH.v7
EVQLVESGGGLVQPGGSLRLSCA

FSGFSLS

TFGMGVGWIRQAPGKGLEWLANI

WWDDDKY

YNPSLKNRLTISKDTSKNQAYLQ

INSLRAE

DTAVYYCARISTGISSYYVMDAW

GQGTLVT

VSS

3893
hBDI-5H1-F6VL.1
NFMLTQPHSVSESPGKTVTISCE

RSSGDIG

DTYVSWYQQRPGSSPTTVIYGND

QRPSGVP

DRFSGSIDSSSNSASLTISGLKT

EDEADYY

CQSYDSDIDIVFGGGTKLTVL

3894
hBDI-5H1-F6VL.1a
NFMLTQPHSVSESPGKTVTISCE

RSSGDIG

DTYVSWYQQRPGSPPTNVIYGND

QRPSGVP

DRFSGSIDSSSNSASLTISGLKT

EDEADYF

CQSYDSDIDIVFGGGTKLTVL

3895
hBDI-5H1-F6VL.1b
QFMLTQPHSVSESPGKTVTIPCE

RSSGDIG

DTYVSWYQQRPGSPPTNVIYGND

QRPSEVS

DRFSGSIDSSSNSASLTISGLKT

EDEADYF

CQSYDSDIDIVFGGGTKLTVL

3896
hBDI-5H1-F6VL.1c
QFMLTQPHSVSESPGKTVTISCE

RSSGDIG

DTYVSWYQQRPGSSPTTVIYGND

QRPSGVP

DRFSGSIDSSSNSASLTISGLKT

EDEADYF

CQSYDSDIDIVFGGGTKLTVL

3897
hBDI-5H1-F6VL.2
EIVLTQSPGTLSLSPGERATLSC

ERSSGDI

GDTYVSWYQQKPGQAPRLLIYGN

DQRPSGI

PDRFSGSGSGTDFTLTISRLEPE

DFAVYYC

QSYDSDIDIVFGGGTKVEIK

3898
hBDI-5H1-F6L.2a
EFVLTQSPGLSLSPGERATLSCE

RSSGDIG

DTYVSWYQQKPGQPPRNVIYGND

QRPSGVP

DRFSGSIDSSSNDATLTISRLEP

EDFAVYF

CQSYDSDIDIVFGGGTKVEIK

3899
hBDI-5H1-F6L.2b
EFVLTQSPGTLSLSPGERATLSC

ERSSGDI

GDTYVSWYQQKPGQAPRLVIYGN

DQRPSGI

PDRFSGSGSGTDFTLTISRLEPE

DFAVYYC

QSYDSDIDIVFGGGTKVEIK

3900
hBDI-5H1-F6L.2c
EFVLTQSPGTLSLSPGERATLSC

ERSSGDI

GDTYVSWYQQKPGQPPRNVIYGN

DQRPSGV

PDRFSGSGSGTDFTLTISRLEPE

DFAVYFC

QSYDSDIDIVFGGGTKVEIK

3901
hBDI-5H1-F6VL.v6
DFVLTQSPDSLAVSLGERATINC

ERSSGDI

GDTYVSWYQQKPGQPPKNVIYGN

DQRPSGV

PDRFSGSGSGNSATLTISSLQAE

DVAVYFC

QSYDSDIDIVFGGGTKVEIK

3902
hBDI-5H1-F6VL.v7
DFQLTQSPSSLSASVGDRVTITC

ERSSGDI

GDTYVSWYQQKPGKAPKNVIYGN

DQRPSGV

PSRFSGSGSGNSATLTISSLQPE

DFATYFC

QSYDSDIDIVFGQGTKVEIK

- hBDI-5H1-F6VH.1z is a CDR-grafted, humanized BDI-5H1-F6 VH containing IGHV2-70*01 and IGHJ6 framework sequences.
- hBDI-5H1-F6VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBDI-5H1-F6VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (A44G, K75N, V78A and M82I).
- hBDI-5H1-F6VH.1b is an intermediate design between .1 and .1a and only has two proposed framework back-mutations (A44G and M82I).
- hBDI-5H1-F6VH.1c is based on .1b with additional one CDR germlining change N65T to improve identity to human germline sequence.
- hBDI-5H1-F6VH.2z is a CDR-grafted, humanized BDI-5H1-F6 VH containing IGHV2-70*04 and IGHJ6 framework sequences.
- hBDI-5H1-F6VH.2 is based on .2z with Q1E change to prevent pyroglutamate formation.
- hBDI-5H1-F6VH.2a (hBDI-5H1-F6VH.1d) is based on .2 and contains four proposed framework back-mutations (K75N, N76S, V78A and M82I).
- hBDI-5H1-F6VH.2b (hBDI-5H1-F6VH.v2) is an intermediate design between .2 and .2a and only has two proposed framework back-mutations (V78A and M82I).
- hBDI-5H1-F6VH.2c (hBDI-5H1-F6VH.v6) is based on .2 and contains three proposed framework back-mutations (K5R, V78A, M82I).
- hBDI-5H1-F6VH.v7 is a humanized BDI-5H1-F6 VH containing IGHV3-66*01 and IGHJ1 framework sequences with ten proposed framework back-mutations (A24F, V37I, V48L, S49A, F67L, R71K, N73T, T77Q, L78A, and M82I).
- hBDI-5H1-F6VL.1 is a CDR-grafted humanized BDI-5H1-F6 VL containing IGLV6-57*01 and IGJL2*01 framework sequences.
- hBDI-5H1-F6VL.1a is a humanized design based on .1 with 3 proposed framework back-mutations (S43P, T46N and Y87F).
- hBDI-5H1-F6VL.1b is a humanized design based on .1 with 7 proposed framework back-mutations (N1Q, S22P, S43P, T46N, G57E, P59S, Y87F).
- hBDI-5H1-F6VL.1c is an intermediate design between .1 and .1b with 2 back-mutations (N1Q and Y87F).
- hBDI-5H1-F6VL.2 is a CDR-grafted humanized BDI-5H1-F6 VL containing IGKV3-20*01 and IGJK4*01 framework sequences.
- hBDI-5H1-F6VL.2a is a humanized design based on .2 with 10 proposed framework back-mutations (I2F, A43P, L46N, L47V, I58V, G66I, G68S, T69N, F71A, Y87F) and one residue deletion (T10) and two residues insertion (D66a and S66b).
- hBDI-5H1-F6VL.2b is based on .2a only with 2 proposed framework back-mutations (12F, L47V) and without residues deletion (T10) and insertion (D66a, S66b).
- hBDI-5H1-F6VL.2c is a humanized design on .2 with 6 proposed framework back-mutations

(I2F, A43P, L46N, L47V, I58V, Y87F) and without residues deletion (T10) and insertion (D66a, S66b).

- hBDI-5H1-F6VL.v6 is a humanized BDI-5H1-F6 VL containing IGKV4-1*01 and IGJK4*01 framework sequences with eight proposed framework back-mutations (I2F, M4L, L46N, L47V, T69N, D70S, F71A, Y87F).
- hBDI-5H1-F6VL.v7 is a humanized BDI-5H1-F6 VL containing IGKV1-39*01 and

IGJK1*01 framework sequences with eight proposed framework back-mutations (I2F, M4L, L46N, L47V, T69N, D70S, F71A, and Y87F).

Example 6.1.4.2
BDI-9E8-E7

TABLE 1.4.2

Sequences of Humanized BDI-9E8-E7 Variable Regions

SEQ
Protein
Sequence

ID NO:
region
123456789012345678901234567890

3903
hBDI-9E8-
QVTLRESGPALVKPTQTLTLTCTFSGFSLS

E7VH.1z

TYGMGVGWIRQPPGKALEWLANIWWDDDKY

YNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTV

SS

3904
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFSGFSLS

E7VH.1

TYGMGVGWIRQPPGKALEWLANIWWDDDKY

YNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTV

SS

3905
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFSGFSLS

E7VH.1a

TYGMGVGWIRQPPGKGLEWLANIWWDDDKY

YNPSLKNRLTISKDTSKNQAVLTITNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTV

SS

3906
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFSGFSLS

E7VH.1b

TYGMGVGWIRQPPGKGLEWLANIWWDDDKY

YNPSLKNRLTISKDTSKNQVVLTITNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTV

SS

3907
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFSGFSLS

E7VH.1c

TYGMGVGWIRQPPGKGLEWLANIWWDDDKY

YNPSLKTRLTISKDTSKNQVVLTITNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTV

SS

3908
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFSGFSLS

E7VH.v6

TYGMGVGWIRQPPGKALEWLANIWWDDDKY

YNPSLKNRLTISKDTSKNQAVLTITNMDPV

DTATYYCARIESIGTTYSFDYWGQGTTVTV

SS

3909
hBDI-9E8-
EVQLVESGGGLVQPGGSLRLSCAFSGFSLS

E7VH.v7

TYGMGVGWIRQAPGKGLEWLANIWWDDDKY

YNPSLKNRLTISKDTSKNQAYLQINSLRAE

DTAVYYCARIESIGTTYSFDYWGQGTLVTV

SS

3910
hBDI-9E8-
NFMLTQPHSVSESPGKTVTISCERSSGDIG

E7VL.1

DSYVSWYQQRPGSSPTTVIYADDQRPSGVP

DRFSGSIDSSSNSASLTISGLKTEDEADYY

CQSYDINIDIVFGGGTKLTVL

3911
hBDI-9E8-
NFMLTQPHSVSESPGKTVTISCERSSGDIG

E7VL.1a

DSYVSWYQQRPGSPPTNVIYADDQRPSGVP

DRFSGSIDSSSNSASLTISGLKTEDEADYF

CQSYDINIDIVFGGGTKLTVL

3912
hBDI-9E8-
EIVLTQSPGTLSLSPGERATLSCERSSGDI

E7VL.2

GDSYVSWYQQKPGQAPRLLIYADDQRPSGI

PDRFSGSGSGTDFTLTISRLEPEDFAVYYC

QSYDINIDIVFGGGTKVEIK

3913
hBDI-9E8-
EFVLTQSPGLSLSPGERATLSCERSSGDIG

E7VL.2a

DSYVSWYQQKPGQPPRNVIYADDQRPSGVP

DRFSGSIDSSGNDATLTISRLEPEDFAVYF

CQSYDINIDIVFGGGTKVEIK

3914
hBDI-9E8-
EFVLTQSPGTLSLSPGERATLSCERSSGDI

E7VL.2b

GDSYVSWYQQKPGQAPRLVIYADDQRPSGI

PDRFSGSGSGTDFTLTISRLEPEDFAVYYC

QSYDINIDIVFGGGTKVEIK

3915
hBDI-9E8-
DFVLTQSPDSLAVSLGERATINCERSSGDI

E7VL.v6

GDSYVSWYQQKPGQPPKNVIYADDQRPSGV

PDRFSGSGSGNSASLTISSLQAEDVAVYFC

QSYDINIDIVFGGGTKVEIK

3916
hBDI-9E8-
DFQLTQSPSSLSASVGDRVTITCERSSGDI

E7VL.v7

GDSYVSWYQQKPGKAPKNVIYADDQRPSGV

PSRFSGSGSGNSASLTISSLQPEDFATYYC

QSYDINIDIVFGQGTKVEIK

- hBDI-9E8-E7VH.1z is a CDR-grafted, humanized BDI-9E8-E7 VH containing IGHV2-70*01 and IGHJ3*01 framework sequences.
- hBDI-9E8-E7VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBDI-9E8-E7VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations (A44G, V78A and M82I).
- hBDI-9E8-E7VH.1b is an intermediate design between .1 and .1a and only has two proposed framework back-mutations (A44G and M82I).
- hBDI-9E8-E7VH.1c is based on .1b with additional one CDR germlining change N65T to improve identity to human germline sequence.
- hBDI-9E8-E7VH.v6 is a humanized BDI-9E8-E7 VH containing IGHV2-70*04 and IGHJ6 framework sequences with four proposed framework back-mutations (Q1E, K5R, V78A, and M82I).
- hBDI-9E8-E7VH.v7 is a humanized BDI-9E8-E7 VH containing IGHV3-66*01 and IGHJ1 framework sequences with ten proposed framework back-mutations (A24F, V37I, V48L, S49A, F67L, R71K, N73T, T77Q, L78A, and M82I).
- hBDI-9E8-E7VL.1 is a CDR-grafted humanized BDI-9E8-E7 VL containing IGLV6-57*01 and IGJL2*01 framework sequences.
- hBDI-9E8-E7VL.1a is a humanized design based on .1 with three proposed framework back-mutations (S43P, T46N and Y87F).
- hBDI-9E8-E7VL.2 is a CDR-grafted humanized BDI-9E8-E7 VL containing IGKV3-20*01 and IGJK4*01 framework sequences.
- hBDI-9E8-E7VL.2a is a humanized design based on .2 with 9 proposed framework back-mutations (I2F, A43P, L46N, L47V, I58V, G66I, T69N, F71A, Y87F) and one residue deletion (T10) and two residues insertion (D66a and S66b).
- hBDI-9E8-E7VL.2b is based on .2a only with 2 proposed framework back-mutations (I2F, L47V) and without residues deletion (T10) and insertion (D66a, S66b).
- hBDI-9E8-E7VL.v6 is a humanized BDI-9E8-E7 VL containing IGKV4-1*01 and

IGJK4*01 framework sequences with nine proposed framework back-mutations: (I2F, M4L, L46N, L47V, T69N, D70S, F71A, T72S, and Y87F).

- hBDI-9E8-E7VL.v7 is a humanized BDI-9E8-E7 VL containing IGKV1-39*01 and

IGJK1*01 framework sequences with eight proposed framework back-mutations: I2F, M4L, L46N, L47V, T69N, D70S, F71A, and T72S.

Example 6.1.4.3
BDI-7H10-D8

TABLE 1.4.3

Sequences of Humanized BDI-7H10-D8 Variable

Regions

SEQ ID
Protein
Sequence

NO:
region
123456789012345678901234567890

3917
hBDI-7H10-
QVQLVQSGAEVKKPGSSVKVSCKASGYTFT

D8VH.1z

DYAMHWVRQAPGQGLEWMGTIIPLIDTTSY

NQKFKGRVTITADESTSTAYMELSSLRSED

TAVYYCARDWDNNWGYFDYWGQGTMVTVSS

3918
hBDI-7H10-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

D8VH.1

DYAMHWVRQAPGQGLEWMGTIIPLIDTTSY

NQKFKGPVTITADESTSTAYMELSSLRSED

TAVYYCARDWDNNWGYFDYWGQGTMVTVSS

3919
hBDI-7H10-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

D8VH.1a

DYAMHWVRQAPGQGLEWIGTIIPLIDTTSY

NQKFKGRATLTADTSTNTAYMELSSLRSED

TAVYYCARDWDNNWGYFDYWGQGTMVTVSS

3920
hBDI-7H10-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

D8VH.1b

DYAMHWVRQAPGQGLEWIGTIIPLIDTTSY

NQKFKGPVTITADESTSTAYMELSSLRSED

TAVYYCARDWDNNWGYFDYWGQGTMVTVSS

3921
hBDI-7H10-
EVQLVQSGAEVKKPGSSVKVSCKASGGTFS

D8VH.1c

DYAMHWVRQAPGQGLEWIGTIIPLIDTTSY

NQKFKGRVTITADESTSTAYMELSSLRSED

TAVYYCARDWDNNWGYFDYWGQGTMVTVSS

3922
hBDI-7H10-
DIVMTQTPLSLSVTPGQPASISCRSSQSLE

D8VL.1

YSDGYTYLEWYLQKPGQSPQLLIYGVSNRF

SGVPDPFSGSGSGTDFTLKISPVEAEDVGV

YYCFQATHDPLTFGQGTKLEIK

3923
hBDI-7H10-
DVVLTQTPLSLSVTPGQPASISCRSSQSLE

D8VL.1a

YSDGYTYLEWYLQKPGQSPQLLIYGVSNRF

SGVPDPFSGSGSGTDFTLKISPVEAEDVGV

YYCFQATHDPLTFGQGTKLEIK

3924
hBDI-7H10-
DVVMTQTPLSLSVTPGQPASISCRSSQSLE

D8VL.1b

YSDGYTYLEWYLQKPGQSPQLLIYGVSNRF

SGVPDPFSGSGSGTDFTLKISPVEAEDVGV

YYCFQATHDPLTFGQGTKLEIK

- hBDI-7H10-D8VH.1z is a CDR-grafted, humanized BDI-7H10-D8 VH containing IGHV1-69*01 and IGHJ3 framework sequences.
- hBDI-7H10-D8VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBDI-7H10-D8VH.1a is a humanized design based on .1 and contains five proposed framework back-mutations (M48I, V67A, I69L, E73T and S76N).
- hBDI-7H10-D8VH.1b is an intermediate design between .1 and .1a and only has one proposed framework back-mutation M48I.
- hBDI-7H10-D8VH.1c is based on .1b with two additional CDR germlining changes Y27G and T30S.
- hBDI-7H10-D8VL.1 is a CDR-grafted humanized BDI-7H10-D8 VL containing IGKV2-29*02 and IGKJ2 framework sequences.
- hBDI-7H10-D8VL.1a is a humanized design based on .1 with 2 proposed framework back-mutations 12V and M4L.
- hBDI-7H10-D8VL.1b is an intermediate design between .1 and .1a with only one proposed framework back-mutation 12V.

Example 6.1.4.4
BDI-1E1-D5

TABLE 1.4.4

Sequences of Humanized BDI-1E1-D5 Variable Regions

SEQ ID
Protein
Sequence

NO:
region
123456789012345678901234567890

3925
hBDI-1E1-
QVQLVQSGAEVKKPGSSVKVSCKASGYTFT

D5VH.1z

DYVMHWVRQAPGQGLEWMGTIIPLIDTTSY

NQKFKGRVTITADKSTSTAYMELSSLRSED

TAVYYCARTSPYYYSSYDVMDAWGQGTTVT

VSS

3926
hBDI-1E1-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

D5VH.1

DYVMHWVRQAPGQGLEWMGTIIPLIDTTSY

NQKFKGRVTITADKSTSTAYMELSSLRSED

TAVYYCARTSPYYYSSYDVMDAWGQGTTVT

VSS

3927
hBDI-1E1-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

D5VH.1a

DYVMHWVRQAPGQGLEWIGTIIPLIDTTSY

NQKFKGRATLTADKSTNTAYMELSSLRSED

TAVYYCARTSPYYYSSYDVMDAWGQGTTVT

VSS

3928
hBDI-1E1-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

D5VH.1b

DYVMHWVRQAPGQGLEWIGTIIPLIDTTSY

NQKFKGRVTITADKSTSTAYMELSSLRSED

TAVYYCARTSPYYYSSYDVMDAWGQGTTVT

VSS

3929
hBDI-1E1-
AIQLTQSPSSLSASVGDRVTITCKGSQNIN

D5VL.1

NYLAWYQQKPGKAPKLLIYKTNNLQTGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCYQ

YDNGYTFGQGTKLEIK

3930
hBDI-
AIQLTQSPSSLSASVGDRVTITCKGSQNIN

1E1-D5VL.1a

NYLAWYQQKPGKAPKLLIYKTNNLQTGIPS

RFSGSGSGTDYTLTISSLQPEDFATYYCYQ

YDNGYTFGQGTKLEIK

3931
hBDI-1E1-
EIVLTQSPATLSLSPGERATLSCKGSQNIN

D5VL.2

NYLAWYQQKPGQAPRLLIYKTNNLQTGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCYQ

YDNGYTFGQGTKLEIK

3932
hBDI-
EIVLTQSPATLSLSPGERATLSCKGSQNIN

1E1-D5VL.2a

NYLAWYQQKPGQAPRLLIYKTNNLQTGIPA

RFSGSGSGTDYTLTISSLEPEDFATYYCYQ

YDNGYTFGQGTKLEIK

- hBDI-1E1-D5VH.1z is a CDR-grafted, humanized BDI-1E1-D5 VH containing IGHV1-69*06 and JH6 framework sequences.
- hBDI-1E1-D5VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBDI-1E1-D5VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (M48I, V67A, I69L and S76N).
- hBDI-1E1-D5VH.1b is an intermediate design between .1 and .1a and only has one back-mutations M48I. This design eliminates Carter residue back-mutations.
- hBDI-1E1-D5VL.1 is a CDR-grafted humanized BDI-1E1-D5 VL containing IGKV1D-13*01 and Jk2 framework sequences.
- hBDI-1E1-D5VL.1a is a humanized design based on .1 with 2 proposed framework back-mutations (V58I and F71Y).
- hBDI-1E1-D5VL.2 is a CDR-grafted humanized BDI-1E1-D5 VL containing IGKV3-11*01 and Jk2 framework sequences.
- hBDI-1E1-D5VL.2a is a humanized design based on .2 with 2 proposed framework back-mutations (F71Y and V85T).

Example 6.1.4.5
BDI-6A3-A9

TABLE 1.4.5

Sequences of Humanized BDI-6A3-A9 Variable Regions

SEQ
Protein
Sequence

ID NO:
region
123456789012345678901234567890

3933
BDI-6A3-
EVQLVESGGGLVQPGGSLRLSCAASGFSFS

A9VH.1

DSAMAWVRQAPGKGLEWVATIIYDGSGTYY

RDSVKGRFTISRDNAKNSLYLQMNSLRAED

TAVYYCARLGFNYGNYGYYVMDAWGQGTTV

TVSS

3934
hBDI-6A3-
EVQLVESGGGLVQPGGSLRLSCAASGFSFS

A9VH.1a

DSAMAWVRQAPGKGLEWVATIIYDGSGTYY

RDSVKGRFTISRDNAKSSLYLQMNSLRAED

TAVYYCARLGFNYGNYGYYVMDAWGQGTTV

TVSS

3935
hBDI-6A3-
EVQLVESGGGLVQPGGSLRLSCAASGFTFS

A9VH.1b

DSAMAWVRQAPGKGLEWVATIIYDGSGTYY

VDSVKGRFTISRDNAKNSLYLQMNSLRAED

TAVYYCARLGFNYGNYGYYVMDAWGQGTTV

TVSS

3936
hBDI-6A3-
QVQLVQSGAEVKKPGASVKVSCKASGFSFS

A9VH.2z

DSAMAWVRQAPGQRLEWMGTIIYDGSGTYY

RDSVKGRVTITRDTSASTAYMELSSLRSED

TAVYYCARLGFNYGNYGYYVMDAWGQGTTV

TVSS

3937
hBDI-6A3-
EVQLVQSGAEVKKPGASVKVSCKASGFSFS

A9VH.2

DSAMAWVRQAPGQRLEWMGTIIYDGSGTYY

RDSVKGRVTITRDTSASTAYMELSSLRSED

TAVYYCARLGFNYGNYGYYVMDAWGQGTTV

TVSS

3938
hBDI-6A3-
EVQLVQSGAEVKKPGASVKVSCKASGFSFS

A9VH.2a

DSAMAWVRQAPGQGLEWVATIIYDGSGTYY

RDSVKGRFTITRDNSASTLYLELSSLRSED

TAVYYCARLGFNYGNYGYYVMDAWGQGTTV

TVSS

3939
hBDI-6A3-
EVQLVQSGAEVKKPGASVKVSCKASGFSFS

A9VH.2b

DSAMAWVRQAPGQGLEWVGTIIYDGSGTYY

RDSVKGRVTITRDTSASTAYLELSSLRSED

TAVYYCARLGFNYGNYGYYVMDAWGQGTTV

TVSS

3940
hBDI-6A3-
NFMLTQPHSVSESPGKTVTISCERSSGDIG

A9VL.1

DSYVSWYQQRPGSSPTTVIYADDQRPSGVP

DRFSGSIDSSSNSASLTISGLKTEDEADYY

CQSYDSNIDINIVFGGGTKLTVL

3941
hBDI-6A3-
NFMLTQPHSVSESPGKTVTISCERSSGDIG

A9VL.1a

DSYVSWYQQRPGSPPTNVIFADDQRPSGVP

DRFSGSIDSSSNSASLTISGLKTEDEADYF

CQSYDSNIDINIVFGGGTKLTVL

3942
hBDI-6A3-
NFMLTQPHSVSESPGKTVTISCERSSGDIG

A9VL.1b

DSYVSWYQQRPGSSPTTVIFADDQRPSGVP

DRFSGSIDSSSNSASLTISGLKTEDEADYY

CQSYDSNIDINIVFGGGTKLTVL

- hBDI-6A3-A9VH.1 is a CDR-grafted, humanized BDI-6A3-A9 VH containing IGHV3-7*01 and JH6 framework sequences.
- hBDI-6A3-A9VH.1a is a humanized design based on .1 and contains one proposed framework back-mutation N76S.
- hBDI-6A3-A9VH.1b is based on .1 with additional two CDR germlining changes S28T and R60V to improve identity to human germline sequence.
- hBDI-6A3-A9VH.2z is a CDR-grafted, humanized BDI-6A3-A9 VH containing IGHV1-3*01 and JH6 framework sequences.
- hBDI-6A3-A9VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
- hBDI-6A3-A9VH.2a is a humanized design based on .2 and contains seven proposed framework back-mutations R44G, M48V, G49A, V67F, T73N, A78L and M80L.
- hBDI-6A3-A9VH.2b is an intermediate design between .2 and .2a with only three proposed framework back-mutations R44G, M48V and M80L.
- hBDI-6A3-A9VL.1 is a CDR-grafted humanized BDI-6A3-A9 VL containing IGLV6-57*01 and JL2 framework sequences.
- hBDI-6A3-A9VL.1a is a humanized design based on .1 with 4 proposed framework back-mutations (S43P, T46N, Y49F and Y87F).
- hBDI-6A3-A9VL.1b is an intermediate design between .1 and .1a with only 1 proposed framework back-mutation Y49F.

Example 6.1.4.6
BFU-3E2

TABLE 1.4.6

Sequences of Humanized BFU-3E2 Variable Regions

SEQ ID
Protein
Sequence

NO:
region
123456789012345678901234567890

3943
hBFU-3E2VH.1z
QVQLVQSGAEVKKPGSSVKVSCKASGYTFT

ESYMYWVRQAPGQGLEWMGRIDPEDGSTDY

VEKFKNRVTITADESTSTAYMELSSLRSED

TAVYYCARFGARSYFYPMDAWGQGTTVTVS

S

3944
hBFU-3E2VH.1
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

ESYMYWVRQAPGQGLEWMGRIDPEDGSTDY

VEKFKNRVTITADESTSTAYMELSSLRSED

TAVYYCARFGARSYFYPMDAWGQGTTVTVS

S

3945
hBFU-3E2VH.1a
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

ESYMYWVKQAPGQGLELIGRIDPEDGSTDY

VEKFKNRVTITADESTSTAYMELSSLRSED

TAVYYCARFGARSYFYPMDAWGQGTTVTVS

S

3946
hBFU-3E2VH.1b
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

ESYMYWVRQAPGQGLELIGRIDPEDGSTDY

VEKFKNRVTLTADESTSTAYMELSSLRSED

TAVYYCARFGARSYFYPMDAWGQGTTVTVS

S

3947
hBFU-3E2VH.1c
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

ESYMYWVRQAPGQGLELIGRIDPEDGSTDY

VEKFKNRVTITADESTSTAYMELSSLRSED

TAVYYCARFGARSYFYPMDAWGQGTTVTVS

S

3948
hBFU-3E2VH.1d
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

ESYMYWVKQAPGQSLELIGRIDPEDGSTDY

VEKFKNKATLTADESTNTAYMELSSLRSED

TAVYFCARFGARSYFYPMDAWGQGTTVTVS

S

3949
hBFU-3E2VL.1
EIVLTQSPATLSLSPGERATLSCRASESVS

TLMHWYQQKPGQAPRLLIYGASNLESGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

SWNDPWTFGGGTKVEIK

3950
hBFU-3E2VL.1a
ETVLTQSPATLSLSPGERATLSCRASESVS

TLMHWYQQKPGQQPRLLIYGASNLESGVPA

RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ

SWNDPWTFGGGTKVEIK

3951
hBFU-3E2VL.1b
ETVLTQSPATLSLSPGERATLSCRASESVS

TLMHWYQQKPGQAPRLLIYGASNLESGVPA

RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ

SWNDPWTFGGGTKVEIK

3952
hBFU-3E2VL.1c
ETVLTQSPATLSLSPGERATLSCRASESVS

TLMHWYQQKPGQAPRLLIYGASNLESGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

SWNDPWTFGGGTKVEIK

3953
hBFU-3E2VL.2
AIQLTQSPSSLSASVGDRVTITCRASESVS

TLMHWYQQKPGKAPKLLIYGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQ

SWNDPWTFGGGTKVEIK

3954
hBFU-3E2VL.2a
ATQLTQSPSSLSASVGDRVTISCRASESVS

TLMHWYQQKPGKQPRLLIYGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYFCQQ

SWNDPWTFGGGTKVEIK

3955
hBFU-3E2VL.2b
ATQLTQSPSSLSASVGDRVTITCRASESVS

TLMHWYQQKPGKAPRLLIYGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYFCQQ

SWNDPWTFGGGTKVEIK

3956
hBFU-3E2VL.2c
ATQLTQSPSSLSASVGDRVTITCRASESVS

TLMHWYQQKPGKAPRLLIYGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQ

SWNDPWTFGGGTKVEIK

- hBFU-3E2VH.1z is a CDR-grafted, humanized BFU-3E2 VH containing IGHV1-69*01 and IGHJ6*01 framework sequences.
- hBFU-3E2VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBFU-3E2VH.1a is a humanized design based on .1 and contains 7 proposed framework back-mutations (R38K, W47L, M48I, R66K, V67A, 169L, Y91F).
- hBFU-3E2VH.1b is an intermediate design between .1 and .1a and contains 3 proposed framework back-mutations (W47L, M48I, I69L).
- hBFU-3E2VH.1c is an intermediate design between .1 and .1a and contains 2 proposed framework back-mutations (W47L, M48I.)
- hBFU-3E2VH.1d is a humanized design based on .1 and contains 9 proposed framework back-mutations (R38K, G44S, W47L, M48I, R66K, V67A, I69L, S76N, Y91F)
- hBFU-3E2VL.1 is a CDR-grafted, humanized BFU-3E2 VL containing IGKV3-11*01 and

IGKJ4*01 framework sequences.

- hBFU-3E2VL.1a is a humanized design based on .1 and contains 4 proposed framework back-mutations (I2T, A43Q, I58V, Y87F).
- hBFU-3E2VL.1b is an intermediate design between .1 and .1a. It contains 3 proposed framework back-mutations (I2T, I58V, Y87F).
- hBFU-3E2VL.1c is a design based on .1b and contains 1 proposed framework back-mutations: I2T.
- hBFU-3E2VL.2 is a CDR-grafted, humanized BFU-3E2 VL containing IGKV1-13*01 and

IGKJ4*01 framework sequences.

- hBFU-3E2VL.2a is a humanized design based on .2 and contains 5 proposed framework back-mutations (I2T, T22S, A43Q, K45R, Y87F).
- hBFU-3E2VL.2b is an intermediate design between .2 and 2a. It contains 3 proposed framework back-mutations (I2T, K45R, Y87F).
- hBFU-3E2VL.2c is a design based on .2b and contains 2 proposed framework back-mutations (I2T, K45R).

Example 6.1.4.7
BFU-11A8

TABLE 1.4.7

Sequences of Humanized BFU-11A8 Variable Regions

SEQ

ID
Protein
Sequence

NO:1
region
1234567891234567891234567890

3957
hBFU-11A8VH.1z
QVQLVQSGAEVKKPGSSVKVSCKASGYTFT

ESYIYWVRQAPGQGLEWMGRIDPEDGSTDY

VEKFKNRVTITADESTSTAYMELSSLRSED

TAVYYCARFGARSYFYPMDAWGQGTTVTVS

S

3958
hBFU-11A8VH.1
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

ESYIYWVRQAPGQGLEWMGRIDPEDGSTDY

VEKFKNRVTITADESTSTAYMELSSLRSED

TAVYYCARFGARSYFYPMDAWGQGTTVTVS

S

3959
hBFU-11A8VH.1a
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

ESYIYWVKQAPGQGLELIGRIDPEDGSTDY

VEKFKNKATLTADESTNTAYMELSSLRSED

TAVYFCARFGARSYFYPMDAWGQGTTVTVS

S

3960
hBFU-11A8VH.1b
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

ESYIYWVRQAPGQGLELIGRIDPEDGSTDY

VEKFKNRVTLTADESTNTAYMELSSLRSED

TAVYYCARFGARSYFYPMDAWGQGTTVTVS

S

3961
hBFU-11A8VH.1c
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

ESYIYWVRQAPGQGLELIGRIDPEDGSTDY

VEKFKNRVTITADESTSTAYMELSSLRSED

TAVYYCARFGARSYFYPMDAWGQGTTVTVS

S

3962
hBFU-11A8VL.1
EIVLTQSPATLSLSPGERATLSCRASESVS

TLMHWYQQKPGQAPRLLIYGASNLESGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

SWNDPWTFGGGTKVEIK

3963
hBFU-11A8VL.1a
ETVLTQSPATLSLSPGERATLPCRASESVS

TLMHWYQQKPGQQPRLLIYGASNLESGVPA

RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ

SWNDPWTFGGGTKVEIK

3964
hBFU-11A8VL.1b
ETVLTQSPATLSLSPGERATLSCRASESVS

TLMHWYQQKPGQAPRLLIYGASNLESGVPA

RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ

SWNDPWTFGGGTKVEIK

3965
hBFU-11A8VL.1c
ETVLTQSPATLSLSPGERATLSCRASESVS

TLMHWYQQKPGQAPRLLIYGASNLESGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

SWNDPWTFGGGTKVEIK

3966
hBFU-11A8VL.2
DIQMTQSPSTLSASVGDRVTITCRASESVS

TLMHWYQQKPGKAPKLLIYGASNLESGVPS

RFSGSGSGTEFTLTISSLQPDDFATYYCQQ

SWNDPWTFGGGTKVEIK

3967
hBFU-11A8VL.2a
DTQLTQSPSTLSASVGDRVTIPCRASESVS

TLMHWYQQKPGKQPKLLIYGASNLESGVPS

RFSGSGSGTEFTLTISSLQPDDFATYFCQQ

SWNDPWTFGGGTKVEIK

3968
hBFU-11A8VL.2b
DTQLTQSPSTLSASVGDRVTITCRASESVS

TLMHWYQQKPGKAPKLLIYGASNLESGVPS

RFSGSGSGTEFTLTISSLQPDDFATYFCQQ

SWNDPWTFGGGTKVEIK

3969
hBFU-11A8VL.2c
DTQMTQSPSTLSASVGDRVTITCRASESVS

TLMHWYQQKPGKAPKLLIYGASNLESGVPS

RFSGSGSGTEFTLTISSLQPDDFATYYCQQ

SWNDPWTFGGGTKVEIK

- hBFU-11A8VH.1z is a CDR-grafted, humanized BFU-11A8 VH containing IGHV1-69*01 and IGHJ6*01 framework sequences.
- hBFU-11A8VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBFU-11A8VH.1a is a humanized design based on .1 and contains 8 proposed framework back-mutations: R38K, W47L, M48I, R66K, V67A, 169L, S76N, Y91F.
- hBFU-11A8VH.1b is an intermediate design between .1 and .1a and contains 4 proposed framework back-mutations: W47L, M48I, I69L, S76N.
- hBFU-11A8VH.1c is a design based on .1b and contains 2 proposed framework back-mutations: W47L, M48I.
- hBFU-11A8VL.1 is a CDR-grafted, humanized BFU-11A8 VL containing IGKV3-11*01 and

IGKJ4*01 framework sequences.

- hBFU-11A8VL.1a is a humanized design based on .1 and contains 5 proposed framework back-mutations: I2T, S22P, A43Q, 158V, Y87F.
- hBFU-11A8VL.1b is an intermediate design between .1 and .1a. It contains 3 proposed framework back-mutations: I2T, 158V, Y87F.
- hBFU-11A8VL.1c is a design based on .1b and contains 1 proposed framework back-mutations: I2T.
- hBFU-11A8VL.2 is a CDR-grafted, humanized BFU-11A8 VL containing IGKV1-5*01 and

IGKJ4*01 framework sequences.

- hBFU-11A8VL.2a is a humanized design based on .2 and contains 5 proposed framework back-mutations: I2T, M4L, T22P, A43Q, Y87F.
- hBFU-11A8VL.2b is an intermediate design between .2 and 2a. It contains 3 proposed framework back-mutations: I2T, M4L, Y87F.
- hBFU-11A8VL.2c is a design based on .2b and contains 1 proposed framework back-mutations: I2T.

Example 6.2
Humanization of VEGF Antibodies
Example 6.2.1
Humanization Method

Example 6.2.2
Human Germline Sequence Selections for Constructing CDR-Grafted, Humanized VEGF Antibodies

By applying the aforementioned method, the CDR sequences of VH and VL chains of monoclonal antibodies BDB-4G8-D4, BEW-9A8-E2, BEW-6C2-C8, BEW-9D2-E8, BEW-9E3-B9, BEW-5C3, BEW-9E10, BEW-1B10, and BEW-1E3 were grafted onto different human heavy and light chain acceptor sequences.

Example 6.2.2.1
BDB-4G8-D4

Based on the alignments with the VH and VL sequences of monoclonal antibody BDB-4G8-D4 of the present invention, the following known human sequences are selected:

1. IGHV7-4-1*02 and IGHJ3*01 for constructing heavy chain acceptor sequences

2. IGHV1-18*01 and IGHJ3*01 as backup acceptor sequences for constructing heavy chain

3. IGHV5-51*01 and IGHJ3*01 as backup acceptor sequences for constructing heavy chain

4. IGHV3-66*01 and IGHJ1*01 as backup acceptor sequences for constructing heavy chain

5. IGKV1D-13*01 and IGKJ2*01 for constructing light chain acceptor sequences

6. IGKV3-11*01 and IGKJ2*01 as alternative acceptor sequences for constructing light chain

7. IGKV3-15*01 and IGKJ5*01 as alternative acceptor sequences for constructing light chain

8. IGKV3-15*01 and IGKJ1*01 as alternative acceptor sequences for constructing light chain

9. IGKV1-39*01 and IGKJ1*01 as alternative acceptor sequences for constructing light chain.

By grafting the corresponding VH and VL CDRs of BDB-4G8-D4 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.2.2.2
BEW-9A8-E2

Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-9A8-E2 of the present invention the following known human sequences are selected:

1. IGHV7-81*01 and IGHJ1*01 for constructing heavy chain acceptor sequences

2. IGHV1-18*01 and IGHJ1*01 as alternative acceptor sequence for constructing heavy chain

3. IGHV7-4-1*01 and IGHJ1*01 as alternative acceptor sequence for constructing heavy chain

4. IGKV6-21*01 and IGKJ2*01 for constructing light chain acceptor sequences

5. IGKV1-39*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain

6. IGKV3-11*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain

7. IGKV1-13*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain

By grafting the corresponding VH and VL CDRs of BEW-9A8-E2 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.2.2.3
BEW-6C2-C8

Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-6C2-C8 of the present invention the following known human sequences are selected:

1. IGHV3-7*01 and IGHJ3*01 for constructing heavy chain acceptor sequences

2. IGKV3-11*01 and IGKJ2*01 for constructing light chain acceptor sequences

3. IGKV1-39*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain

By grafting the corresponding VH and VL CDRs of BEW-6C2-C8 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.2.2.4
BEW-9D2-E8

Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-9D2-E8 of the present invention the following known human sequences are selected:

1. IGHV7-81*01 and IGHJ4*01 for constructing heavy chain acceptor sequences

2. IGHV1-18*01 and IGHJ4*01 as alternative acceptor sequence for constructing heavy chain

3. IGKV3-11*01 and IGKJ2*01 for constructing light chain acceptor sequences

4. IGKV1-39*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain

By grafting the corresponding VH and VL CDRs of BEW-9D2-E8 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.2.2.5
BEW-9E3-B9

Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-9E3-B9 of the present invention the following known human sequences are selected:

1. IGHV7-81*01 and IGHJ4*01 for constructing heavy chain acceptor sequences

2. IGHV1-18*01 and IGHJ4*01 as alternative acceptor sequence for constructing heavy chain

3. IGKV3-11*01 and IGKJ2*01 for constructing light chain acceptor sequences

4. IGKV1-39*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain

By grafting the corresponding VH and VL CDRs of BEW-9E3-B9 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.2.2.6
BEW-5C3

Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-5C3 of the present invention, the following known human sequences are selected:

1. IGHV7-4-1*01 and IGHJ1*01 for constructing heavy chain acceptor sequences

2. IGHV1-69*06 and IGHJ1*01 as alternative acceptor for constructing heavy chain

3. IGKV3-11*01 and IGKJ4*01 for constructing light chain acceptor sequences

4. IGKV1-13*01 and IGKJ4*01 as alternative acceptor for constructing light chain

By grafting the corresponding VH and VL CDRs of BEW-5C3 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.2.2.7
BEW-9E10

Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-9E10 of the present invention, the following known human sequences are selected:

1. IGHV7-4-1*01 and IGHJ1*01 for constructing heavy chain acceptor sequences

2. IGHV1-69*06 and IGHJ1*01 as alternative acceptor for constructing heavy chain

3. IGKV1-27*01 and IGKJ2*01 for constructing light chain acceptor sequences

By grafting the corresponding VH and VL CDRs of BEW-9E10 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.2.2.8
BEW-1B10

Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-1B10 of the present invention, the following known human sequences are selected:

1. IGHV3-7*01 and IGHJ6*01 for constructing heavy chain acceptor sequences

2. IGKV1-39*01 and IGKJ4*01 for constructing light chain acceptor sequences

By grafting the corresponding VH and VL CDRs of BEW-1B10 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.2.2.9
BEW-1E3

Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-1E3 of the present invention, the following known human sequences are selected:

1. IGHV7-4-1*01(0-1) and IGHJ1*01 for constructing heavy chain acceptor sequences

2. IGHV1-18*01 and IGHJ1*01 as alternative acceptor for constructing heavy chain

3. IGKV3-11*01 and IGKJ2*01 for constructing light chain acceptor sequences

4. IGKV1-13*01 and IGKJ2*01 as alternative acceptor for constructing light chain

By grafting the corresponding VH and VL CDRs of BEW-1E3 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.2.3
Introducing Potential Framework Back-Mutations in CDR-Grafted Antibodies

Example 6.2.3.1
BDB-4G8-D4

When IGHV7-4-1*02 and IGHJ3*01 selected as BDB-4G8-D4 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→, V2→I, W47→Y, and Y91→F.

When IGHV1-18*01 and IGHJ3*01 selected as BDB-4G8-D4 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, W47→Y, V67→F, M69→F, T71→L and Y91→F.

When IGHV5-51*01 and IGHJ3*01 selected as BDB-4G8-D4 heavy chain acceptor sequences, one or more following residues could be back-mutated as follows: V2→I, A9→T, G24→A, R38→K, W47→Y, Q66→R, V67→F, I69→F, A71→L, I75→F, S76→N, Y79→F and Y91→F.

When IGHV3-66*01 and IGHJ1*01 selected as BDB-4G8-D4 heavy chain acceptor sequences, one or more following residues could be back-mutated as follows: V2→I, E6→Q, L11→V, R38→K, W47→Y, V48→M, S49→G, I69→F, R71→L, N73→T, N76→S, L78→A, M82→L and Y91→F.

When IGKV1D-13*01 and IGKJ2*01 selected as BDB-4G8-D4 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, A43→Q and Y87→F with or without one residue deletion (S10).

When IGKV3-11*01 and IGKJ2*01 selected as BDB-4G8-D4 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: E1→D, I2→T, I58→V, and Y87→F.

When IGKV3-15*01 and IGKJ5*01 or IGKJ5*01 selected as BDB-4G8-D4 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: E1→D, I2→T, M4→L, A9→S, L13→A, L21→I, R45→K, I58→V, A60→S, G66→R, E70→D, E79→Q and Y87→F.

When IGKV1-39*01 and IGKJ1*01 selected as BDB-4G8-D4 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, M4→L, T22→S, and Y87→F.

Example 6.2.3.2
BEW-9A8-E2

When IGHV7-81*01 and IGHJ1*01 selected as BEW-9A8-E2 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E V2→I, P38→K, W47→Y, M71→L, Y90→F and Y91→F with or without CDR change T28→S.

When IGHV1-18*01 and IGHJ1*01 selected as BEW-9A8-E2 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, R38→K, W47→Y, V67→F, M69→F, T71→L, Y90→F and Y91→F.

When IGHV7-4-1*01 and IGHJ1*01 selected as BEW-9A8-E2 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, R38→K, W47→Y, Y90→F, Y91→F.

When IGKV6-21*01 and IGKJ2*01 selected as BEW-9A8-E2 light chain accepter sequences, one or more of the following residues could be back-mutated as follows: I2→T, S434Q, K49→H and Y87→F. Additional mutations include the following: F10 deletion.

When IGKV1-39*01 and IGKJ2*01 selected as BEW-9A8-E2 light chain accepter sequences, one or more of the following residues could be back-mutated as follows: I2→T, M4→L, A43→Q, Y49→H and Y87→F. Additional mutations include the following: S10 deletion.

When IGKV3-11*01 and IGKJ2*01 selected as BEW-9A8-E2 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, Y49→H, I58→V, V85→T, and Y87→F.

When IGKV1-13*01 and IGKJ2*01 selected as BEW-9A8-E2 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, T22→S, Y49→H, Y87→F.

Example 6.2.3.3
BEW-6C2-C8

When IGHV3-7*01 and IGHJ3*01 selected as BEW-6C2-C8 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V37→I, V48→M and R94→A.

When IGKV3-11*01 and IGKJ2*01 selected as BEW-6C2-C8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: F71→Y and Y87→F.

When IGKV1-39*01 and IGKJ2*01 selected as BEW-6C2-C8 light chain acceptor sequence, one or more of the following residues could be back-mutated as follows: M4→L, V58→I, F71→Y and Y87→F.

Example 6.2.3.4
BEW-9D2-E8

When IGHV7-81*01 and IGHJ4*01 selected as BEW-9D2-E8 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, P38→K, Q39→L, W47→Y, M48→L, M71→L and Y91→F with or without CDR change T28→S.

When IGHV1-18*01 and IGHJ4*01 selected as BEW-9D2-E8 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, R38→K, Q39→L, W47→Y, M48→L, V67→F, M69→F, T71→L, M80→L and Y91→F.

When IGKV3-11*01 and IGKJ2*01 selected as BEW-9D2-E8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, A43→Q, I58→V and Y87→F. Additional mutations include the following: T10 deletion.

When IGKV1-39*01 and IGKJ2*01 selected as BEW-9D2-E8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, M4→L, A43→Q and Y87→F. Additional mutations include the following: T10 deletion.

Example 6.2.3.5
BEW-9E3-B9

When IGHV7-81*01 and IGHJ4*01 selected as BEW-9E3-B9 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1E, V2→I, W47→Y, M71→L and Y91→F with or without CDR change T28→S.

When IGHV1-18*01 and IGHJ4*01 selected as BEW-9E3-B9 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, W47→Y, V67→F, M69→F, T71→L and Y91→F.

When IGKV3-11*01 and IGKJ2*01 selected as BEW-9E3-B9 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, A43→Q, I58→V and Y87→F. Additional mutations include the following: S10 deletion.

When IGKV1-39*01 and IGKJ2*01 selected as BEW-9E3-B9 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, M4→L, A43→Q and Y87→F. Additional mutations include the following: S10 deletion.

Example 6.2.3.6
BEW-5C3

When IGHV7-4-1*01 and IGHJ1*01 selected as BEW-5C3 heavy chain accepter sequences, one or more of the following residues could be back-mutated as follows: V2→I, R38→K, W47→Y, Y90→F, Y91→F.

When IGHV1-69*01 and IGHJ1*01 selected as BEW-5C3 heavy chain accepter sequences, one or more of the following residues could be back-mutated as follows: V67→F, I69→F, A71→L. Additional mutations include the following: V2→I, R38→K, W47→Y, T68→V, M80→L, Y90→F, Y91→F.

When IGKV3-11*01 and IGKJ4*01 selected as BEW-5C3 light chain accepter sequences, one or more of the following residues could be back-mutated as follows: E1→D, I2→T, Y36→F, Y87→F. Additional mutations include the following: A43→Q, I58→V, C34→S (CDR change).

When IGKV1-13*01 and IGKJ4*01 selected as BEW-5C3 light chain accepter sequences, one or more of the following residues could be back-mutated as follows: A1→D, I2→T, T22→S, Y36→F, A43→Q, Y87→F with CDR change C34→S.

Example 6.2.3.7
BEW-9E10

When IGHV7-4-1*01 and IGHJ1*01 selected as BEW-9E10 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V2→I, R38→K, W47→Y, Y91→F.

When IGHV1-69*06 and IGHJ1*01 selected as BEW-9E10 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V67→F, I69→F. Additional mutations include the following: V2→I, R38→K, W47→Y, Y91→F.

When IGKV1-27*01 and IGKJ2*01 selected as BEW-9E10 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q3→R, V43→S, F71→Y, Y87→F. Additional mutations include the following: T22→E, T72→S.

Example 6.2.3.8
BEW-1B10

When IGHV3-7*01 and IGHJ6*01 selected as BEW-1B10 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V37→F, I69→V. Additional mutations include the following: N76→S, S77→T.

When IGKV1-39*01 and IGKJ4*01 selected as BEW-1B10 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: A43→S, F71→Y. Additional mutations include the following: L47→V.

Example 6.2.3.9
BEW-1E3

When IGHV7-4-1*01 and IGHJ1*01 selected as BEW-1E3 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V2→I, R38→K, W47→Y, Y91→F.

When IGHV1-18*01 and IGHJ1*01 selected as BEW-1E3 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V67→F, M69→F, T71→L. Additional mutations include the following: V2→I, R38→K, W47→Y, Y91→F.

When IGKV3-11*01 and IGKJ2*01 selected as BEW-1E3 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I58→V, Y87→F. Additional mutations include the following: I2→T, A43→Q.

When IGKV1-13*01 and IGKJ2*01 selected as BEW-1E3 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Y87→F. Additional mutations include the following: I2→T, T22→S, A43→Q.

Example 6.2.4
Generation of Humanized Antibodies to VEGF Containing Framework Back-Mutations in CDR-Grafted Antibodies

The following humanized variable regions of the murine monoclonal VEGF antibodies were cloned into IgG expression vectors for functional characterization.

Example 6.2.4.1
BDB-4G8-D4

TABLE 2.4.1

Sequences of Humanized BDB-4G8-D4 Variable Regions

SEQ

ID

Sequence

NO:
Protein region
123456789012345678901234567890

654
hBDB-4G8-D4VH.1z
QVQLVQSGSELKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWINTETGKPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSS

655
hBDB-4G8-D4VH.1
EVQLVQSGSELKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWINTETGKPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSS

656
hBDB-4G8-D4VH.1a
EIQLVQSGSELKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEYMGWINTETGKPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYFCARTNYYYRSYIFYFDYWGQGTMVT

VSS

657
hBDB-4G8-D4VH.1b
EVQLVQSGSELKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEYMGWINTETGKPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSS

658
hBDB-4G8-D4VH.2z
QVQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWINTETGKPTY

ADDFKGRVTMTTDTSTSTAYMELRSLRSDD

TAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSS

659
hBDB-4G8-D4VH.2
EVQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWINTETGKPTY

ADDFKGRVTMTTDTSTSTAYMELRSLRSDD

TAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSS

660
hBDB-4G8-D4VH.2a
EIQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEYMGWINTETGKPTY

ADDFKGRFTFTLDTSTSTAYMELRSLRSDD

TAVYFCARTNYYYRSYIFYFDYWGQGTMVT

VSS

661
hBDB-4G8-D4VH.2b
EVQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEYMGWINTETGKPTY

ADDFKGRVTMTLDTSTSTAYMELRSLRSDD

TAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSS

662
hBDB-4G8-D4VH.v3
EIQLVQSGTEVKKPGESLKISCKASGYTFT

NYGMYWVKQMPGKGLEYMCWINTETGKPTY

ADDFKGRFTFSLDKSFNTAFLQWSSLKASD

TAMYFCARTNYYYRSYIFYFDYWGQGTMVT

VSS

663
hBDB-4G8-D4VH.v4
EIQLVQSGGGVVQPGGSLRLSCAASGYTFT

NYGMYWVKQAPGKGLEYMCWINTETGKPTY

ADDFKGRFTFSLDTSKSTAYLQLNSLRAED

TAVYFCARTNYYYRSYIFYFDYWGQGTLVT

VSS

664
hBDB-4G8-D4VH.v5
EVQLVESGGGLVQPGGSLRLSCAASGYTFT

NYGMYWVKQAPGKGLEYMGWINTETGKPTY

ADDFKGRFTFSLDTSKSTAYLQMNSLRAED

TAVYFCARTNYYYRSYIFYFDYWGQGTLVT

VSS

665
hBDB-4G8-D4VL.1
AIQLTQSPSSLSASVGDRVTITCRASESVS

THMHWYQQKPGKAPKLLIYGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQ

SWNDPFTFGQGTKLEIK

666
hBDB-4G8-D4VL.1a
ATQLTQSPSLSASVGDRVTITCRASESVST

HMHWYQQKPGKQPKLLIYGASNLESGVPSR

FSGSGSGTDFTLTISSLQPEDFATYFCQQS

WNDPFTFGQGTKLEIK

667
hBDB-4G8-D4VL.1b
ATQLTQSPSLSASVGDRVTITCRASESVST

HMHWYQQKPGKAPKLLIYGASNLESGVPSR

FSGSGSGTDFTLTISSLQPEDFATYYCQQS

WNDPFTFGQGTKLEIK

668
hBDB-4G8-D4VL.1c
ATQLTQSPSSLSASVGDRVTITCRASESVS

THMHWYQQKPGKAPKLLIYGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQ

SWNDPFTFGQGTKLEIK

669
hBDB-4G8-D4VL.v2
DTVLTQSPATLSLSPGERATLSCRASESVS

THMHWYQQKPGQAPRLLIYGASNLESGVPA

RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ

SWNDPFTFGQGTKLEIK

670
hBDB-4G8-D4VL.v3
ETVLTQSPATLSVSPGERATLSCRASESVS

THMHWYQQKPGQAPRLLIYGASNLESGVPA

RFSGSGSGTDFTLTISSLQSEDFAVYFCQQ

SWNDPFTFGQGTRLEIK

671
hBDB-4G8-D4VL.v4
DTVLTQSPSTLSASPGERATISCRASESVS

THMHWYQQKPGQAPKLLIYGASNLESGVPS

RFSGSRSGTDFTLTISSLQPEDFAVYFCQQ

SWNDPFTFGQGTKVEIK

672
hBDB-4G8-D4VL.v5
DTQLTQSPSSLSASVGDRVTISCRASESVS

THMHWYQQKPGKAPKLLIYGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYFCQQ

SWNDPFTFGQGTKVEIK

- hBDB-4G8-D4VH.1z is a CDR-grafted, humanized BDB-4G8-D4 VH containing IGHV7-4-1*02 and IGHJ3*01 framework sequences.
- hBDB-4G8-D4VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBDB-4G8-D4VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations (V2I, W47Y and Y91F).
- hBDB-4G8-D4VH.1b is an intermediate design between .1 and .1a and only has one back-mutations W47Y.
- hBDB-4G8-D4VH.2z is a CDR-grafted, humanized BDB-4G8-D4 VH containing IGHV1-18*01 and IGHJ3*01 framework sequences.
- hBDB-4G8-D4VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
- hBDB-4G8-D4VH.2a is a humanized design based on .2 and contains six proposed framework back-mutations (V2I, W47Y, V67F, M69F, T71L and Y91F).
- hBDB-4G8-D4VH.2b is an intermediate design between .2 and .2a and only has two proposed framework back-mutations (W47Y and T71L).
- hBDB-4G8-D4VH.v3 is a humanized BDB-4G8-D4 VH containing IGHV5-51*01 and

IGHJ3*01 framework sequences with thirteen proposed framework back-mutations (V21, A9T, G24A, R38K, W47Y, Q66R, V67F, 169F, A71L, I75F, S76N, Y79F and Y91F).

- hBDB-4G8-D4VH.v4 is a humanized BDB-4G8-D4 VH containing IGHV3-66*01 and

IGHJ1*01 framework sequences with thirteen proposed framework back-mutations (V21, E6Q, L11V, W47Y, V48M, S49G, 169F, R71L, N73T, N76S, L78A, M82L and Y91F).

- hBDB-4G8-D4VH.v5 is a humanized BDB-4G8-D4 containing IGHV3-66*01 and IGHJ1*01 framework sequences with ten proposed framework back-mutations (R38K, W47Y, V48M, S49G, 169F, R71L, N73T, N76S, L78A and Y91F).
- hBDB-4G8-D4VL.1 is a CDR-grafted humanized BDB-4G8-D4 VL containing IGKV1D-13*01 and IGKJ2*01 framework sequences.
- hBDB-4G8-D4VL.1a is a humanized design based on .1 with 3 proposed framework back-mutations (I2T, A43Q and Y87F) and one residue deletion (S10).
- hBDB-4G8-D4VL.1b is an intermediate design between .1 and .1a with only one proposed framework back-mutation 12T.
- hBDB-4G8-D4VL.1c is a humanized design based on .1b with one residue insertion (S10).
- hBDB-4G8-D4VL.v2 is a humanized BDB-4G8-D4 VL containing IGKV3-11*01 and

IGKJ2*01 framework sequences with four proposed framework back-mutations (E1D, 12T, I58V, and Y87F).

- hBDB-4G8-D4VL.v3 is a humanized BDB-4G8-D4 VL design containing IGKV3-15*01 and

IGKJ5*01 framework sequences with five proposed framework back-mutations (I2T, M4L, I58V, E70D, and Y87F).

- hBDB-4G8-D4VL.v4 is a humanized BDB-4G8-D4 VL containing IGKV3-15*01 and

IGKJ1*01 framework sequences with eleven proposed framework back-mutations (E1D, 12T, A9S, L13A, L21I, R45K, I58V, A605, G66R, E79Q, and Y87F).

- hBDB-4G8-D4VL.v5 is a humanized BDB-4G8-D4 VL containing IGKV1-39*01 and

IGKJ1*01 framework sequences with four proposed framework back-mutations (I2T, M4L, T22S, and Y87F).

Example 6.2.4.2
BEW-9A8-E2

TABLE 2.4.2

Sequences of Humanized BEW-9A8-E2 Variable Regions

SEQ ID
Protein
Sequence

NO:
region
123456789012345678901234567890

673
hBEW-9A8-
QVQLVQSGHEVKQPGASVKVSCKASGYTFT

E2VH.1z

NYGMYWVPQAPGQGLEWMGWINTETGKPIY

ADDFKGRFVFSMDTSASTAYLQISSLKAED

MAMYYCARVDYDGSFWFAYWGQGTLVTVSS

674
hBEW-9A8-
EVQLVQSGHEVKQPGASVKVSCKASGYTFT

E2VH.1

NYGMYWVPQAPGQGLEWMGWINTETGKPIY

ADDFKGRFVFSMDTSASTAYLQISSLKAED

MAMYYCARVDYDGSFWFAYWGQGTLVTVSS

675
hBEW-9A8-
EIQLVQSGHEVKQPGASVKVSCKASGYTFT

E2VH.1a

NYGMYWVKQAPGQGLEYMGWINTETGKPIY

ADDFKGRFVFSLDTSASTAYLQISSLKAED

MAMFFCARVDYDGSFWFAYWGQGTLVTVSS

676
hBEW-9A8-
EVQLVQSGHEVKQPGASVKVSCKASGYTFT

E2VH.1b

NYGMYWVPQAPGQGLEYMGWINTETGKPIY

ADDFKGRFVFSLDTSASTAYLQISSLKAED

MAMFYCARVDYDGSFWFAYWGQGTLVTVSS

677
hBEW-9A8-
EVQLVQSGHEVKQPGASVKVSCKASGYSFT

E2VH.1c

NYGMYWVPQAPGQGLEYMGWINTETGKPIY

ADDFKGRFVFSLDTSASTAYLQISSLKAED

MAMFYCARVDYDGSFWFAYWGQGTLVTVSS

678
hBEW-9A8-
QVQLVQSGAEVKKPGASVKVSCKASGYTFT

E2VH.2z

NYGMYWVRQAPGQGLEWMGWINTETGKPIY

ADDFKGRVTMTTDTSTSTAYMELRSLRSDD

TAVYYCARVDYDGSFWFAYWGQGTLVTVSS

679
hBEW-9A8-
EVQLVQSGAEVKKPGASVKVSCKASGYTFT

E2VH.2

NYGMYWVRQAPGQGLEWMGWINTETGKPIY

ADDFKGRVTMTTDTSTSTAYMELRSLRSDD

TAVYYCARVDYDGSFWFAYWGQGTLVTVSS

680
hBEW-9A8-
EIQLVQSGAEVKKPGASVKVSCKASGYTFT

E2VH.2a

NYGMYWVKQAPGQGLEYMGWINTETGKPIY

ADDFKGRFTFTLDTSTSTAYMELRSLRSDD

TAVFFCARVDYDGSFWFAYWGQGTLVTVSS

681
hBEW-9A8-
EVQLVQSGAEVKKPGASVKVSCKASGYTFT

E2VH.2b

NYGMYWVRQAPGQGLEYMGWINTETGKPIY

ADDFKGRVTMTLDTSTSTAYMELRSLRSDD

TAVFYCARVDYDGSFWFAYWGQGTLVTVSS

682
hBEW-9A8-
EIQLVQSGAEVKKPGASVKVSCKASGYTFT

E2VH.2c

NYGMYWVKQAPGQGLEYMGWINTETGKPIY

ADDFKGRFTFTLDTSTSTAYMELRSLRSDD

TAVYYCARVDYDGSFWFAYWGQGTLVTVSS

683
hBEW-9A8-
EIQLVQSGAEVKKPGASVKVSCKASGYTFT

E2VH.2d

NYGMYWVRQAPGQGLEWMGWINTETGKPIY

ADDFKGRFTFTLDTSTSTAYMELRSLRSDD

TAVYYCARVDYDGSFWFAYWGQGTLVTVSS

684
hBEW-9A8-
QVQLVQSGSELKKPGASVKVSCKASGYTFT

E2VH.3z

NYGMYWVRQAPGQGLEWMGWINTETGKPIY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARVDYDGSFWFAYWGQGTLVTVSS

685
hBEW-9A8-
EVQLVQSGSELKKPGASVKVSCKASGYTFT

E2VH.3

NYGMYWVRQAPGQGLEWMGWINTETGKPIY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARVDYDGSFWFAYWGQGTLVTVSS

686
hBEW-9A8-
EIQLVQSGSELKKPGASVKVSCKASGYTFT

E2VH.3a

NYGMYWVKQAPGQGLEYMGWINTETGKPIY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARVDYDGSFWFAYWGQGTLVTVSS

687
hBEW-9A8-
EIQLVQSGSELKKPGASVKVSCKASGYTFT

E2VH.3b

NYGMYWVRQAPGQGLEWMGWINTETGKPIY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARVDYDGSFWFAYWGQGTLVTVSS

688
hBEW-9A8-
EIQLVQSGSELKKPGASVKVSCKASGYTFT

E2VH.3c

NYGMYWVKQAPGQGLEYMGWINTETGKPIY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVFFCARVDYDGSFWFAYWGQGTLVTVSS

689
hBEW-9A8-
EIVLTQSPDFQSVTPKEKVTITCRASESVS

E2VL.1

TVIHWYQQKPDQSPKLLIKGASNLESGVPS

RFSGSGSGTDFTLTINSLEAEDAATYYCQQ

HWNDPPTFGQGTKLEIK

690
hBEW-9A8-
ETVLTQSPDFQSVTPKEKVTITCRASESVS

E2VL.1a

TVIHWYQQKPDQQPKLLIHGASNLESGVPS

RFSGSGSGTDFTLTINSLEAEDAATYFCQQ

HWNDPPTFGQGTKLEIK

691
hBEW-9A8-
ETVLTQSPDFQSVTPKEKVTITCRASESVS

E2VL.1b

TVIHWYQQKPDQSPKLLIHGASNLESGVPS

RFSGSGSGTDFTLTINSLEAEDAATYYCQQ

HWNDPPTFGQGTKLEIK

692
hBEW-9A8-
ETVLTQSPDQSVTPKEKVTITCRASESVST

E2VL.1c

VIHWYQQKPDQSPKLLIHGASNLESGVPSR

FSGSGSGTDFTLTINSLEAEDAATYYCQQH

WNDPPTFGQGTKLEIK

693
hBEW-9A8-
DIQMTQSPSSLSASVGDRVTITCRASESVS

E2VL.2

TVIHWYQQKPGKAPKLLIYGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQ

HWNDPPTFGQGTKLEIK

694
hBEW-9A8-
DTQLTQSPSSLSASVGDRVTITCRASESVS

E2VL.2a

TVIHWYQQKPGKQPKLLIHGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYFCQQ

HWNDPPTFGQGTKLEIK

695
hBEW-9A8-
DTQMTQSPSSLSASVGDRVTITCRASESVS

E2VL.2b

TVIHWYQQKPGKAPKLLIHGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQ

HWNDPPTFGQGTKLEIK

696
hBEW-9A8-
DTQMTQSPSLSASVGDRVTITCRASESVST

E2VL.2c

VIHWYQQKPGKAPKLLIHGASNLESGVPSR

FSGSGSGTDFTLTISSLQPEDFATYYCQQH

WNDPPTFGQGTKLEIK

697
hBEW-9A8-
EIVLTQSPATLSLSPGERATLSCRASESVS

E2VL.3

TVIHWYQQKPGQAPRLLIYGASNLESGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

HWNDPPTFGQGTKLEIK

698
hBEW-9A8-
ETVLTQSPATLSLSPGERATLSCRASESVS

E2VL.3a

TVIHWYQQKPGQAPRLLIHGASNLESGVPA

RFSGSGSGTDFTLTISSLEPEDFATYFCQQ

HWNDPPTFGQGTKLEIK

699
hBEW-9A8-
ETVLTQSPATLSLSPGERATLSCRASESVS

E2VL.3b

TVIHWYQQKPGQAPRLLIYGASNLESGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ

HWNDPPTFGQGTKLEIK

700
hBEW-9A8-
ETVLTQSPATLSLSPGERATLSCRASESVS

E2VL.3c

TVIHWYQQKPGQAPRLLIYGASNLESGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

HWNDPPTFGQGTKLEIK

701
hBEW-9A8-
AIQLTQSPSSLSASVGDRVTITCRASESVS

E2VL.4

TVIHWYQQKPGKAPKLLIYGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQ

HWNDPPTFGQGTKLEIK

702
hBEW-9A8-
ATQLTQSPSSLSASVGDRVTISCRASESVS

E2VL.4a

TVIHWYQQKPGKAPKLLIHGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYFCQQ

HWNDPPTFGQGTKLEIK

703
hBEW-9A8-
ATQLTQSPSSLSASVGDRVTITCRASESVS

E2VL.4b

TVIHWYQQKPGKAPKLLIYGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYFCQQ

HWNDPPTFGQGTKLEIK

704
hBEW-9A8-
ATQLTQSPSSLSASVGDRVTITCRASESVS

E2VL.4c

TVIHWYQQKPGKAPKLLIYGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQ

HWNDPPTFGQGTKLEIK

- hBEW-9A8-E2VH.1z is a CDR-grafted, humanized BEW-9A8-E2 VH containing IGHV7-81*01 and IGHJ1*01 framework sequences.
- hBEW-9A8-E2VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBEW-9A8-E2VH.1a is a humanized design based on .1 and contains six proposed framework back-mutations (V2I, P38K, W47Y, M71L, Y90F and Y91F).
- hBEW-9A8-E2VH.1b is an intermediate design between .1 and .1a and only has three proposed framework back-mutations (W47Y, M71L and Y90F).
- hBEW-9A8-E2VH.1c is based on .1b with additional one CDR germlining change T28S to improve identity to human germline sequence.
- hBEW-9A8-E2VH.2z is a CDR-grafted, humanized BEW-9A8-E2 VH containing IGHV1-18*01 and IGHJ1*01 framework sequences.
- hBEW-9A8-E2VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
- hBEW-9A8-E2VH.2a is a humanized design based on .2 and contains eight proposed framework back-mutations (V2I, R38K, W47Y, V67F, M69F, T71L, Y90F and Y91F).
- hBEW-9A8-E2VH.2b is an intermediate design between .2 and .2a and contains three back-mutations (W47Y, M71L and Y90F).
- hBEW-9A8-E2VH.2c (hBEW-9A8VH.4a) is an intermediate design between .2 and .2a and contains six proposed framework back-mutations (V21, R38K, W47Y, V67F, M69F, and T71L).
- hBEW-9A8-E2VH.2d (hBEW-9A8VH.4b) is an intermediate design between .2 and .2a contains four proposed framework back-mutations (V2I, V67F, M69F, and T71L).
- hBEW-9A8VH.3z is a CDR-grafted, humanized BEW-9A8 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
- hBEW-9A8VH.3 is based on .3z with a Q1E change to prevent pyroglutamate formation.
- hBEW-9A8VH.3a is a humanized design based on .3 and contains 3 proposed framework back-mutations (V2I, R38K, W47Y).
- hBEW-9A8VH.3b is an intermediate design between .3 and .3a and contains 1 proposed framework back-mutations: V21.
- hBEW-9A8VH.3c is a humanized design based on .3 and contains 5 proposed framework back-mutations (V2I, R38K, W47Y, Y90F, Y91F).
- hBEW-9A8-E2VL.1 is a CDR-grafted humanized BEW-9A8-E2 VL containing IGKV6-21*01 and IGKJ2*01 framework sequences.
- hBEW-9A8-E2VL.1a is a humanized design based on .1 with four proposed framework back-mutations (I2T, S43Q, K49H and Y87F).
- hBEW-9A8-E2VL.1b is an intermediate design between .1 and .1a with only two proposed framework back-mutation (I2T and K49H).
- hBEW-9A8-E2VL.1c is based on .1b with one residue deletion of F10.
- hBEW-9A8-E2VL.2 is a CDR-grafted humanized BEW-9A8-E2 VL containing IGKV1-39*01 and IGKJ2*01 framework sequences.
- hBEW-9A8-E2VL.2a is a humanized design based on .2 with five proposed framework back-mutations (I2T, M4L, A43Q, Y49H and Y87F).
- hBEW-9A8-E2VL.2b is an intermediate design between .1 and .1a with only two proposed framework back-mutation (I2T and Y49H).
- hBEW-9A8-E2VL.2c is based on .2b with one residue deletion of S10.
- hBEW-9A8VL.3 is a CDR-grafted, humanized BEW-9A8 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
- hBEW-9A8VL.3a is a humanized design based on .3 and contains 5 proposed framework back-mutations: (I2T, Y49H, I58V, V85T, Y87F).
- hBEW-9A8VL.3b is an intermediate design between .3 and 3a. It contains 2 proposed framework back-mutations: (I2T, Y87F).
- hBEW-9A8VL.3c is a design based on .3b and contains 1 proposed framework back-mutations: I2T.
- hBEW-9A8VL.4 is a CDR-grafted, humanized BEW-9A8 VL containing IGKV1-13*01 and IGKJ2*01 framework sequences.
- hBEW-9A8VL.4a is a humanized design based on .4 and contains 4 proposed framework back-mutations: I2T, T22S, Y49H, Y87F.
- hBEW-9A8VL.4b is an intermediate design between .4 and 4a. It contains 2 proposed framework back-mutations: I2T, Y87F.
- hBEW-9A8VL.4c is a design based on .4b and eliminated Carter residue back-mutations. It contains 1 proposed framework back-mutations: I2T.

Example 6.2.4.3
BEW-6C2-C8

TABLE 2.4.3

Sequences of Humanized BEW-6C2-C8 Variable Regions

SEQ

ID
Protein
Sequence

NO:
region
123456789012345678901234567890

705
hBEW-6C2-C8VH.1
EVQLVESGGGLVQPGGSLRLSCAASGFTFS

YYGMHWVRQAPGKGLEWVALIYYDSSKMYY

ADSVKGRFTISRDNAKNSLYLQMNSLRAED

TAVYYCARGGTAPVYWGQGTMVTVSS

706
hBEW-6C2-
EVQLVESGGGLVQPGGSLRLSCAASGFTFS

C8VH.1a

YYGMHWIRQAPGKGLEWMALIYYDSSKMYY

ADSVKGRFTISRDNAKNSLYLQMNSLRAED

TAVYYCAAGGTAPVYWGQGTMVTVSS

707
hBEW-6C2-
EVQLVESGGGLVQPGGSLRLSCAASGFTFS

C8VH.1b

YYGMHWVRQAPGKGLEWMALIYYDSSKMYY

ADSVKGRFTISRDNAKNSLYLQMNSLRAED

TAVYYCAAGGTAPVYWGQGTMVTVSS

708
hBEW-6C2-C8VL.1
EIVLTQSPATLSLSPGERATLSCKGSQNIA

NYLAWYQQKPGQAPRLLIYNTDSLQTGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCYQ

SNNGYTFGQGTKLEIK

709
hBEW-6C2-
EIVLTQSPATLSLSPGERATLSCKGSQNIA

C8VL.1a

NYLAWYQQKPGQAPRLLIYNTDSLQTGIPA

RFSGSGSGTDYTLTISSLEPEDFAVYFCYQ

SNNGYTFGQGTKLEIK

710
hBEW-6C2-C8VL.2
DIQMTQSPSSLSASVGDRVTITCKGSQNIA

NYLAWYQQKPGKAPKLLIYNTDSLQTGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCYQ

SNNGYTFGQGTKLEIK

711
hBEW-6C2-
DIQLTQSPSSLSASVGDRVTITCKGSQNIA

C8VL.2a

NYLAWYQQKPGKAPKLLIYNTDSLQTGIPS

RFSGSGSGTDYTLTISSLQPEDFATYFCYQ

SNNGYTFGQGTKLEIK

- hBEW-6C2-C8VH.1 is a CDR-grafted, humanized BEW-6C2-C8 VH containing IGHV3-7*01 and IGHJ3*01 framework sequences.
- hBEW-6C2-C8VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations V37I, V48M and R94A.
- hBEW-6C2-C8VH.1b is an intermediate design between .1 and .1a and only has two back-mutations V48M and R94A. This design eliminates Carter residue back-mutations.
- hBEW-6C2-C8VL.1 is a CDR-grafted humanized BEW-6C2-C8 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
- hBEW-6C2-C8VL.1a is a humanized design based on .1 with 2 proposed framework back-mutations (F71Y and Y87F).
- hBEW-6C2-C8VL.2 is a CDR-grafted humanized BEW-6C2-C8 VL containing IGKV1-39*01 and IGKJ2*01 framework sequences.
- hBEW-6C2-C8VL.2a is a humanized design based on .2 with 4 proposed framework back-mutations (M4L, V58I, F71Y and Y87F).

Example 6.2.4.4
BEW-9D2-E8

TABLE 2.4.4

Sequences of Humanized BEW-9D2-E8 Variable Regions

SEQ

ID
Protein
Sequence

NO:
region
123456789012345678901234567890

712
hBEW-9D2-E8VH.1z
QVQLVQSGHEVKQPGASVKVSCKASGYTFT

NYGMYWVPQAPGQGLEWMGWINTETGKPTY

ADDFKGRFVFSMDTSASTAYLQISSLKAED

MAMYYCARPSDYYDGFWFAYWGQGTLVTVS

S

713
hBEW-9D2-E8VH.1
EVQLVQSGHEVKQPGASVKVSCKASGYTFT

NYGMYWVPQAPGQGLEWMGWINTETGKPTY

ADDFKGRFVFSMDTSASTAYLQISSLKAED

MAMYYCARPSDYYDGFWFAYWGQGTLVTVS

S

714
hBEW-9D2-E8VH.1a
EIQLVQSGHEVKQPGASVKVSCKASGYTFT

NYGMYWVKLAPGQGLEYLGWINTETGKPTY

ADDFKGRFVFSLDTSASTAYLQISSLKAED

MAMYFCARPSDYYDGFWFAYWGQGTLVTVS

S

715
hBEW-9D2-E8VH.1b
EVQLVQSGHEVKQPGASVKVSCKASGYTFT

NYGMYWVKQAPGQGLEYLGWINTETGKPTY

ADDFKGRFVFSLDTSASTAYLQISSLKAED

MAMYYCARPSDYYDGFWFAYWGQGTLVTVS

S

716
hBEW-9D2-E8VH.1c
EVQLVQSGHEVKQPGASVKVSCKASGYSFT

NYGMYWVKQAPGQGLEYLGWINTETGKPTY

ADDFKGRFVFSLDTSASTAYLQISSLKAED

MAMYYCARPSDYYDGFWFAYWGQGTLVTVS

S

717
hBEW-9D2-E8VH.2z
QVQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWINTETGKPTY

ADDFKGRVTMTTDTSTSTAYMELRSLRSDD

TAVYYCARPSDYYDGFWFAYWGQGTLVTVS

S

718
hBEW-9D2-E8VH.2
EVQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWINTETGKPTY

ADDFKGRVTMTTDTSTSTAYMELRSLRSDD

TAVYYCARPSDYYDGFWFAYWGQGTLVTVS

S

719
hBEW-9D2-E8VH.2a
EIQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVKLAPGQGLEYLGWINTETGKPTY

ADDFKGRFTFTLDTSTSTAYLELRSLRSDD

TAVYFCARPSDYYDGFWFAYWGQGTLVTVS

S

720
hBEW-9D2-E8VH.2B
EVQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVKQAPGQGLEYLGWINTETGKPTY

ADDFKGRVTMTLDTSTSTAYLELRSLRSDD

TAVYYCARPSDYYDGFWFAYWGQGTLVTVS

S

721
hBEW-9D2-E8VL.1
EIVLTQSPATLSLSPGERATLSCRASEWVN

SYMHWYQQKPGQAPRLLIYKASNLASGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

SWNDPLTFGQGTKLEIK

722
hBEW-9D2-E8VL.1a
ETVLTQSPATLSLSPGERATLSCRASEWVN

SYMHWYQQKPGQQPRLLIYKASNLASGVPA

RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ

SWNDPLTFGQGTKLEIK

723
hBEW-9D2-E8VL.1b
ETVLTQSPATLSLSPGERATLSCRASEWVN

SYMHWYQQKPGQAPRLLIYKASNLASGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

SWNDPLTFGQGTKLEIK

724
hBEW-9D2-E8VL.2
DIQMTQSPSSLSASVGDRVTITCRASEWVN

SYMHWYQQKPGKAPKLLIYKASNLASGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQ

SWNDPLTFGQGTKLEIK

725
hBEW-9D2-E8VL.2a
DTQLTQSPSSLSASVGDRVTITCRASEWVN

SYMHWYQQKPGKQPKLLIYKASNLASGVPS

RFSGSGSGTDFTLTISSLQPEDFATYFCQQ

SWNDPLTFGQGTKLEIK

726
hBEW-9D2-E8VL.2b
DTQMTQSPSSLSASVGDRVTITCRASEWVN

SYMHWYQQKPGKAPKLLIYKASNLASGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQ

SWNDPLTFGQGTKLEIK

- hBEW-9D2-E8VH.1z is a CDR-grafted, humanized BEW-9D2-E8 VH containing IGHV7-81*01 and IGHJ4*01 framework sequences.
- hBEW-9D2-E8VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBEW-9D2-E8VH.1a is a humanized design based on .1 and contains seven proposed framework back-mutations (V2I, P38K, Q39L, W47Y, M48L, M71L and Y91F).
- hBEW-9D2-E8VH.1b is an intermediate design between .1 and .1a and only has four proposed framework back-mutations (P38K, W47Y, M48L, M71L).
- BEW-9D2-E8VH.1c is based on .1b with additional one CDR germlining change T28S to improve identity to human germline sequence.
- hBEW-9D2-E8VH.2z is a CDR-grafted, humanized BEW-9D2-E8 VH containing IGHV1-18*01 and IGHJ4*01 framework sequences.
- hBEW-9D2-E8VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
- hBEW-9D2-E8VH.2a is a humanized design based on .2 and contains ten proposed framework back-mutations (V21, R38K, Q39L, W47Y, M48L, V67F, M69F, T71L, M80L and Y91F).
- hBEW-9D2-E8VH.2b is an intermediate design between .2 and .2a and only has five proposed framework back-mutations (R38K, W47Y, M48L, T71L and M80L).
- hBEW-9D2-E8VL.1 is a CDR-grafted humanized BEW-9D2-E8 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
- hBEW-9D2-E8VL.1a is a humanized design based on .1 with four proposed framework back-mutations (I2T, A43Q, I58V and Y87F).
- hBEW-9D2-E8VL.1b is an intermediate design between .1 and .1a with one proposed framework back-mutation 12V.
- hBEW-9D2-E8VL.2 is a CDR-grafted humanized BEW-9D2-E8 VL containing IGKV1-39*01 and IGKJ2*01 framework sequences.
- hBEW-9D2-E8VL.2a is a humanized design based on .2 with four proposed framework back-mutations (I2T, M4L, A43Q and Y87F).
- hBEW-9D2-E8VL.2b is an intermediate design between .2 and .2a with one proposed framework back-mutation 12V.

Example 6.2.4.5
BEW-9E3-B9

TABLE 2.4.5

Sequences of Humanized BEW-9E3-B9 Variable Regions

SEQ

ID
Protein
Sequence

NO:
region
123456789012345678901234567890

727
hBEW-9E3-B9VH.1z
QVQLVQSGHEVKQPGASVKVSCKASGYTFT

NYGMYWVPQAPGQGLEWMGWINTETGKPTY

ADDFKGRFVFSMDTSASTAYLQISSLKAED

MAMYYCARPSDYYDGFWFPYWGQGTLVTVS

S

728
hBEW-9E3-B9VH.1
EVQLVQSGHEVKQPGASVKVSCKASGYTFT

NYGMYWVPQAPGQGLEWMGWINTETGKPTY

ADDFKGRFVFSMDTSASTAYLQISSLKAED

MAMYYCARPSDYYDGFWFPYWGQGTLVTVS

S

729
hBEW-9E3-B9VH.1a
EIQLVQSGHEVKQPGASVKVSCKASGYTFT

NYGMYWVPQAPGQGLEYMGWINTETGKPTY

ADDFKGRFVFSLDTSASTAYLQISSLKAED

MAMYFCARPSDYYDGFWFPYWGQGTLVTVS

S

730
hBEW-9E3-B9VH.1b
EVQLVQSGHEVKQPGASVKVSCKASGYTFT

NYGMYWVPQAPGQGLEYMGWINTETGKPTY

ADDFKGPFVFSLDTSASTAYLQISSLKAED

MAMYYCARPSDYYDGFWFPYWGQGTLVTVS

S

731
hBEW-9E3-B9VH.1c
EVQLVQSGHEVKQPGASVKVSCKASGYSFT

NYGMYWVPQAPGQGLEYMGWINTETGKPTY

ADDFKGRFVFSLDTSASTAYLQISSLKAED

MAMYYCARPSDYYDGFWFPYWGQGTLVTVS

S

732
hBEW-9E3-B9VH.2z
QVQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWINTETGKPTY

ADDFKGPVTMTTDTSTSTAYMELRSLPSDD

TAVYYCARPSDYYDGFWFPYWGQGTLVTVS

S

733
hBEW-9E3-B9VH.2
EVQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWINTETGKPTY

ADDFKGRVTMTTDTSTSTAYMELRSLRSDD

TAVYYCARPSDYYDGFWFPYWGQGTLVTVS

S

734
hBEW-9E3-B9VH.2a
EIQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEYMGWINTETGKPTY

ADDFKGRFTFTLDTSTSTAYMELRSLRSDD

TAVYFCARPSDYYDGFWFPYWGQGTLVTVS

S

735
hBEW-9E3-B9VH.2b
EVQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEYMGWINTETGKPTY

ADDFKGRVTMTLDTSTSTAYMELRSLRSDD

TAVYYCARPSDYYDGFWFPYWGQGTLVTVS

S

736
hBEW-9E3-B9VL.1
EIVLTQSPATLSLSPGERATLSCRASEGVN

SYMHWYQQKPGQAPRLLIYKASNLASGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

SWNDPLTFGQGTKLEIK

737
hBEW-9E3-B9VL.1a
ETVLTQSPATLSLSPGERATLSCRASEGVN

SYMHWYQQKPGQQPRLLIYKASNLASGVPA

RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ

SWNDPLTFGQGTKLEIK

738
hBEW-9E3-B9VL.1b
ETVLTQSPATLSLSPGERATLSCRASEGVN

SYMHWYQQKPGQAPRLLIYKASNLASGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

SWNDPLTFGQGTKLEIK

739
hBEW-9E3-B9VL.2
DIQMTQSPSSLSASVGDRVTITCRASEGVN

SYMHWYQQKPGKAPKLLIYKASNLASGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQ

SWNDPLTFGQGTKLEIK

740
hBEW-9E3-B9VL.2a
DTQLTQSPSSLSASVGDRVTITCRASEGVN

SYMHWYQQKPGKQPKLLIYKASNLASGVPS

RFSGSGSGTDFTLTISSLQPEDFATYFCQQ

SWNDPLTFGQGTKLEIK

741
hBEW-9E3-B9VL.2b
DTQMTQSPSSLSASVGDRVTITCRASEGVN

SYMHWYQQKPGKAPKLLIYKASNLASGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQ

SWNDPLTFGQGTKLEIK

- hBEW-9E3-B9VH.1z is a CDR-grafted, humanized BEW-9E3-B9 VH containing IGHV7-81*01 and IGHJ4*01 framework sequences.
- hBEW-9E3-B9VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBEW-9E3-B9VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (V2I, W47Y, M71L and Y91F).
- hBEW-9E3-B9VH.1b is an intermediate design between .1 and .1a and only has two back-mutations (W47Y and M71L).
- hBEW-9E3-B9VH.1c is based on .1b with additional one CDR germlining change T28S to improve identity to human germline sequence.
- hBEW-9E3-B9VH.2z is a CDR-grafted, humanized BEW-9E3-B9 VH containing IGHV1-18*01 and IGHJ4*01 framework sequences.
- hBEW-9E3-B9VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
- hBEW-9E3-B9VH.2a is a humanized design based on .2 and contains six proposed framework back-mutations (V2I, W47Y, V67F, M69F, T71L and Y91F).
- hBEW-9E3-B9VH.2b is an intermediate design between .2 and .2a and only has two back-mutations W47Y and T71L.
- hBEW-9E3-B9VL.1 is a CDR-grafted humanized BEW-9E3-B9 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
- hBEW-9E3-B9VL.1a is a humanized design based on .1 with four proposed framework back-mutations (I2T, A43Q, I58V and Y87F).
- hBEW-9E3-B9VL.1b is an intermediate design between .1 and .1a with 1 proposed framework back-mutation 12T.
- hBEW-9E3-B9VL.2 is a CDR-grafted humanized BEW-9E3-B9 VL containing IGKV1-39*01 and IGKJ2*01 framework sequences.
- hBEW-9E3-B9VL.2a is a humanized design based on .1 with four proposed framework back-mutations (I2T, M4L, A43Q and Y87F).
- hBEW-9E3-B9VL.2b is an intermediate design between .1 and .1a with 1 proposed framework back-mutation 12T.

Example 6.2.4.6
BEW-5C3

TABLE 2.4.6

Sequences of Humanized BEW-5C3 Variable Regions

SEQ

ID

Sequence

NO:
Protein region
123456789012345678901234567890

742
hBEW-5c3VH.1z
QVQLVQSGSELKKPGASVKVSCKASGYTFT

NYGVYWVRQAPGQGLEWMGWINTETGKPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARARQLDWFVYWGQGTLVTVSS

743
hBEW-5C3VH.1
EVQLVQSGSELKKPGASVKVSCKASGYTFT

NYGVYWVRQAPGQGLEWMGWINTETGKPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARARQLDWFVYWGQGTLVTVSS

744
hBEW-5C3VH.1a
EIQLVQSGSELKKPGASVKVSCKASGYTFT

NYGVYWVKQAPGQGLEYMGWINTETGKPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARARQLDWFVYWGQGTLVTVSS

745
hBEW-5C3VH.1b
EIQLVQSGSELKKPGASVKVSCKASGYTFT

NYGVYWVKQAPGQGLEYMGWINTETGKPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVFFCARARQLDWFVYWGQGTLVTVSS

746
hBEW-5C3VH.2z
QVQLVQSGAEVKKPGSSVKVSCKASGYTFT

NYGVYWVRQAPGQGLEWMGWINTETGKPTY

ADDFKGRVTITADKSTSTAYMELSSLRSED

TAVYYCARARQLDWFVYWGQGTLVTVSS

747
hBEW-5C3VH.2
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

NYGVYWVRQAPGQGLEWMGWINTETGKPTY

ADDFKGRVTITADKSTSTAYMELSSLRSED

TAVYYCARARQLDWFVYWGQGTLVTVSS

748
hBEW-5C3VH.2a
EIQLVQSGAEVKKPGSSVKVSCKASGYTFT

NYGVYWVKQAPGQGLEYMGWINTETGKPTY

ADDFKGRFTFTLDKSTSTAYMELSSLRSED

TAVYFCARARQLDWFVYWGQGTLVTVSS

749
hBEW-5C3VH.2b
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

NYGVYWVRQAPGQGLEWMGWINTETGKPTY

ADDFKGRFTFTLDKSTSTAYMELSSLRSED

TAVYYCARARQLDWFVYWGQGTLVTVSS

750
hBEW-5C3VH.2C
EIQLVQSGAEVKKPGSSVKVSCKASGYTFT

NYGVYWVKQAPGQGLEYMGWINTETGKPTY

ADDFKGRFVFTLDKSTSTAYLELSSLRSED

TAVFFCARARQLDWFVYWGQGTLVTVSS

751
hBEW-5C3VL.1
EIVLTQSPATLSLSPGERATLSCRARESLT

TSLCWYQQKPGQAPRLLIYGASKLESGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

SWYDPPTFGGGTKVEIK

752
hBEW-5C3VL.1a
DTVLTQSPATLSLSPGERATLSCRARESLT

TSLSWFQQKPGQQPRLLIYGASKLESGVPA

RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ

SWYDPPTFGGGTKVEIK

753
hBEW-5C3VL.1b
DTVLTQSPATLSLSPGERATLSCRARESLT

TSLSWFQQKPGQAPRLLIYGASKLESGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYFCQQ

SWYDPPTFGGGTKVEIK

754
hBEW-5C3VL.1c
DTVLTQSPATLSLSPGERATLSCRARESLT

TSLSWYQQKPGQAPRLLIYgasklesGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCQQ

SWYDPPTFGGGTKVEIK

755
hBEW-5C3VL.2
AIQLTQSPSSLSASVGDRVTITCRARESLT

TSLSWYQQKPGKAPKLLIYGASKLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQ

SWYDPPTFGGGTKVEIK

756
hBEW-5C3VL.2a
DTQLTQSPSSLSASVGDRVTISCRARESLT

TSLSWFQQKPGKQPKLLIYGASKLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYFCQQ

SWYDPPTFGGGTKVEIK

757
hBEW-5C3VL.2b
DTQLTQSPSSLSASVGDRVTITCRARESLT

TSLSWFQQKPGKAPKLLIYGASKLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYFCQQ

SWYDPPTFGGGTKVEIK

758
hBEW-5C3VL.2c
DTQLTQSPSSLSASVGDRVTITCRARESLT

TSLSWYQQKPGKAPKLLIYGASKLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCQQ

SWYDPPTFGGGTKVEIK

- hBEW-5C3VH.1z is a CDR-grafted, humanized BEW-5C3 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
- hBEW-5C3VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBEW-5C3VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations (V2I, R38K, W47Y).
- hBEW-5C3VH.1b is a humanized design based on .1 and contains five proposed framework back-mutations (V2I, R38K, W47Y, Y90F, Y91F).
- hBEW-5C3VH.2z is a CDR-grafted, humanized BEW-5C3 VH containing IGHV1-69*06 and IGHJ1*01 framework sequences.
- hBEW-5C3VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
- hBEW-5C3VH.2a is a humanized design based on .2 and contains seven proposed framework back-mutations (V2I, R38K, W47Y, V67F, I69F, A71L, Y91F).
- hBEW-5C3VH.2b is an intermediate design between .2 and .2a and contains three proposed framework back-mutations (V67F, I69F, A71L).
- hBEW-5C3VH.2c is a humanized design based on .2 and contains ten proposed framework back-mutations (V2I, R38K, W47Y, V67F, T68V, I69F, A71L, M80L, Y90F, Y91F).
- hBEW-5C3VL.1 is a CDR-grafted, humanized BEW-5C3 VL containing IGKV3-11*01 and IGKJ4*01 framework sequences.
- hBEW-5C3VL.1a is a humanized design based on .1 and contains six proposed framework back-mutations (E1D, I2T, Y36F, A43Q, I58V, Y87F).
- hBEW-5C3VL.1b is an intermediate design between .1 and .1a. It contains four proposed framework back-mutations (E1D, I2T, Y36F, Y87F).
- hBEW-5C3VL.1c is a design based on .1b and contains two proposed framework back-mutations (E1D, I2T)
- hBEW-5C3VL.2 is a CDR-grafted, humanized BEW-5C3 VL containing IGKV1-13*01 and IGKJ4*01 framework sequences.
- hBEW-5C3VL.2a is a humanized design based on .2 and contains six proposed framework back-mutations (A1D, I2T, T22S, Y36F, A43Q, Y87F).
- hBEW-5C3VL.2b is an intermediate design between .2 and 2a. It contains four proposed framework back-mutations (A1D, I2T, Y36F, Y87F).
- hBEW-5C3VL.2c is a design based on .2b and contains two proposed framework back-mutations (A1D, I2T)

Example 6.2.4.7
BEW-9E10

TABLE 2.4.7

Sequences of Humanized BEW-9E10 Variable Regions

SEQ

ID

Sequence

NO:
Protein region
123456789012345678901234567890

759
hBEW-9E10VH.1z
QVQLVQSGSELKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWIDTETGRPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARWSGDTTGIRGPWFAYWGQGTLV

TVSS

760
hBEW-9E10VH.1
EVQLVQSGSELKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWIDTETGRPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARWSGDTTGIRGPWFAYWGQGTLV

TVSS

761
hBEW-9E10VH.1a
EIQLVQSGSELKKPGASVKVSCKASGYTFT

NYGMYWVKQAPGQGLEYMGWIDTETGRPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYFCARWSGDTTGIRGPWFAYWGQGTLV

TVSS

762
hBEW-9E10VH.2z
QVQLVQSGAEVKKPGSSVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWIDTETGRPTY

ADDFKGRVTITADKSTSTAYMELSSLRSED

TAVYYCARWSGDTTGIRGPWFAYWGQGTLV

TVSS

763
hBEW-9E10VH.2
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWIDTETGRPTY

ADDFKGRVTITADKSTSTAYMELSSLRSED

TAVYYCARWSGDTTGIRGPWFAYWGQGTLV

TVSS

764
hBEW-9E10VH.2a
EIQLVQSGAEVKKPGSSVKVSCKASGYTFT

NYGMYWVKQAPGQGLEYMGWIDTETGRPTY

ADDFKGRFTFTADKSTSTAYMELSSLRSED

TAVYFCARWSGDTTGIRGPWFAYWGQGTLV

TVSS

765
hBEW-9E10VH.2b
EVQLVQSGAEVKKPGSSVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWIDTETGRPTY

ADDFKGRFTFTADKSTSTAYMELSSLRSED

TAVYYCARWSGDTTGIRGPWFAYWGQGTLV

TVSS

766
hBEW-9E10VL.1
DIQMTQSPSSLSASVGDRVTITCLASEDIY

SDLAWYQQKPGKVPKLLIYNANGLQNGVPS

RFSGSGSGTDFTLTISSLQPEDVATYYCQQ

YNYFPGTFGQGTKLEIK

767
hBEW-9E10VL.1a
DIRMTQSPSSLSASVGDRVTIECLASEDIY

SDLAWYQQKPGKSPKLLIYNANGLQNGVPS

RFSGSGSGTDYSLTISSLQPEDVATYFCQQ

YNYFPGTFGQGTKLEIK

768
hBEW-9E10VL.1b
DIRMTQSPSSLSASVGDRVTITCLASEDIY

SDLAWYQQKPGKSPKLLIYNANGLQNGVPS

RFSGSGSGTDYTLTISSLQPEDVATYFCQQ

YNYFPGTFGQGTKLEIK

- hBEW-9E10VH.1z is a CDR-grafted, humanized BEW-9E10 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
- hBEW-9E10VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBEW-9E10VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (V2I, R38K, W47Y, Y91F).
- hBEW-9E10VH.2z is a CDR-grafted, humanized BEW-9E10 VH containing IGHV1-69*06 and IGHJ1*01 framework sequences.
- hBEW-9E10VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
- hBEW-9E10VH.2a is a humanized design based on .2 and contains six proposed framework back-mutations (V2I, R38K, W47Y, V67F, I69F, Y91F).
- hBEW-9E10VH.2b is an intermediate design between .2 and .2a and contains two proposed framework back-mutations: (V67F, I69F).
- hBEW-9E10VL.1 is a CDR-grafted, humanized BEW-9E10 VL containing IGKV1-27*01 and IGKJ2*01 framework sequences.
- hBEW-9E10VL.1a is a humanized design based on .1 and contains six proposed framework back-mutations (Q3R, T22E, V43S, F71Y, T72S, Y87F).
- hBEW-9E10VL.1b is an intermediate design between .1 and .1a. It contains four proposed framework back-mutations (Q3R, V43S, F71Y, Y87F).

Example 6.2.4.8
BEW-1B10

TABLE 2.4.8

Sequences of Humanized BEW-1B10 Variable Regions

SEQ

ID

Sequence

NO:
Protein region
123456789012345678901234567890

769
hBEW-1B10VH.1
EVQLVESGGGLVQPGGSLRLSCAASGFSFS

KYDMAWVRQAPGKGLEWVASITTSGVGTYY

RDSVKGRFTISRDNAKNSLYLQMNSLRAED

TAVYYCARGYGAMDAWGQGTTVTVSS

770
hBEW-1B10VH.1a
EVQLVESGGGLVQPGGSLRLSCAASGFSFS

KYDMAWFRQAPGKGLEWVASITTSGVGTYY

RDSVKGRFTVSRDNAKSTLYLQMNSLRAED

TAVYYCARGYGAMDAWGQGTTVTVSS

771
hBEW-1B10VH.1b
EVQLVESGGGLVQPGGSLRLSCAASGFSFS

KYDMAWFRQAPGKGLEWVASITTSGVGTYY

RDSVKGRFTVSRDNAKNSLYLQMNSLRAED

TAVYYCARGYGAMDAWGQGTTVTVSS

772
hBEW-1B10VL.1
DIQMTQSPSSLSASVGDRVTITCKASQDID

DYLSWYQQKPGKAPKLLIYAATRLADGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCLQ

SSSTPWTFGGGTKVEIK

773
hBEW-1B10VL.1a
DIQMTQSPSSLSASVGDRVTITCKASQDID

DYLSWYQQKPGKSPKLVIYAATRLADGVPS

RFSGSGSGTDYTLTISSLQPEDFATYYCLQ

SSSTPWTFGGGTKVEIK

774
hBEW-1B10VL.1b
DIQMTQSPSSLSASVGDRVTITCKASQDID

DYLSWYQQKPGKSPKLLIYAATRLADGVPS

RFSGSGSGTDYTLTISSLQPEDFATYYCLQ

SSSTPWTFGGGTKVEIK

- hBEW-1B10VH.1 is a CDR-grafted, humanized BEW-1B10 VH containing IGHV3-7*01 and IGHJ6*01 framework sequences.
- hBEW-1B10VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (V37F, I69V, N76S, S77T).
- hBEW-1B10VH.1b is an intermediate design between .1 and .1a and contains two proposed framework back-mutations: (V37F, I69V).
- hBEW-9E10VH.1z is a CDR-grafted, humanized BEW-9E10 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
- hBEW-9E10VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBEW-1B10VL.1 is a CDR-grafted, humanized BEW-1B10 VL containing IGKV1-39*01 and IGKJ4*01 framework sequences.
- hBEW-1B10VL.1a is a humanized design based on .1 and contains three proposed framework back-mutations: (A43S, L47V, F71Y).
- hBEW-1B10VL.1b is an intermediate design between .1 and .1a. It contains two proposed framework back-mutations (A43S, F71Y).

Example 6.2.4.9
BEW-1E3

TABLE 2.4.9

Sequences of Humanized BEW-1E3 Variable Regions

SEQ

ID

Sequence

NO:
Protein region
123456789012345678901234567890

775
hBEW-1E3VH.1z
QVQLVQSGSELKKPGASVKVSCKASGYPFT

NSGMYWVRQAPGQGLEWMGWINTEAGKPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARWGYISDNSYGWFDYWGQGTLVT

VSS

776
hBEW-1E3VH.1
EVQLVQSGSELKKPGASVKVSCKASGYPFT

NSGMYWVRQAPGQGLEWMGWINTEAGKPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARWGYISDNSYGWFDYWGQGTLVT

VSS

777
hBEW-1E3VH.1a
EIQLVQSGSELKKPGASVKVSCKASGYPFT

NSGMYWVKQAPGQGLEYMGWINTEAGKPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYFCARWGYISDNSYGWFDYWGQGTLVT

VSS

778
hBEW-1E3VH.2z
QVQLVQSGAEVKKPGASVKVSCKASGYPFT

NSGMYWVRQAPGQGLEWMGWINTEAGKPTY

ADDFKGRVTMTTDTSTSTAYMELRSLRSDD

TAVYYCARWGYISDNSYGWFDYWGQGTLVT

VSS

779
hBEW-1E3VH.2
EVQLVQSGAEVKKPGASVKVSCKASGYPFT

NSGMYWVRQAPGQGLEWMGWINTEAGKPTY

ADDFKGRVTMTTDTSTSTAYMELRSLRSDD

TAVYYCARWGYISDNSYGWFDYWGQGTLVT

VSS

780
hBEW-1E3VH.2a
EIQLVQSGAEVKKPGASVKVSCKASGYPFT

NSGMYWVKQAPGQGLEYMGWINTEAGKPTY

ADDFKGRFTFTLDTSTSTAYLEIRSLRSDD

TAVYFCARWGYISDNSYGWFDYWGQGTLVT

VSS

781
hBEW-1E3VH.2b
EVQLVQSGAEVKKPGASVKVSCKASGYPFT

NSGMYWVRQAPGQGLEWMGWINTEAGKPTY

ADDFKGRFTFTLDTSTSTAYLEIRSLRSDD

TAVYYCARWGYISDNSYGWFDYWGQGTLVT

VSS

782
hBEW-1E3VL.1
EIVLTQSPATLSLSPGERATLSCRASEGVY

SYMHWYQQKPGQAPRLLIYKASNLASGIPA

RFSGSGSGTDFTLTISSLEPEDFAVYYCHQ

NWNDPLTFGQGTKLEIK

783
hBEW-1E3VL.1a
ETVLTQSPATLSLSPGERATLSCRASEGVY

SYMHWYQQKPGQQPRLLIYKASNLASGVPA

RFSGSGSGTDFTLTISSLEPEDFAVYFCHQ

NWNDPLTFGQGTKLEIK

784
hBEW-1E3VL.1b
EIVLTQSPATLSLSPGERATLSCRASEGVY

SYMHWYQQKPGQAPRLLIYKASNLASGVPA

RFSGSGSGTDFTLTISSLEPEDFAVYFCHQ

NWNDPLTFGQGTKLEIK

785
hBEW-1E3VL.2
AIQLTQSPSSLSASVGDRVTITCRASEGVY

SYMHWYQQKPGKAPKLLIYKASNLASGVPS

RFSGSGSGTDFTLTISSLQPEDFATYYCHQ

NWNDPLTFGQGTKLEIK

786
hBEW-1E3VL.2a
ATQLTQSPSSLSASVGDRVTISCRASEGVY

SYMHWYQQKPGKQPKLLIYKASNLASGVPS

RFSGSGSGTDFTLTISSLQPEDFATYFCHQ

NWNDPLTFGQGTKLEIK

787
hBEW-1E3VL.2b
AIQLTQSPSSLSASVGDRVTITCRASEGVY

SYMHWYQQKPGKAPKLLIYKASNLASGVPS

RFSGSGSGTDFTLTISSLQPEDFATYFCHQ

NWNDPLTFGQGTKLEIK

- hBEW-1E3VH.1z is a CDR-grafted, humanized BEW-1E3 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
- hBEW-1E3VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBEW-1E3VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (V2I, R38K, W47Y, Y91F).
- hBEW-1E3VH.2z is a CDR-grafted, humanized BEW-1E3 VH containing IGHV1-18*01 and IGHJ1*01 framework sequences.
- hBEW-1E3VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
- hBEW-1E3VH.2a is a humanized design based on .2 and contains seven proposed framework back-mutations (V2I, R38K, W47Y, V67F, M69F, T71L, Y91F).
- hBEW-1E3VH.2b is an intermediate design between .2 and .2a and contains three proposed framework back-mutations (V67F, M69F, T71L).
- hBEW-1E3VL.1 is a CDR-grafted, humanized BEW-1E3 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
- hBEW-1E3VL.1a is a humanized design based on .1 and contains four proposed framework back-mutations (I2T, A43Q, I58V, Y87F).
- hBEW-1E3VL.1b is an intermediate design between .1 and .1a. It contains two proposed framework back-mutations (I58V, Y87F).
- hBEW-1E3VL.2 is a CDR-grafted, humanized BEW-1E3 VL containing IGKV1-13*01 and IGKJ2*01 framework sequences.
- hBEW-1E3VL.2a is a humanized design based on .2 and contains four proposed framework back-mutations (I2T, T22S, A43Q, Y87F).
- hBEW-1E3VL.2b is an intermediate design between .2 and 2a. It contains one proposed framework back-mutations Y87F.

Example 6.3
Humanization of VEGFRII Antibodies
Example 6.3.1
Humanization Method

Example 6.3.2
Human Germline Sequence Selections for Constructing CDR-Grafted, Humanized VEGFRII Antibodies

By applying the aforementioned method, the CDR sequences of VH and VL chains of monoclonal antibody BCU-6B1-G6 were grafted onto different human heavy and light chain acceptor sequences.

Example 6.3.2.1
BCU-6B1-G6

Based on the alignments with the VH and VL sequences of monoclonal antibody BCU-6B1-G6 of the present invention, the following known human sequences are selected:

1. IGHV7-4-1*01 and IGHJ1*01 for constructing heavy chain acceptor sequences

2. IGHV1-18*01 and IGHJ1*01 as alternative acceptor for constructing heavy chain

3. IGKV1-27*01 and IGKJ4*01 for constructing light chain acceptor sequences

By grafting the corresponding VH and VL CDRs of BCU-6B1-G6 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.3.3
Introducing Potential Framework Back-Mutations in CDR-Grafted Antibodies

Example 6.3.3.1
BCU-6B1-G6

When IGHV7-4-1*01 and IGHJ1*01 selected as BCU-6B1-G6 heavy chain acceptor sequence, one or more of the following residues could back-mutated as follows: W47→F. Additional mutations include the following: R38→K, Y91→F.

When IGHV1-18*01 and IGHJ1*01 selected as BCU-6B1-G6 heavy chain acceptor sequence, one or more of the following residues could back-mutated as follows: W47→F, V67→F, M69→F, T71→L. Additional mutations include the following: R38→K, Y91→F.

When IGKV1-27*01 and IGKJ4*01 selected as BCU-6B1-G6 light chain acceptor sequence, one or more of the following residues could back-mutated as follows: V43→S, Y49→F, F71→Y, Y87→F. Additional mutations include the following: T22→E, T72→S.

Example 6.3.4
Generation of Humanized Antibodies to VEGFRII Containing Framework Back-Mutations in CDR-Grafted Antibodies

The following humanized variable regions of the murine monoclonal VEGFRII antibodies were cloned into IgG expression vectors for functional characterization.

Example 6.3.4.1
BCU-6B1-G6

TABLE 3.4.1

Sequences of Humanized BCU-6B1-G6 Variable Regions

SEQ

ID
Protein
Sequence

NO:
region
123456789012345678901234567890

788
hBCU-6B1-G6VH.1z
QVQLVQSGSELKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWINTETGQPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARLGNNYGIWFAYWGQGTLVTVSS

789
hBCU-6B1-G6VH.1
EVQLVQSGSELKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWINTETGQPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARLGNNYGIWFAYWGQGTLVTVSS

790
hBCU-6B1-G6VH.1a
EVQLVQSGSELKKPGASVKVSCKASGYTFT

NYGMYWVKQAPGQGLEFMGWINTETGQPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYFCARLGNNYGIWFAYWGQGTLVTVSS

791
hBCU-6B1-G6VH.1b
EVQLVQSGSELKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEFMGWINTETGQPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARLGNNYGIWFAYWGQGTLVTVSS

792
hBCU-6B1-G6VH.2z
QVQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWINTETGQPTY

ADDFKGRVTMTTDTSTSTAYMELRSLRSDD

TAVYYCARLGNNYGIWFAYWGQGTLVTVSS

793
hBCU-6B1-G6VH.2
EVQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEWMGWINTETGQPTY

ADDFKGRVTMTTDTSTSTAYMELRSLRSDD

TAVYYCARLGNNYGIWFAYWGQGTLVTVSS

794
hBCU-6B1-G6VH.2a
EVQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVKQAPGQGLEFMGWINTETGQPTY

ADDFKGRFTFTLDTSTSTAYMELRSLRSDD

TAVYFCARLGNNYGIWFAYWGQGTLVTVSS

795
hBCU-6B1-G6VH.2b
EVQLVQSGAEVKKPGASVKVSCKASGYTFT

NYGMYWVRQAPGQGLEFMGWINTETGQPTY

ADDFKGRFTFTLDTSTSTAYMELRSLRSDD

TAVYYCARLGNNYGIWFAYWGQGTLVTVSS

796
hBCU-6B1-
DIQMTQSPSSLSASVGDRVTITCRASDDLY

G6VL.1

STLAWYQQKPGKVPKLLIYDANRLAAGVPS

RFSGSGSGTDFTLTISSLQPEDVATYYCQQ

YNKFPWTFGGGTKVEIK

797
hBCU-6B1-
DIQMTQSPSSLSASVGDRVTIECRASDDLY

G6VL.1a

STLAWYQQKPGKSPKLLIFDANRLAAGVPS

RFSGSGSGTDYSLTISSLQPEDVATYFCQQ

YNKFPWTFGGGTKVEIK

798
hBCU-6B1-
DIQMTQSPSSLSASVGDRVTITCRASDDLY

G6VL.1b

STLAWYQQKPGKSPKLLIFDANRLAAGVPS

RFSGSGSGTDYTLTISSLQPEDVATYFCQQ

YNKFPWTFGGGTKVEIK

- hBCU-6B1-G6VH.1z is a CDR-grafted, humanized BCU-6B1-G6 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
- hBCU-6B1-G6VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
- hBCU-6B1-G6VH.1a is a humanized design based on .1 and contains 3 proposed framework back-mutations: (R38K, W47F, Y91F).
- hBCU-6B1-G6VH.1b is an intermediate design between .1 and .1a and contains 1 proposed framework back-mutations: W47F
- hBCU-6B1-G6VH.2z is a CDR-grafted, humanized BCU-6B1-G6 VH containing IGHV1-18*01 and IGHJ1*01 framework sequences.
- hBCU-6B1-G6VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
- hBCU-6B1-G6VH.2a is a humanized design based on .2 and contains six proposed framework back-mutations (R38K, W47F, V67F, M69F, T71L, Y91F).
- hBCU-6B1-G6VH.2b is an intermediate design between .2 and .2a and contains four proposed framework back-mutations: W47F, V67F, M69F, T71L.
- hBCU-6B1-G6VL.1 is a CDR-grafted, humanized BCU-6B1-G6 VL containing IGKV1-27*01 and IGKJ4*01 framework sequences.
- hBCU-6B1-G6VL.1a is a humanized design based on .1 and contains six proposed framework back-mutations (T22E, V43S, Y49F, F71Y, T72S, Y87F).
- hBCU-6B1-G6VL.1b is an intermediate design between .1 and .1a. It contains four proposed framework back-mutations (V43S, Y49F, F71Y, Y87F).

Example 6.4
Humanization of PDGFRB Antibodies
Example 6.4.1
Humanization Method

Example 6.4.2
Human Germline Sequence Selections for Constructing CDR-Grafted, Humanized PDGFRB Antibodies

By applying the aforementioned method, the CDR sequences of VH and VL chains of monoclonal antibody BDE-3C9-G4 was grafted onto different human heavy and light chain acceptor sequences.

Example 6.4.2.1
BDE-3C9-G4

Based on the alignments with the VH and VL sequences of monoclonal antibody BDE-3C9-G4 of the present invention, the following known human sequences are selected:

1. IGHV3-7*01 and IGHJ3*01 for constructing heavy chain acceptor sequences

2. IGKV1-33*01 and IGKJ4*01 for constructing light chain acceptor sequences

By grafting the corresponding VH and VL CDRs of BDE-3C9-G4 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.

Example 6.4.3
Introducing Potential Framework Back-Mutations in CDR-Grafted Antibodies

Example 6.4.3.1
BDE-3C9-G4

When IGHV3-7*01 and IGHJ3*01 selected as BDE-3C9-G4 heavy chain acceptor sequence, one or more of the following residues could back-mutated as follows: S77→T, L78→Q, Y91→F.

When IGKV1-33*01 and IGKJ4*01 selected as BDE-3C9-G4 light chain acceptor sequence, one or more of the following residues could back-mutated as follows: Q38→L, K45→R, I48→M, Y49→R, T69→R, F71→Y. Additional mutations include the following: V584T.

Example 6.4.4
Generation of Humanized Antibodies to PDGFRB Containing Framework Back-Mutations in CDR-Grafted Antibodies

The following humanized variable regions of the murine monoclonal PDGFRB antibodies were cloned into IgG expression vectors for functional characterization.

Example 6.4.4.1
BDE-3C9-G4

TABLE 4.4.1

Sequences of Humanized BDE-3C9-G4

Variable Regions

SEQ ID
Protein
Sequence

NO:
region
123456789012345678901234567890

799
hBDE-3C9-
EVQLVESGGGLVQPGGSLRLSCAASGFTFS

G4VH.1

NYGMAWVRQAPGKGLEWVASITNSGGNTYY

RDSVKGRFTISRDNAKNSLYLQMNSLRAED

TAVYYCARHTPGANYFDYWGQGTMVTVSS

800
hBDE-3C9-
EVQLVESGGGLVQPGGSLRLSCAASGFTFS

G4VH.1a

NYGMAWVRQAPGKGLEWVASITNSGGNTYY

RDSVKGRFTISRDNAKNTQYLQMNSLRAED

TAVYFCARHTPGANYFDYWGQGTMVTVSS

801
hBDE-3C9-
DIQMTQSPSSLSASVGDRVTITCQASQSIK

G4VL.1

NYIAWYQQKPGKAPKLLIYYTSTLESGVPS

RFSGSGSGTDFTFTISSLQPEDIATYYCVQ

YANLYTFGGGTKVEIK

802
hBDE-3C9-
DIQMTQSPSSLSASVGDRVTITCQASQSIK

G4VL.1a

NYIAWYQLKPGKAPRLLMRYTSTLESGTPS

RFSGSGSGRDYTFTISSLQPEDIATYYCVQ

YANLYTFGGGTKVEIK

803
hBDE-3C9-
DIQMTQSPSSLSASVGDRVTITCQASQSIK

G4VL.1b

NYIAWYQQKPGKAPRLLIRYTSTLESGVPS

RFSGSGSGRDYTFTISSLQPEDIATYYCVQ

YANLYTFGGGTKVEIK

- hBDE-3C9-G4VH.1 is a CDR-grafted, humanized BDE-3C9-G4 VH containing IGHV3-7*01 and IGHJ3*01 framework sequences.
- hBDE-3C9-G4VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations (S77T, L78Q, Y91F).
- hBDE-3C9-G4VL.1 is a CDR-grafted, humanized BDE-3C9-G4 VL containing IGKV1-33*01 and IGKJ4*01 framework sequences.
- hBDE-3C9-G4VL.1a is a humanized design based on .1 and contains seven proposed framework back-mutations (Q38L, K45R, 148M, Y49R, V58T, T69R, F71Y).
- hBDE-3C9-G4VL.1b is an intermediate design between .1 and .1a. It contains four proposed framework back-mutations (K45R, Y49R, T69R, F71Y).

Summary of VH and VL Amino Acid Sequences of Humanized Rat Anti-human VEGF-A and Humanized Rat Anti-human PDGF-BB Monoclonal Antibodies

TABLE 27

VH and VL Amino Acid Sequences of Humanized

Rat Anti-Human VEGF-A Monoclonal Antibodies

(CDRs in bold)

SEQ ID

Protein
V Region

NO:
Clone
Region
123456789012345678901234567890

804
hBDB-4G8.1 VH

EVQLVQSGSELKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEWMGWIN

TETGKPTYADDFKGRFVFSLDTSVST

AYLQISSLKAEDTAVYYCARTNYYYR

SYIFYFDYWGQGTMVTVSS

805
hBDB-4G8.1
CDR-H1

GYTFTNYGMY

806
hBDB-4G8.1
CDR-H2

WINTETGKPTYADDFKG

807
hBDB-4G8.1
CDR-H3

TNYYYRSYIFYFDY

808
hBDB-4G8.1 VL

AIQLTQSPSSLSASVGDRVTITCRAS

ESVSTHMHWYQQKPGKAPKLLIYGAS

NLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYYCQQSWNDPFTFGQGTKL

EIK

809
hBDB-4G8.1
CDR-L1

RASESVSTHMH

810
hBDB-4G8.1
CDR-L2

GASNLES

811
hBDB-4G8.1
CDR-L3

QQSWNDPFT

812
hBDB-4G8.10 VH

EIQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEYMGWIN

TETGKPTYADDFKGRFTFTLDTSTST

AYMELRSLRSDDTAVYFCARTNYYYR

SYIFYFDYWGQGTMVTVSS

813
hBDB-4G8.10
CDR-H1

GYTFTNYGMY

814
hBDB-4G8.10
CDR-H2

WINTETGKPTYADDFKG

815
hBDB-4G8.10
CDR-H3

TNYYYRSYIFYFDY

816
hBDB-4G8.10 VL

AIQLTQSPSSLSASVGDRVTITCRAS

ESVSTHMHWYQQKPGKAPKLLIYGAS

NLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYYCQQSWNDPFTFGQGTKL

EIK

817
hBDB-4G8.10
CDR-L1

RASESVSTHMH

818
hBDB-4G8.10
CDR-L2

GASNLES

819
hBDB-4G8.10
CDR-L3

QQSWNDPFT

820
hBDB-4G8.11 VH

EIQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEYMGWIN

TETGKPTYADDFKGRFTFTLDTSTST

AYMELRSLRSDDTAVYFCARTNYYYR

SYIFYFDYWGQGTMVTVSS

821
hBDB-4G8.11
CDR-H1

GYTFTNYGMY

822
hBDB-4G8.11
CDR-H2

WINTETGKPTYADDFKG

823
hBDB-4G8.11
CDR-H3

TNYYYRSYIFYFDY

824
hBDB-4G8.11 VL

ATQLTQSPSLSASVGDRVTITCRASE

SVSTHMHWYQQKPGKQPKLLIYGASN

LESGVPSRFSGSGSGTDFTLTISSLQ

PEDFATYFCQQSWNDPFTFGQGTKLE

IK

825
hBDB-4G8.11
CDR-L1

RASESVSTHMH

826
hBDB-4G8.11
CDR-L2

GASNLES

827
hBDB-4G8.11
CDR-L3

QQSWNDPFT

828
hBDB-4G8.12 VH

EIQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEYMGWIN

TETGKPTYADDFKGRFTFTLDTSTST

AYMELRSLRSDDTAVYFCARTNYYYR

SYIFYFDYWGQGTMVTVSS

829
hBDB-4G8.12
CDR-H1

GYTFTNYGMY

830
hBDB-4G8.12
CDR-H2

WINTETGKPTYADDFKG

831
hBDB-4G8.12
CDR-H3

TNYYYRSYIFYFDY

832
hBDB-4G8.12 VL

DTVLTQSPATLSLSPGERATLSCRAS

ESVSTHMHWYQQKPGQAPRLLIYGAS

NLESGVPARFSGSGSGTDFTLTISSL

EPEDFAVYFCQQSWNDPFTFGQGTKL

EIK

833
hBDB-4G8.12
CDR-L1

RASESVSTHMH

834
hBDB-4G8.12
CDR-L2

GASNLES

835
hBDB-4G8.12
CDR-L3

QQSWNDPFT

836
hBDB-4G8.13 VH

EIQLVQSGTEVKKPGESLKISCKASG

YTFTNYGMYWVKQMPGKGLEYMGWIN

TETGKPTYADDFKGRFTFSLDKSFNT

AFLQWSSLKASDTAMYFCARTNYYYR

SYIFYFDYWGQGTMVTVSS

837
hBDB-4G8.13
CDR-H1

GYTFTNYGMY

838
hBDB-4G8.13
CDR-H2

WINTETGKPTYADDFKG

839
hBDB-4G8.13
CDR-H3

TNYYYRSYIFYFDY

840
hBDB-4G8.13 VL

ETVLTQSPATLSVSPGERATLSCRAS

ESVSTHMHWYQQKPGQAPRLLIYGAS

NLESGVPARFSGSGSGTDFTLTISSL

QSEDFAVYFCQQSWNDPFTFGQGTRL

EIK

841
hBDB-4G8.13
CDR-L1

RASESVSTHMH

842
hBDB-4G8.13
CDR-L2

GASNLES

843
hBDB-4G8.13
CDR-L3

QQSWNDPFT

844
hBDB-4G8.14 VH

EIQLVQSGGGVVQPGGSLRLSCAASG

YTFTNYGMYWVKQAPGKGLEYMGWIN

TETGKPTYADDFKGRFTFSLDTSKST

AYLQLNSLRAEDTAVYFCARTNYYYR

SYIFYFDYWGQGTLVTVSS

845
hBDB-4G8.14
CDR-H1

GYTFTNYGMY

846
hBDB-4G8.14
CDR-H2

WINTETGKPTYADDFKG

847
hBDB-4G8.14
CDR-H3

TNYYYRSYIFYFDY

848
hBDB-4G8.14 VL

DTVLTQSPSTLSASPGERATISCRAS

ESVSTHMHWYQQKPGQAPKLLIYGAS

NLESGVPSRFSGSRSGTDFTLTISSL

QPEDFAVYFCQQSWNDPFTFGQGTKV

EIK

849
hBDB-4G8.14
CDR-L1

RASESVSTHMH

850
hBDB-4G8.14
CDR-L2

GASNLES

851
hBDB-4G8.14
CDR-L3

QQSWNDPFT

852
hBDB-4G8.15 VH

EVQLVESGGGLVQPGGSLRLSCAASG

YTFTNYGMYWVKQAPGKGLEYMGWIN

TETGKPTYADDFKGRFTFSLDTSKST

AYLQMNSLRAEDTAVYFCARTNYYYR

SYIFYFDYWGQGTLVTVSS

853
hBDB-4G8.15
CDR-H1

GYTFTNYGMY

854
hBDB-4G8.15
CDR-H2

WINTETGKPTYADDFKG

855
hBDB-4G8.15
CDR-H3

TNYYYRSYIFYFDY

856
hBDB-4G8.15 VL

DTQLTQSPSSLSASVGDRVTISCRAS

ESVSTHMHWYQQKPGKAPKLLIYGAS

NLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYFCQQSWNDPFTFGQGTKV

EIK

857
hBDB-4G8.15
CDR-L1

RASESVSTHMH

858
hBDB-4G8.15
CDR-L2

GASNLES

859
hBDB-4G8.15
CDR-L3

QQSWNDPFT

860
hBDB-4G8.2 VH

EVQLVQSGSELKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEWMGWIN

TETGKPTYADDFKGRFVFSLDTSVST

AYLQISSLKAEDTAVYYCARTNYYYR

SYIFYFDYWGQGTMVTVSS

861
hBDB-4G8.2
CDR-H1

GYTFTNYGMY

862
hBDB-4G8.2
CDR-H2

WINTETGKPTYADDFKG

863
hBDB-4G8.2
CDR-H3

TNYYYRSYIFYFDY

864
hBDB-4G8.2 VL

ATQLTQSPSLSASVGDRVTITCRASE

SVSTHMHWYQQKPGKQPKLLIYGASN

LESGVPSRFSGSGSGTDFTLTISSLQ

PEDFATYFCQQSWNDPFTFGQGTKLE

IK

865
hBDB-4G8.2
CDR-L1

RASESVSTHMH

866
hBDB-4G8.2
CDR-L2

GASNLES

867
hBDB-4G8.2
CDR-L3

QQSWNDPFT

868
hBDB-4G8.3 VH

EVQLVQSGSELKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEWMGWIN

TETGKPTYADDFKGRFVFSLDTSVST

AYLQISSLKAEDTAVYYCARTNYYYR

SYIFYFDYWGQGTMVTVSS

869
hBDB-4G8.3
CDR-H1

GYTFTNYGMY

870
hBDB-4G8.3
CDR-H2

WINTETGKPTYADDFKG

871
hBDB-4G8.3
CDR-H3

TNYYYRSYIFYFDY

872
hBDB-4G8.3 VL

DTVLTQSPATLSLSPGERATLSCRAS

ESVSTHMHWYQQKPGQAPRLLIYGAS

NLESGVPARFSGSGSGTDFTLTISSL

EPEDFAVYFCQQSWNDPFTFGQGTKL

EIK

873
hBDB-4G8.3
CDR-L1

RASESVSTHMH

874
hBDB-4G8.3
CDR-L2

GASNLES

875
hBDB-4G8.3
CDR-L3

QQSWNDPFT

876
hBDB-4G8.4 VH

EIQLVQSGSELKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEYMGWIN

TETGKPTYADDFKGRFVFSLDTSVST

AYLQISSLKAEDTAVYFCARTNYYYR

SYIFYFDYWGQGTMVTVSS

877
hBDB-4G8.4
CDR-H1

GYTFTNYGMY

878
hBDB-4G8.4
CDR-H2

WINTETGKPTYADDFKG

879
hBDB-4G8.4
CDR-H3

TNYYYRSYIFYFDY

880
hBDB-4G8.4 VL

AIQLTQSPSSLSASVGDRVTITCRAS

ESVSTHMHWYQQKPGKAPKLLIYGAS

NLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYYCQQSWNDPFTFGQGTKL

EIK

881
hBDB-4G8.4
CDR-L1

RASESVSTHMH

882
hBDB-4G8.4
CDR-L2

GASNLES

883
hBDB-4G8.4
CDR-L3

QQSWNDPFT

884
hBDB-4G8.5 VH

EIQLVQSGSELKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEYMGWIN

TETGKPTYADDFKGRFVFSLDTSVST

AYLQISSLKAEDTAVYFCARTNYYYR

SYIFYFDYWGQGTMVTVSS

885
hBDB-4G8.5
CDR-H1

GYTFTNYGMY

886
hBDB-4G8.5
CDR-H2

WINTETGKPTYADDFKG

887
hBDB-4G8.5
CDR-H3

TNYYYRSYIFYFDY

888
hBDB-4G8.5 VL

ATQLTQSPSLSASVGDRVTITCRASE

SVSTHMHWYQQKPGKQPKLLIYGASN

LESGVPSRFSGSGSGTDFTLTISSLQ

PEDFATYFCQQSWNDPFTFGQGTKLE

IK

889
hBDB-4G8.5
CDR-L1

RASESVSTHMH

890
hBDB-4G8.5
CDR-L2

GASNLES

891
hBDB-4G8.5
CDR-L3

QQSWNDPFT

892
hBDB-4G8.6 VH

EIQLVQSGSELKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEYMGWIN

TETGKPTYADDFKGRFVFSLDTSVST

AYLQISSLKAEDTAVYFCARTNYYYR

SYIFYFDYWGQGTMVTVSS

893
hBDB-4G8.6
CDR-H1

GYTFTNYGMY

894
hBDB-4G8.6
CDR-H2

WINTETGKPTYADDFKG

895
hBDB-4G8.6
CDR-H3

TNYYYRSYIFYFDY

896
hBDB-4G8.6 VL

DTVLTQSPATLSLSPGERATLSCRAS

ESVSTHMHWYQQKPGQAPRLLIYGAS

NLESGVPARFSGSGSGTDFTLTISSL

EPEDFAVYFCQQSWNDPFTFGQGTKL

EIK

897
hBDB-4G8.6
CDR-L1

RASESVSTHMH

898
hBDB-4G8.6
CDR-L2

GASNLES

899
hBDB-4G8.6
CDR-L3

QQSWNDPFT

900
hBDB-4G8.7 VH

EVQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEWMGWIN

TETGKPTYADDFKGRVTMTTDTSTST

AYMELRSLRSDDTAVYYCARTNYYYR

SYIFYFDYWGQGTMVTVSS

901
hBDB-4G8.7
CDR-H1

GYTFTNYGMY

902
hBDB-4G8.7
CDR-H2

WINTETGKPTYADDFKG

903
hBDB-4G8.7
CDR-H3

TNYYYRSYIFYFDY

904
hBDB-4G8.7 VL

AIQLTQSPSSLSASVGDRVTITCRAS

ESVSTHMHWYQQKPGKAPKLLIYGAS

NLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYYCQQSWNDPFTFGQGTKL

EIK

905
hBDB-4G8.7
CDR-L1

RASESVSTHMH

906
hBDB-4G8.7
CDR-L2

GASNLES

907
hBDB-4G8.7
CDR-L3

QQSWNDPFT

908
hBDB-4G8.8 VH

EVQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEWMGWIN

TETGKPTYADDFKGRVTMTTDTSTST

AYMELRSLRSDDTAVYYCARTNYYYR

SYIFYFDYWGQGTMVTVSS

909
hBDB-4G8.8
CDR-H1

GYTFTNYGMY

910
hBDB-4G8.8
CDR-H2

WINTETGKPTYADDFKG

911
hBDB-4G8.8
CDR-H3

TNYYYRSYIFYFDY

912
hBDB-4G8.8 VL

ATQLTQSPSLSASVGDRVTITCRASE

SVSTHMHWYQQKPGKQPKLLIYGASN

LESGVPSRFSGSGSGTDFTLISSLQ

PEDFATYFCQQSWNDPFTFGQGTKLE

IK

913
hBDB-4G8.8
CDR-L1

RASESVSTHMH

914
hBDB-4G8.8
CDR-L2

GASNLES

915
hBDB-4G8.8
CDR-L3

QQSWNDPFT

916
hBDB-4G8.9 VH

EVQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEWMGWIN

TETGKPTYADDFKGRVTMTTDTSTST

AYMELRSLRSDDTAVYYCARTNYYYR

SYIFYFDYWGQGTMVTVSS

917
hBDB-4G8.9
CDR-H1

GYTFTNYGMY

918
hBDB-4G8.9
CDR-H2

WINTETGKPTYADDFKG

919
hBDB-4G8.9
CDR-H3

TNYYYRSYIFYFDY

920
hBDB-4G8.9 VL

DTVLTQSPATLSLSPGERATLSCRAS

ESVSTHMHWYQQKPGQAPRLLIYGAS

NLESGVPARFSGSGSGTDFTLTISSL

EPEDFAVYFCQQSWNDPFTFGQGTKL

EIK

921
hBDB-4G8.9
CDR-L1

RASESVSTHMH

922
hBDB-4G8.9
CDR-L2

GASNLES

923
hBDB-4G8.9
CDR-L3

QQSWNDPFT

924
hBEW-1B10.1 VH

EVQLVESGGGLVQPGGSLRLSCAASG

FSFSKYDMAWFRQAPGKGLEWVASIT

TSGVGTYYRDSVKGRFTVSRDNAKST

LYLQMNSLRAEDTAVYYCARGYGAMD

AWGQGTTVTVSS

925
hBEW-1B10.1
CDR-H1

GFSFSKYDMA

926
hBEW-1B10.1
CDR-H2

SITTSGVGTYYRDSVKG

927
hBEW-1B10.1
CDR-H3

GYGAMDA

928
hBEW-1B10.1 VL

DIQMTQSPSSLSASVGDRVTITCKAS

QDIDDYLSWYQQKPGKSPKLVIYAAT

RLADGVPSRFSGSGSGTDYTLTISSL

QPEDFATYYCLQSSSTPWTFGGGTKV

EIK

929
hBEW-1B10.1
CDR-L1

KASQDIDDYLS

930
hBEW-1B10.1
CDR-L2

AATRLAD

931
hBEW-1B10.1
CDR-L3

LQSSSTPWT

932
hBEW-1B10.2 VH

EVQLVESGGGLVQPGGSLRLSCAASG

FSFSKYDMAWFRQAPGKGLEWVASIT

TSGVGTYYRDSVKGRFTVSRDNAKNS

LYLQMNSLRAEDTAVYYCARGYGAMD

AWGQGTTVTVSS

933
hBEW-1B10.2
CDR-H1

GFSFSKYDMA

934
hBEW-1B10.2
CDR-H2

SITTSGVGTYYRDSVKG

935
hBEW-1B10.2
CDR-H3

GYGAMDA

936
hBEW-1B10.2 VL

DIQMTQSPSSLSASVGDRVTITCKAS

QDIDDYLSWYQQKPGKSPKLVIYAAT

RLADGVPSRFSGSGSGTDYTLTISSL

QPEDFATYYCLQSSSTPWTFGGGTKV

EIK

937
hBEW-1B10.2
CDR-L1

KASQDIDDYLS

938
hBEW-1B10.2
CDR-L2

AATRLAD

939
hBEW-1B10.2
CDR-L3

LQSSSTPWT

940
hBEW-1E3.1 VH

EIQLVQSGSELKKPGASVKVSCKASG

YPFTNSGMYWVKQAPGQGLEYMGWIN

TEAGKPTYADDFKGRFVFSLDTSVST

AYLQISSLKAEDTAVYFCARWGYISD

NSYGWFDYWGQGTLVTVSS

941
hBEW-1E3.1
CDR-H1

GYPFTNSGMY

942
hBEW-1E3.1
CDR-H2

WINTEAGKPTYADDFKG

943
hBEW-1E3.1
CDR-H3

WGYISDNSYGWFDY

944
hBEW-1E3.1 VL

ETVLTQSPATLSLSPGERATLSCRAS

EGVYSYMHWYQQKPGQQPRLLIYKAS

NLASGVPARFSGSGSGTDFTLTISSL

EPEDFAVYFCHQNWNDPLTFGQGTKL

EIK

945
hBEW-1E3.1
CDR-L1

RASEGVYSYMH

946
hBEW-1E3.1
CDR-L2

KASNLAS

947
hBEW-1E3.1
CDR-L3

HQNWNDPLT

948
hBEW-1E3.2 VH

EIQLVQSGAEVKKPGASVKVSCKASG

YPFTNSGMYWVKQAPGQGLEYMGWIN

TEAGKPTYADDFKGRFTFTLDTSTST

AYLEIRSLRSDDTAVYFCARWGYISD

NSYGWFDYWGQGTLVTVSS

949
hBEW-1E3.2
CDR-H1

GYPFTNSGMY

950
hBEW-1E3.2
CDR-H2

WINTEAGKPTYADDFKG

951
hBEW-1E3.2
CDR-H3

WGYISDNSYGWFDY

952
hBEW-1E3.2 VL

ETVLTQSPATLSLSPGERATLSCRAS

EGVYSYMHWYQQKPGQQPRLLIYKAS

NLASGVPARFSGSGSGTDFTLTISSL

EPEDFAVYFCHQNWNDPLTFGQGTKL

EIK

953
hBEW-1E3.2
CDR-L1

RASEGVYSYMH

954
hBEW-1E3.2
CDR-L2

KASNLAS

955
hBEW-1E3.2
CDR-L3

HQNWNDPLT

956
hBEW-1E3.3 VH

EVQLVQSGAEVKKPGASVKVSCKASG

YPFTNSGMYWVRQAPGQGLEWMGWIN

TEAGKPTYADDFKGRFTFTLDTSTST

AYLEIRSLRSDDTAVYYCARWGYISD

NSYGWFDYWGQGTLVTVSS

957
hBEW-1E3.3
CDR-H1

GYPFTNSGMY

958
hBEW-1E3.3
CDR-H2

WINTEAGKPTYADDFKG

959
hBEW-1E3.3
CDR-H3

WGYISDNSYGWFDY

960
hBEW-1E3.3 VL

ETVLTQSPATLSLSPGERATLSCRAS

EGVYSYMHWYQQKPGQQPRLLIYKAS

NLASGVPARFSGSGSGTDFTLTISSL

EPEDFAVYFCHQNWNDPLTFGQGTKL

EIK

961
hBEW-1E3.3
CDR-L1

RASEGVYSYMH

962
hBEW-1E3.3
CDR-L2

KASNLAS

963
hBEW-1E3.3
CDR-L3

HQNWNDPLT

964
hBEW-1E3.4 VH

EIQLVQSGSELKKPGASVKVSCKASG

YPFTNSGMYWVKQAPGQGLEYMGWIN

TEAGKPTYADDFKGRFVFSLDTSVST

AYLQISSLKAEDTAVYFCARWGYISD

NSYGWFDYWGQGTLVTVSS

965
hBEW-1E3.4
CDR-H1

GYPFTNSGMY

966
hBEW-1E3.4
CDR-H2

WINTEAGKPTYADDFKG

967
hBEW-1E3.4
CDR-H3

WGYISDNSYGWFDY

968
hBEW-1E3.4 VL

ATQLTQSPSSLSASVGDRVTISCRAS

EGVYSYMHWYQQKPGKQPKLLIYKAS

NLASGVPSRFSGSGSGTDFTLTISSL

QPEDFATYFCHQNWNDPLTFGQGTKL

EIK

969
hBEW-1E3.4
CDR-L1

RASEGVYSYMH

970
hBEW-1E3.4
CDR-L2

KASNLAS

971
hBEW-1E3.4
CDR-L3

HQNWNDPLT

972
hBEW-1E3.5 VH

EIQLVQSGAEVKKPGASVKVSCKASG

YPFTNSGMYWVKQAPGQGLEYMGWIN

TEAGKPTYADDFKGRFTFTLDTSTST

AYLEIRSLRSDDTAVYFCARWGYISD

NSYGWFDYWGQGTLVTVSS

973
hBEW-1E3.5
CDR-H1

GYPFTNSGMY

974
hBEW-1E3.5
CDR-H2

WINTEAGKPTYADDFKG

975
hBEW-1E3.5
CDR-H3

WGYISDNSYGWFDY

976
hBEW-1E3.5 VL

ATQLTQSPSSLSASVGDRVTISCRAS

EGVYSYMHWYQQKPGKQPKLLIYKAS

NLASGVPSRFSGSGSGTDFTLTISSL

QPEDFATYFCHQNWNDPLTFGQGTKL

EIK

977
hBEW-1E3.5
CDR-L1

RASEGVYSYMH

978
hBEW-1E3.5
CDR-L2

KASNLAS

979
hBEW-1E3.5
CDR-L3

HQNWNDPLT

980
hBEW-5C3.1 VH

EIQLVQSGSELKKPGASVKVSCKASG

YTFTNYGVYWVKQAPGQGLEYMGWIN

TETGKPTYADDFKGRFVFSLDTSVST

AYLQISSLKAEDTAVYYCARARQLDW

FVYWGQGTLVTVSS

981
hBEW-5C3.1
CDR-H1

GYTFTNYGVY

982
hBEW-5C3.1
CDR-H2

WINTETGKPTYADDFKG

983
hBEW-5C3.1
CDR-H3

ARQLDWFVY

984
hBEW-5C3.1 VL

DTVLTQSPATLSLSPGERATLSCRAR

ESLTTSLSWFQQKPGQQPRLLIYGAS

KLESGVPARFSGSGSGTDFTLTISSL

EPEDFAVYFCQQSWYDPPTFGGGTKV

EIK

985
hBEW-5C3.1
CDR-L1

RARESLTTSLS

986
hBEW-5C3.1
CDR-L2

GASKLES

987
hBEW-5C3.1
CDR-L3

QQSWYDPPT

988
hBEW-5C3.2 VH

EIQLVQSGAEVKKPGSSVKVSCKASG

YTFTNYGVYWVKQAPGQGLEYMGWIN

TETGKPTYADDFKGRFTFTLDKSTST

AYMELSSLRSEDTAVYFCARARQLDW

FVYWGQGTLVTVSS

989
hBEW-5C3.2
CDR-H1

GYTFTNYGVY

990
hBEW-5C3.2
CDR-H2

WINTETGKPTYADDFKG

991
hBEW-5C3.2
CDR-H3

ARQLDWFVY

992
hBEW-5C3.2 VL

DTVLTQSPATLSLSPGERATLSCRAR

ESLTTSLSWFQQKPGQQPRLLIYGAS

KLESGVPARFSGSGSGTDFTLTISSL

EPEDFAVYFCQQSWYDPPTFGGGTKV

EIK

993
hBEW-5C3.2
CDR-L1

RARESLTTSLS

994
hBEW-5C3.2
CDR-L2

GASKLES

995
hBEW-5C3.2
CDR-L3

QQSWYDPPT

996
hBEW-5C3.3 VH

EVQLVQSGAEVKKPGSSVKVSCKASG

YTFTNYGVYWVRQAPGQGLEWMGWIN

TETGKPTYADDFKGRFTFTLDKSTST

AYMELSSLRSEDTAVYYCARARQLDW

FVYWGQGTLVTVSS

997
hBEW-5C3.3
CDR-H1

GYTFTNYGVY

998
hBEW-5C3.3
CDR-H2

WINTETGKPTYADDFKG

999
hBEW-5C3.3
CDR-H3

ARQLDWFVY

1000
hBEW-5C3.3 VL

DTVLTQSPATLSLSPGERATLSCRAR

ESLTTSLSWFQQKPGQQPRLLIYGAS

KLESGVPARFSGSGSGTDFTLTISSL

EPEDFAVYFCQQSWYDPPTFGGGTKV

EIK

1001
hBEW-5C3.3
CDR-L1

RARESLTTSLS

1002
hBEW-5C3.3
CDR-L2

GASKLES

1003
hBEW-5C3.3
CDR-L3

QQSWYDPPT

1004
hBEW-5C3.4 VH

EIQLVQSGSELKKPGASVKVSCKASG

YTFTNYGVYWVKQAPGQGLEYMGWIN

TETGKPTYADDFKGRFVFSLDTSVST

AYLQISSLKAEDTAVYYCARARQLDW

FVYWGQGTLVTVSS

1005
hBEW-5C3.4
CDR-H1

GYTFTNYGVY

1006
hBEW-5C3.4
CDR-H2

WINTETGKPTYADDFKG

1007
hBEW-5C3.4
CDR-H3

ARQLDWFVY

1008
hBEW-5C3.4 VL

DTQLTQSPSSLSASVGDRVTISCRAR

ESLTTSLSWFQQKPGKQPKLLIYGAS

KLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYFCQQSWYDPPTFGGGTKV

EIK

1009
hBEW-5C3.4
CDR-L1

RARESLTTSLS

1010
hBEW-5C3.4
CDR-L2

GASKLES

1011
hBEW-5C3.4
CDR-L3

QQSWYDPPT

1012
hBEW-5C3.5 VH

EIQLVQSGAEVKKPGSSVKVSCKASG

YTFTNYGVYWVKQAPGQGLEYMGWIN

TETGKPTYADDFKGRFTFTLDKSTST

AYMELSSLRSEDTAVYFCARARQLDW

FVYWGQGTLVTVSS

1013
hBEW-5C3.5
CDR-H1

GYTFTNYGVY

1014
hBEW-5C3.5
CDR-H2

WINTETGKPTYADDFKG

1015
hBEW-5C3.5
CDR-H3

ARQLDWFVY

1016
hBEW-5C3.5 VL

DTQLTQSPSSLSASVGDRVTISCRAR

ESLTTSLSWFQQKPGKQPKLLIYGAS

KLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYFCQQSWYDPPTFGGGTKV

EIK

1017
hBEW-5C3.5
CDR-L1

RARESLTTSLS

1018
hBEW-5C3.5
CDR-L2

GASKLES

1019
hBEW-5C3.5
CDR-L3

QQSWYDPPT

1020
hBEW-5C3.6 VH

EVQLVQSGAEVKKPGSSVKVSCKASG

YTFTNYGVYWVRQAPGQGLEWMGWIN

TETGKPTYADDFKGRFTFTLDKSTST

AYMELSSLRSEDTAVYYCARARQLDW

FVYWGQGTLVTVSS

1021
hBEW-5C3.6
CDR-H1

GYTFTNYGVY

1022
hBEW-5C3.6
CDR-H2

WINTETGKPTYADDFKG

1023
hBEW-5C3.6
CDR-H3

ARQLDWFVY

1024
hBEW-5C3.6 VL

DTQLTQSPSSLSASVGDRVTISCRAR

ESLTTSLSWFQQKPGKQPKLLIYGAS

KLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYFCQQSWYDPPTFGGGTKV

EIK

1025
hBEW-5C3.6
CDR-L1

RARESLTTSLS

1026
hBEW-5C3.6
CDR-L2

GASKLES

1027
hBEW-5C3.6
CDR-L3

QQSWYDPPT

1028
hBEW-6C2.1 VH

EVQLVESGGGLVQPGGSLRLSCAASG

FTFSYYGMHWVRQAPGKGLEWVALIY

YDSSKMYYADSVKGRFTISRDNAKNS

LYLQMNSLRAEDTAVYYCARGGTAPV

YWGQGTMVTVSS

1029
hBEW-6C2.1
CDR-H1

GFTFSYYGMH

1030
hBEW-6C2.1
CDR-H2

LIYYDSSKMYYADSVKG

1031
hBEW-6C2.1
CDR-H3

GGTAPVY

1032
hBEW-6C2.1 VL

EIVLTQSPATLSLSPGERATLSCKGS

QNIANYLAWYQQKPGQAPRLLIYNTD

SLQTGIPARFSGSGSGTDFTLTISSL

EPEDFAVYYCYQSNNGYTFGQGTKLE

IK

1033
hBEW-6C2.1
CDR-L1

KGSQNIANYLA

1034
hBEW-6C2.1
CDR-L2

NTDSLQT

1035
hBEW-6C2.1
CDR-L3

YQSNNGYT

1036
hBEW-6C2.2 VH

EVQLVESGGGLVQPGGSLRLSCAASG

FTFSYYGMHWVRQAPGKGLEWVALIY

YDSSKMYYADSVKGRFTISRDNAKNS

LYLQMNSLRAEDTAVYYCARGGTAPV

YWGQGTMVTVSS

1037
hBEW-6C2.2
CDR-H1

GFTFSYYGMH

1038
hBEW-6C2.2
CDR-H2

LIYYDSSKMYYADSVKG

1039
hBEW-6C2.2
CDR-H3

GGTAPVY

1040
hBEW-6C2.2 VL

EIVLTQSPATLSLSPGERATLSCKGS

QNIANYLAWYQQKPGQAPRLLIYNTD

SLQTGIPARFSGSGSGTDYTLTISSL

EPEDFAVYFCYQSNNGYTFGQGTKLE

IK

1041
hBEW-6C2.2
CDR-L1

KGSQNIANYLA

1042
hBEW-6C2.2
CDR-L2

NTDSLQT

1043
hBEW-6C2.2
CDR-L3

YQSNNGYT

1044
hBEW-6C2.3 VH

EVQLVESGGGLVQPGGSLRLSCAASG

FTFSYYGMHWVRQAPGKGLEWVALIY

YDSSKMYYADSVKGRFTISRDNAKNS

LYLQMNSLRAEDTAVYYCARGGTAPV

YWGQGTMVTVSS

1045
hBEW-6C2.3
CDR-H1

GFTFSYYGMH

1046
hBEW-6C2.3
CDR-H2

LIYYDSSKMYYADSVKG

1047
hBEW-6C2.3
CDR-H3

GGTAPVY

1048
hBEW-6C2.3 VL

DIQMTQSPSSLSASVGDRVTITCKGS

QNIANYLAWYQQKPGKAPKLLIYNTD

SLQTGVPSRFSGSGSGTDFTLTISSL

QPEDFATYYCYQSNNGYTFGQGTKLE

IK

1049
hBEW-6C2.3
CDR-L1

KGSQNIANYLA

1050
hBEW-6C2.3
CDR-L2

NTDSLQT

1051
hBEW-6C2.3
CDR-L3

YQSNNGYT

1052
hBEW-6C2.4 VH

EVQLVESGGGLVQPGGSLRLSCAASG

FTFSYYGMHWVRQAPGKGLEWVALIY

YDSSKMYYADSVKGRFTISRDNAKNS

LYLQMNSLRAEDTAVYYCARGGTAPV

YWGQGTMVTVSS

1053
hBEW-6C2.4
CDR-H1

GFTFSYYGMH

1054
hBEW-6C2.4
CDR-H2

LIYYDSSKMYYADSVKG

1055
hBEW-6C2.4
CDR-H3

GGTAPVY

1056
hBEW-6C2.4 VL

DIQLTQSPSSLSASVGDRVTITCKGS

QNIANYLAWYQQKPGKAPKLLIYNTD

SLQTGIPSRFSGSGSGTDYTLTISSL

QPEDFATYFCYQSNNGYTFGQGTKLE

IK

1057
hBEW-6C2.4
CDR-L1

KGSQNIANYLA

1058
hBEW-6C2.4
CDR-L2

NTDSLQT

1059
hBEW-6C2.4
CDR-L3

YQSNNGYT

1060
hBEW-6C2.5 VH

EVQLVESGGGLVQPGGSLRLSCAASG

FTFSYYGMHWIRQAPGKGLEWMALIY

YDSSKMYYADSVKGRFTISRDNAKNS

LYLQMNSLRAEDTAVYYCAAGGTAPV

YWGQGTMVTVSS

1061
hBEW-6C2.5
CDR-H1

GFTFSYYGMH

1062
hBEW-6C2.5
CDR-H2

LIYYDSSKMYYADSVKG

1063
hBEW-6C2.5
CDR-H3

GGTAPVY

1064
hBEW-6C2.5 VL

EIVLTQSPATLSLSPGERATLSCKGS

QNIANYLAWYQQKPGQAPRLLIYNTD

SLQTGIPARFSGSGSGTDFTLTISSL

EPEDFAVYYCYQSNNGYTFGQGTKLE

IK

1065
hBEW-6C2.5
CDR-L1

KGSQNIANYLA

1066
hBEW-6C2.5
CDR-L2

NTDSLQT

1067
hBEW-6C2.5
CDR-L3

YQSNNGYT

1068
hBEW-6C2.6 VH

EVQLVESGGGLVQPGGSLRLSCAASG

FTFSYYGMHWIRQAPGKGLEWMALIY

YDSSKMYYADSVKGRFTISRDNAKNS

LYLQMNSLRAEDTAVYYCAAGGTAPV

YWGQGTMVTVSS

1069
hBEW-6C2.6
CDR-H1

GFTFSYYGMH

1070
hBEW-6C2.6
CDR-H2

LIYYDSSKMYYADSVKG

1071
hBEW-6C2.6
CDR-H3

GGTAPVY

1072
hBEW-6C2.6 VL

EIVLTQSPATLSLSPGERATLSCKGS

QNIANYLAWYQQKPGQAPRLLIYNTD

SLQTGIPARFSGSGSGTDYTLTISSL

EPEDFAVYFCYQSNNGYTFGQGTKLE

IK

1073
hBEW-6C2.6
CDR-L1

KGSQNIANYLA

1074
hBEW-6C2.6
CDR-L2

NTDSLQT

1075
hBEW-6C2.6
CDR-L3

YQSNNGYT

1076
hBEW-6C2.7 VH

EVQLVESGGGLVQPGGSLRLSCAASG

FTFSYYGMHWIRQAPGKGLEWMALIY

YDSSKMYYADSVKGRFTISRDNAKNS

LYLQMNSLRAEDTAVYYCAAGGTAPV

YWGQGTMVTVSS

1077
hBEW-6C2.7
CDR-H1

GFTFSYYGMH

1078
hBEW-6C2.7
CDR-H2

LIYYDSSKMYYADSVKG

1079
hBEW-6C2.7
CDR-H3

GGTAPVY

1080
hBEW-6C2.7 VL

DIQMTQSPSSLSASVGDRVTITCKGS

QNIANYLAWYQQKPGKAPKLLIYNTD

SLQTGVPSRFSGSGSGTDFTLTISSL

QPEDFATYYCYQSNNGYTFGQGTKLE

IK

1081
hBEW-6C2.7
CDR-L1

KGSQNIANYLA

1082
hBEW-6C2.7
CDR-L2

NTDSLQT

1083
hBEW-6C2.7
CDR-L3

YQSNNGYT

1084
hBEW-6C2.8 VH

EVQLVESGGGLVQPGGSLRLSCAASG

FTFSYYGMHWIRQAPGKGLEWMALIY

YDSSKMYYADSVKGRFTISRDNAKNS

LYLQMNSLRAEDTAVYYCAAGGTAPV

YWGQGTMVTVSS

1085
hBEW-6C2.8
CDR-H1

GFTFSYYGMH

1086
hBEW-6C2.8
CDR-H2

LIYYDSSKMYYADSVKG

1087
hBEW-6C2.8
CDR-H3

GGTAPVY

1088
hBEW-6C2.8 VL

DIQLTQSPSSLSASVGDRVTITCKGS

QNIANYLAWYQQKPGKAPKLLIYNTD

SLQTGIPSRFSGSGSGTDYTLTISSL

QPEDFATYFCYQSNNGYTFGQGTKLE

IK

1089
hBEW-6C2.8
CDR-L1

KGSQNIANYLA

1090
hBEW-6C2.8
CDR-L2

NTDSLQT

1091
hBEW-6C2.8
CDR-L3

YQSNNGYT

1092
hBEW-9A8.1 VH

EVQLVQSGHEVKQPGASVKVSCKASG

YTFTNYGMYWVPQAPGQGLEWMGWIN

TETGKPIYADDFKGRFVFSMDTSAST

AYLQISSLKAEDMAMYYCARVDYDGS

FWFAYWGQGTLVTVSS

1093
hBEW-9A8.1
CDR-H1

GYTFTNYGMY

1094
hBEW-9A8.1
CDR-H2

WINTETGKPIYADDFKG

1095
hBEW-9A8.1
CDR-H3

VDYDGSFWFAY

1096
hBEW-9A8.1 VL

EIVLTQSPDFQSVTPKEKVTITCRAS

ESVSTVIHWYQQKPDQSPKLLIKPGAS

NLESGVPSRFSGSGSGTDFTLTINSL

EAEDAATYYCQQHWNDPPTFGQGTKL

EIK

1097
hBEW-9A8.1
CDR-L1

RASESVSTVIH

1098
hBEW-9A8.1
CDR-L2

GASNLES

1099
hBEW-9A8.1
CDR-L3

QQHWNDPPT

1100
hBEW-9A8.10 VH

EVQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEWMGWIN

TETGKPIYADDFKGRVTMTTDTSTST

AYMELRSLRSDDTAVYYCARVDYDGS

FWFAYWGQGTLVTVSS

1101
hBEW-9A8.10
CDR-H1

GYTFTNYGMY

1102
hBEW-9A8.10
CDR-H2

WINTETGKPIYADDFKG

1103
hBEW-9A8.10
CDR-H3

VDYDGSFWFAY

1104
hBEW-9A8.10 VL

ETVLTQSPDFQSVTPKEKVTITCRAS

ESVSTVIHWYQQKPDQQPKLLIHGAS

NLESGVPSRFSGSGSGTDFTLTINSL

EAEDAATYFCQQHWNDPPTFGQGTKL

EIK

1105
hBEW-9A8.10
CDR-L1

RASESVSTVIH

1106
hBEW-9A8.10
CDR-L2

GASNLES

1107
hBEW-9A8.10
CDR-L3

QQHWNDPPT

1108
hBEW-9A8.11 VH

EVQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEWMGWIN

TETGKPIYADDFKGRVTMTTDTSTST

AYMELRSLRSDDTAVYYCARVDYDGS

FWFAYWGQGTLVTVSS

1109
hBEW-9A8.11
CDR-H1

GYTFTNYGMY

1110
hBEW-9A8.11
CDR-H2

WINTETGKPIYADDFKG

1111
hBEW-9A8.11
CDR-H3

VDYDGSFWFAY

1112
hBEW-9A8.11 VL

DIQMTQSPSSLSASVGDRVTITCRAS

ESVSTVIHWYQQKPGKAPKLLIYGAS

NLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYYCQQHWNDPPTFGQGTKL

EIK

1113
hBEW-9A8.11
CDR-L1

RASESVSTVIH

1114
hBEW-9A8.11
CDR-L2

GASNLES

1115
hBEW-9A8.11
CDR-L3

QQHWNDPPT

1116
hBEW-9A8.12 VH

EVQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEWMGWIN

TETGKPIYADDFKGRVTMTTDTSTST

AYMELRSLRSDDTAVYYCARVDYDGS

FWFAYWGQGTLVTVSS

1117
hBEW-9A8.12
CDR-H1

GYTFTNYGMY

1118
hBEW-9A8.12
CDR-H2

WINTETGKPIYADDFKG

1119
hBEW-9A8.12
CDR-H3

VDYDGSFWFAY

1120
hBEW-9A8.12 VL

DTQLTQSPSSLSASVGDRVTITCRAS

ESVSTVIHWYQQKPGKQPKLLIHGAS

NLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYFCQQHWNDPPTFGQGTKL

EIK

1121
hBEW-9A8.12
CDR-L1

RASESVSTVIH

1122
hBEW-9A8.12
CDR-L2

GASNLES

1123
hBEW-9A8.12
CDR-L3

QQHWNDPPT

1124
hBEW-9A8.13 VH

EIQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVKQAPGQGLEYMGWIN

TETGKPIYADDFKGRFTFTLDTSTST

AYMELRSLRSDDTAVFFCARVDYDGS

FWFAYWGQGTLVTVSS

1125
hBEW-9A8.13
CDR-H1

GYTFTNYGMY

1126
hBEW-9A8.13
CDR-H2

WINTETGKPIYADDFKG

1127
hBEW-9A8.13
CDR-H3

VDYDGSFWFAY

1128
hBEW-9A8.13 VL

EIVLTQSPDFQSVTPKEKVTITCRAS

ESVSTVIHWYQQKPDQSPKLLIKGAS

NLESGVPSRFSGSGSGTDFTLTINSL

EAEDAATYYCQQHWNDPPTFGQGTKL

EIK

1129
hBEW-9A8.13
CDR-L1

RASESVSTVIH

1130
hBEW-9A8.13
CDR-L2

GASNLES

1131
hBEW-9A8.13
CDR-L3

QQHWNDPPT

1132
hBEW-9A8.14 VH

EIQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVKQAPGQGLEYMGWIN

TETGKPIYADDFKGRFTFTLDTSTST

AYMELRSLRSDDTAVFFCARVDYDGS

FWFAYWGQGTLVTVSS

1133
hBEW-9A8.14
CDR-H1

GYTFTNYGMY

1134
hBEW-9A8.14
CDR-H2

WINTETGKPIYADDFKG

1135
hBEW-9A8.14
CDR-H3

VDYDGSFWFAY

1136
hBEW-9A8.14 VL

ETVLTQSPDFQSVTPKEKVTITCRAS

ESVSTVIHWYQQKPDQQPKLLIHGAS

NLESGVPSRFSGSGSGTDFTLTINSL

EAEDAATYFCQQHWNDPPTFGQGTKL

EIK

1137
hBEW-9A8.14
CDR-L1

RASESVSTVIH

1138
hBEW-9A8.14
CDR-L2

GASNLES

1139
hBEW-9A8.14
CDR-L3

QQHWNDPPT

1140
hBEW-9A8.15 VH

EIQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVKQAPGQGLEYMGWIN

TETGKPIYADDFKGRFTFTLDTSTST

AYMELRSLRSDDTAVFFCARVDYDGS

FWFAYWGQGTLVTVSS

1141
hBEW-9A8.15
CDR-H1

GYTFTNYGMY

1142
hBEW-9A8.15
CDR-H2

WINTETGKPIYADDFKG

1143
hBEW-9A8.15
CDR-H3

VDYDGSFWFAY

1144
hBEW-9A8.15 VL

DIQMTQSPSSLSASVGDRVTITCRAS

ESVSTVIHWYQQKPGKAPKLLIYGAS

NLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYYCQQHWNDPPTFGQGTKL

EIK

1145
hBEW-9A8.15
CDR-L1

RASESVSTVIH

1146
hBEW-9A8.15
CDR-L2

GASNLES

1147
hBEW-9A8.15
CDR-L3

QQHWNDPPT

1148
hBEW-9A8.16 VH

EIQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVKQAPGQGLEYMGWIN

TETGKPIYADDFKGRFTFTLDTSTST

AYMELRSLRSDDTAVFFCARVDYDGS

FWFAYWGQGTLVTVSS

1149
hBEW-9A8.16
CDR-H1

GYTFTNYGMY

1150
hBEW-9A8.16
CDR-H2

WINTETGKPIYADDFKG

1151
hBEW-9A8.16
CDR-H3

VDYDGSFWFAY

1152
hBEW-9A8.16 VL

DTQLTQSPSSLSASVGDRVTITCRAS

ESVSTVIHWYQQKPGKQPKLLIHGAS

NLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYFCQQHWNDPPTFGQGTKL

EIK

1153
hBEW-9A8.16
CDR-L1

RASESVSTVIH

1154
hBEW-9A8.16
CDR-L2

GASNLES

1155
hBEW-9A8.16
CDR-L3

QQHWNDPPT

1156
hBEW-9A8.17 VH

EIQLVQSGSELKKPGASVKVSCKASG

YTFTNYGMYWVKQAPGQGLEYMGWIN

TETGKPIYADDFKGRFVFSLDTSVST

AYLQISSLKAEDTAVYYCARVDYDGS

FWFAYWGQGTLVTVSS

1157
hBEW-9A8.17
CDR-H1

GYTFTNYGMY

1158
hBEW-9A8.17
CDR-H2

WINTETGKPIYADDFKG

1159
hBEW-9A8.17
CDR-H3

VDYDGSFWFAY

1160
hBEW-9A8.17 VL

ETVLTQSPATLSLSPGERATLSGRAS

ESVSTVIHWYQQKPGQQPRLLIHGAS

NLESGVPARFSGSGSGTDFTLTISSL

EPEDFAVYFCQQHWNDPPTFGQGTKL

EIK

1161
hBEW-9A8.17
CDR-L1

RASESVSTVIH

1162
hBEW-9A8.17
CDR-L2

GASNLES

1163
hBEW-9A8.17
CDR-L3

QQHWNDPPT

1164
hBEW-9A8.2 VH

EVQLVQSGHEVKQPGASVKVSCKASG

YTFTNYGMYWVPQAPGQGLEWMGWIN

TETGKPIYADDFKGRFVFSMDTSAST

AYLQISSLKAEDMAMYYCARVDYDGS

FWFAYWGQGTLVTVSS

1165
hBEW-9A8.2
CDR-H1

GYTFTNYGMY

1166
hBEW-9A8.2
CDR-H2

WINTETGKPIYADDFKG

1167
hBEW-9A8.2
CDR-H3

VDYDGSFWFAY

1168
hBEW-9A8.2 VL

ETVLTQSPDFQSVTPKEKVTITGRAS

ESVSTVIHWYQQKPDQQPKLLIHGAS

NLESGVPSRFSGSGSGTDFTLTINSL

EAEDAATYFCQQHWNDPPTFGQGTKL

EIK

1169
hBEW-9A8.2
CDR-L1

RASESVSTVIH

1170
hBEW-9A8.2
CDR-L2

GASNLES

1171
hBEW-9A8.2
CDR-L3

QQHWNDPPT

1172
hBEW-9A8.20 VH

EIQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVKQAPGQGLEYMGWIN

TETGKPIYADDFKGRFTFTLDTSTST

AYMELRSLRSDDTAVYYCARVDYDGS

FWFAYWGQGTLVTVSS

1173
hBEW-9A8.20
CDR-H1

GYTFTNYGMY

1174
hBEW-9A8.20
CDR-H2

WINTETGKPIYADDFKG

1175
hBEW-9A8.20
CDR-H3

VDYDGSFWFAY

1176
hBEW-9A8.20 VL

ETVLTQSPATLSLSPGERATLSCRAS

ESVSTVIHWYQQKPGQQPRLLIHGAS

NLESGVPARFSGSGSGTDFTLTISSL

EPEDFAVYFCQQHWNDPPTFGQGTKL

EIK

1177
hBEW-9A8.20
CDR-L1

RASESVSTVIH

1178
hBEW-9A8.20
CDR-L2

GASNLES

1179
hBEW-9A8.20
CDR-L3

QQHWNDPPT

1180
hBEW-9A8.21 VH

EIQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEWMGWIN

TETGKPIYADDFKGRFTFTLDTSTST

AYMELRSLRSDDTAVYYCARVDYDGS

FWFAYWGQGTLVTVSS

1181
hBEW-9A8.21
CDR-H1

GYTFTNYGMY

1182
hBEW-9A8.21
CDR-H2

WINTETGKPIYADDFKG

1183
hBEW-9A8.21
CDR-H3

VDYDGSFWFAY

1184
hBEW-9A8.21 VL

ETVLTQSPATLSLSPGERATLSCRAS

ESVSTVIHWYQQKPGQQPRLLIHGAS

NLESGVPARFSGSGSGTDFTLTISSL

EPEDFAVYFCQQHWNDPPTFGQGTKL

EIK

1185
hBEW-9A8.21
CDR-L1

RASESVSTVIH

1186
hBEW-9A8.21
CDR-L2

GASNLES

1187
hBEW-9A8.21
CDR-L3

QQHWNDPPT

1188
hBEW-9A8.3 VH

EVQLVQSGHEVKQPGASVKVSCKASG

YTFTNYGMYWVPQAPGQGLEWMGWIN

TETGKPIYADDFKGRFVFSMDTSAST

AYLQISSLKAEDMAMYYCARVDYDGS

FWFAYWGQGTLVTVSS

1189
hBEW-9A8.3
CDR-H1

GYTFTNYGMY

1190
hBEW-9A8.3
CDR-H2

WINTETGKPIYADDFKG

1191
hBEW-9A8.3
CDR-H3

VDYDGSFWFAY

1192
hBEW-9A8.3 VL

DIQMTQSPSSLSASVGDRVTITCRAS

ESVSTVIHWYQQKPGKAPKLLIYGAS

NLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYYCQQHWNDPPTFGQGTKL

EIK

1193
hBEW-9A8.3
CDR-L1

RASESVSTVIH

1194
hBEW-9A8.3
CDR-L2

GASNLES

1195
hBEW-9A8.3
CDR-L3

QQHWNDPPT

1196
hBEW-9A8.4 VH

EVQLVQSGHEVKQPGASVKVSCKASG

YTFTNYGMYWVPQAPGQGLEWMGWIN

TETGKPIYADDFKGRFVFSMDTSAST

AYLQISSLKAEDMAMYYCARVDYDGS

FWFAYWGQGTLVTVSS

1197
hBEW-9A8.4
CDR-H1

GYTFTNYGMY

1198
hBEW-9A8.4
CDR-H2

WINTETGKPIYADDFKG

1199
hBEW-9A8.4
CDR-H3

VDYDGSFWFAY

1200
hBEW-9A8.4 VL

DTQLTQSPSSLSASVGDRVTITCRAS

ESVSTVIHWYQQKPGKQPKLLIHGAS

NLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYFCQQHWNDPPTFGQGTKL

EIK

1201
hBEW-9A8.4
CDR-L1

RASESVSTVIH

1202
hBEW-9A8.4
CDR-L2

GASNLES

1203
hBEW-9A8.4
CDR-L3

QQHWNDPPT

1204
hBEW-9A8.5 VH

EIQLVQSGHEVKQPGASVKVSCKASG

YTFTNYGMYWVKQAPGQGLEYMGWIN

TETGKPIYADDFKGRFVFSLDTSAST

AYLQISSLKAEDMAMFFCARVDYDGS

FWFAYWGQGTLVTVSS

1205
hBEW-9A8.5
CDR-H1

GYTFTNYGMY

1206
hBEW-9A8.5
CDR-H2

WINTETGKPIYADDFKG

1207
hBEW-9A8.5
CDR-H3

VDYDGSFWFAY

1208
hBEW-9A8.5 VL

EIVLTQSPDFQSVTPKEKVTITCRAS

ESVSTVIHWYQQKPDQSPKLLIKGAS

NLESGVPSRFSGSGSGTDFTLTINSL

EAEDAATYYCQQHWNDPPTFGQGTKL

EIK

1209
hBEW-9A8.5
CDR-L1

RASESVSTVIH

1210
hBEW-9A8.5
CDR-L2

GASNLES

1211
hBEW-9A8.5
CDR-L3

QQHWNDPPT

1212
hBEW-9A8.6 VH

EIQLVQSGHEVKQPGASVKVSCKASG

YTFTNYGMYWVKQAPGQGLEYMGWIN

TETGKPIYADDFKGRFVFSLDTSAST

AYLQISSLKAEDMAMFFCARVDYDGS

FWFAYWGQGTLVTVSS

1213
hBEW-9A8.6
CDR-H1

GYTFTNYGMY

1214
hBEW-9A8.6
CDR-H2

WINTETGKPIYADDFKG

1215
hBEW-9A8.6
CDR-H3

VDYDGSFWFAY

1216
hBEW-9A8.6 VL

ETVLTQSPDFQSVTPKEKVTITCRAS

ESVSTVIHWYQQKPDQQPKLLIHGAS

NLESGVPSRFSGSGSGTDFTLTINSL

EAEDAATYFCQQHWNDPPTFGQGTKL

EIK

1217
hBEW-9A8.6
CDR-L1

RASESVSTVIH

1218
hBEW-9A8.6
CDR-L2

GASNLES

1219
hBEW-9A8.6
CDR-L3

QQHWNDPPT

1220
hBEW-9A8.7 VH

EIQLVQSGHEVKQPGASVKVSCKASG

YTFTNYGMYWVKQAPGQGLEYMGWIN

TETGKPIYADDFKGRFVFSLDTSAST

AYLQISSLKAEDMAMFFCARVDYDGS

FWFAYWGQGTLVTVSS

1221
hBEW-9A8.7
CDR-H1

GYTFTNYGMY

1222
hBEW-9A8.7
CDR-H2

WINTETGKPIYADDFKG

1223
hBEW-9A8.7
CDR-H3

VDYDGSFWFAY

1224
hBEW-9A8.7 VL

DIQMTQSPSSLSASVGDRVTITCRAS

ESVSTVIHWYQQKPGKAPKLLIYGAS

NLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYYCQQHWNDPPTFGQGTKL

EIK

1225
hBEW-9A8.7
CDR-L1

RASESVSTVIH

1226
hBEW-9A8.7
CDR-L2

GASNLES

1227
hBEW-9A8.7
CDR-L3

QQHWNDPPT

1228
hBEW-9A8.8 VH

EIQLVQSGHEVKQPGASVKVSCKASG

YTFTNYGMYWVKQAPGQGLEYMGWIN

TETGKPIYADDFKGRFVFSLDTSAST

AYLQISSLKAEDMAMFFCARVDYDGS

FWFAYWGQGTLVTVSS

1229
hBEW-9A8.8
CDR-H1

GYTFTNYGMY

1230
hBEW-9A8.8
CDR-H2

WINTETGKPIYADDFKG

1231
hBEW-9A8.8
CDR-H3

VDYDGSFWFAY

1232
hBEW-9A8.8 VL

DTQLTQSPSSLSASVGDRVTITCRAS

ESVSTVIHWYQQKPGKQPKLLIHGAS

NLESGVPSRFSGSGSGTDFTLTISSL

QPEDFATYFCQQHWNDPPTFGQGTKL

EIK

1233
hBEW-9A8.8
CDR-L1

RASESVSTVIH

1234
hBEW-9A8.8
CDR-L2

GASNLES

1235
hBEW-9A8.8
CDR-L3

QQHWNDPPT

1236
hBEW-9A8.9 VH

EVQLVQSGAEVKKPGASVKVSCKASG

YTFTNYGMYWVRQAPGQGLEWMGWIN

TETGKPIYADDFKGRVTMTTDTSTST

AYMELRSLRSDDTAVYYCARVDYDGS

FWFAYWGQGTLVTVSS

1237
hBEW-9A8.9
CDR-H1

GYTFTNYGMY

1238
hBEW-9A8.9
CDR-H2

WINTETGKPIYADDFKG

1239
hBEW-9A8.9
CDR-H3

VDYDGSFWFAY

1240
hBEW-9A8.9 VL

EIVLTQSPDFQSVTPKEKVTITCRAS

ESVSTVIHWYQQKPDQSPKLLIKGAS

NLESGVPSRFSGSGSGTDFTLTINSL

EAEDAATYYCQQHWNDPPTFGQGTKL

EIK

1241
hBEW-9A8.9
CDR-L1

RASESVSTVIH

1242
hBEW-9A8.9
CDR-L2

GASNLES

1243
hBEW-9A8.9
CDR-L3

QQHWNDPPT

1244
hBEW-9E10.1 VH

EIQLVQSGSELKKPGASVKVSCKASG

YTFTNYGMYWVKQAPGQGLEYMGWID

TETGRPTYADDFKGRFVFSLDTSVST

AYLQISSLKAEDTAVYFCARWSGDTT

GIRGPWFAYWGQGTLVTVSS

1245
hBEW-9E10.1
CDR-H1

GYTFTNYGMY

1246
hBEW-9E10.1
CDR-H2

WIDTETGRPTYADDFKG

1247
hBEW-9E10.1
CDR-H3

WSGDTTGIRGPWFAY

1248
hBEW-9E10.1 VL

DIRMTQSPSSLSASVGDRVTIECLAS

EDIYSDLAWYQQKPGKSPKLLIYNAN

GLQNGVPSRFSGSGSGTDYSLTISSL

QPEDVATYFCQQYNYFPGTFGQGTKL

EIK

1249
hBEW-9E10.1
CDR-L1

LASEDIYSDLA

1250
hBEW-9E10.1
CDR-L2

NANGLQN

1251
hBEW-9E10.1
CDR-L3

QQYNYFPGT

1252
hBEW-9E10.2 VH

EIQLVQSGAEVKKPGSSVKVSCKASG

YTFTNYGMYWVKQAPGQGLEYMGWID

TETGRPTYADDFKGRFTFTADKSTST

AYMELSSLRSEDTAVYFCARWSGDTT

GIRGPWFAYWGQGTLVTVSS

1253
hBEW-9E10.2
CDR-H1

GYTFTNYGMY

1254
hBEW-9E10.2
CDR-H2

WIDTETGRPTYADDFKG

1255
hBEW-9E10.2
CDR-H3

WSGDTTGIRGPWFAY

1256
hBEW-9E10.2 VL

DIRMTQSPSSLSASVGDRVTIECLAS

EDIYSDLAWYQQKPGKSPKLLIYNAN

GLQNGVPSRFSGSGSGTDYSLTISSL

QPEDVATYFCQQYNYFPGTFGQGTKL

EIK

1257
hBEW-9E10.2
CDR-L1

LASEDIYSDLA

1258
hBEW-9E10.2
CDR-L2

NANGLQN

1259
hBEW-9E10.2
CDR-L3

QQYNYFPGT

1260
hBEW-9E10.3 VH

EVQLVQSGAEVKKPGSSVKVSCKASG

YTFTNYGMYWVRQAPGQGLEWMGWID

TETGRPTYADDFKGRFTFTADKSTST

AYMELSSLRSEDTAVYYCARWSGDTT

GIRGPWFAYWGQGTLVTVSS

1261
hBEW-9E10.3
CDR-H1

GYTFTNYGMY

1262
hBEW-9E10.3
CDR-H2

WIDTETGRPTYADDFKG

1263
hBEW-9E10.3
CDR-H3

WSGDTTGIRGPWFAY

1264
hBEW-9E10.3 VL

DIRMTQSPSSLSASVGDRVTIECLAS

EDIYSDLAWYQQKPGKSPKLLTYNAN

GLQNGVPSRFSGSGSGTDYSLTISSL

QPEDVATYFCQQYNYFPGTFGQGTKL

EIK

1265
hBEW-9E10.3
CDR-L1

LASEDIYSDLA

1266
hBEW-9E10.3
CDR-L2

NANGLQN

1267
hBEW-9E10.3
CDR-L3

QQYNYFPGT

1268
hBEW-9E10.4 VH

EIQLVQSGSELKKPGASVKVSCKASG

YTFTNYGMYWVKQAPGQGLEYMGWID

TETGRPTYADDFKGRFVFSLDTSVST

AYLQISSLKAEDTAVYFCARWSGDTT

GIRGPWFAYWGQGTLVTVSS

1269
hBEW-9E10.4
CDR-H1

GYTFTNYGMY

1270
hBEW-9E10.4
CDR-H2

WIDTETGRPTYADDFKG

1271
hBEW-9E10.4
CDR-H3

WSGDTTGIRGPWFAY

1272
hBEW-9E10.4 VL

DIRMTQSPSSLSASVGDRVTITCLAS

EDIYSDLAWYQQKPGKSPKLLTYNAN

GLQNGVPSRFSGSGSGTDYTLTISSL

QPEDVATYFCQQYNYFPGTFGQGTKL

EIK

1273
hBEW-9E10.4
CDR-L1

LASEDIYSDLA

1274
hBEW-9E10.4
CDR-L2

NANGLQN

1275
hBEW-9E10.4
CDR-L3

QQYNYFPGT

1276
hBEW-9E10.5 VH

EIQLVQSGAEVKKPGSSVKVSCKASG

YTFTNYGMYWVKQAPGQGLEYMGWID

TETGRPTYADDFKGRFTFTADKSTST

AYMELSSLRSEDTAVYFCARWSGDTT

GIRGPWFAYWGQGTLVTVSS

1277
hBEW-9E10.5
CDR-H1

GYTFTNYGMY

1278
hBEW-9E10.5
CDR-H2

WIDTETGRPTYADDFKG

1279
hBEW-9E10.5
CDR-H3

WSGDTTGIRGPWFAY

1280
hBEW-9E10.5 VL

DIRMTQSPSSLSASVGDRVTITCLAS

EDIYSDLAWYQQKPGKSPKLLTYNAN

GLQNGVPSRFSGSGSGTDYTLTISSL

QPEDVATYFCQQYNYFPGTFGQGTKL

EIK

1281
hBEW-9E10.5
CDR-L1

LASEDIYSDLA

1282
hBEW-9E10.5
CDR-L2

NANGLQN

1283
hBEW-9E10.5
CDR-L3

QQYNYFPGT

1284
hBEW-9E10.6 VH

EVQLVQSGAEVKKPGSSVKVSCKASG

YTFTNYGMYWVRQAPGQGLEWMGWID

TETGRPTYADDFKGRFTFTADKSTST

AYMELSSLRSEDTAVYYCARWSGDTT

GIRGPWFAYWGQGTLVTVSS

1285
hBEW-9E10.6
CDR-H1

GYTFTNYGMY

1286
hBEW-9E10.6
CDR-H2

WIDTETGRPTYADDFKG

1287
hBEW-9E10.6
CDR-H3

WSGDTTGIRGPWFAY

1288
hBEW-9E10.6 VL

DIRMTQSPSSLSASVGDRVTITCLAS

EDIYSDLAWYQQKPGKSPKLLIYNAN

GLQNGVPSRFSGSGSGTDYTLTISSL

QPEDVATYFCQQYNYFPGTFGQGTKL

EIK

1289
hBEW-9E10.6
CDR-L1

LASEDIYSDLA

1290
hBEW-9E10.6
CDR-L2

NANGLQN

1291
hBEW-9E10.6
CDR-L3

QQYNYFPGT

1292
AB014 VH

EVQLVESGGGLVQPGGSLR

LSCAASGYTFTNYGMNWVR

QAPGKGLEWVGWINTYTGE

PTYAADFKRRFTFSLDTSK

STAYLQMNSLRAEDTAVYY

CAKYPHYYGSSHWYFDVWG

QGTLVTVSS

1293
AB014
CDR-H1

GYTFTNYGMN

1294
AB014
CDR-H2

WINTYTGEPTYAADFKR

1295
AB014
CDR-H3

YPHYYGSSHWYFDV

1296
AB014 VL

DIQMTQSPSSLSASVGDRV

TITCSASQDISNYLNWYQQ

KPGKAPKVLIYFTSSLHSG

VPSRFSGSGSGTDFTLTIS

SLQPEDFATYYCQQYSTVP

WTFGQGTKVEIK

1297
AB014
CDR-L1

SASQDISNYLN

1298
AB014
CDR-L2

FTSSLHS

1299
AB014
CDR-L3

QQYSTVPWT

TABLE 28

VH and VL Amino Acid Sequences of Humanized Versions of

Rat Anti-Human PDGF-BB Monoclonal Antibodies (CDRs in bold)

SEQ ID

Protein
V Region

NO:
Clone
Region
123456789012345678901234567890

1300
hBDI-1E1.1 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW

VRQAPGQGLEWMGTIIPLIDTTSYNQKFKGRVTITA

DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD

VMDAWGQGTTVTVSS

1301
hBDI-1E1.1
CDR-H1

GYTFTDYVMH

1302
hBDI-1E1.1
CDR-H2

TIIPLIDTTSYNQKFKG

1303
hBDI-1E1.1
CDR-H3

TSPYYYSSYDVMDA

1304
hBDI-1E1.1 VL

AIQLTQSPSSLSASVGDRVTITCKGSQNINNYLAWY

QQKPGKAPKLLIYKTNNLQTGVPSRFSGSGSGTDFT

LTISSLQPEDFATYYCYQYDNGYTFGQGTKLEIK

1305
hBDI-1E1.1
CDR-L1

KGSQNINNYLA

1306
hBDI-1E1.1
CDR-L2

KTNNLQT

1307
hBDI-1E1.1
CDR-L3

YQYDNGYT

1308
hBDI-1E1.10 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW

VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRVTITA

DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD

VMDAWGQGTTVTVSS

1309
hBDI-1E1.10
CDR-H1

GYTFTDYVMH

1310
hBDI-1E1.10
CDR-H2

TIIPLIDTTSYNQKFKG

1311
hBDI-1E1.10
CDR-H3

TSPYYYSSYDVMDA

1312
hBDI-1E1.10 VL

AIQLTQSPSSLSASVGDRVTITCKGSQNINNYLAWY

QQKPGKAPKLLIYKTNNLQTGIPSRFSGSGSGTDYT

LTISSLQPEDFATYYCYQYDNGYTFGQGTKLEIK

1313
hBDI-1E1.10
CDR-L1

KGSQNINNYLA

1314
hBDI-1E1.10
CDR-L2

KTNNLQT

1315
hBDI-1E1.10
CDR-L3

YQYDNGYT

1316
hBDI-1E1.11 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW

VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRVTITA

DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD

VMDAWGQGTTVTVSS

1317
hBDI-1E1.11
CDR-H1

GYTFTDYVMH

1318
hBDI-1E1.11
CDR-H2

TIIPLIDTTSYNQKFKG

1319
hBDI-1E1.11
CDR-H3

TSPYYYSSYDVMDA

1320
hBDI-1E1.11 VL

EIVLTQSPATLSLSPGERATLSCKGSQNINNYLAWY

QQKPGQAPRLLIYKTNNLQTGIPARFSGSGSGTDFT

LTISSLEPEDFAVYYCYQYDNGYTFGQGTKLEIK

1321
hBDI-1E1.11
CDR-L1

KGSQNINNYLA

1322
hBDI-1E1.11
CDR-L2

KTNNLQT

1323
hBDI-1E1.11
CDR-L3

YQYDNGYT

1324
hBDI-1E1.12 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW

VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRVTITA

DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD

VMDAWGQGTTVTVSS

1325
hBDI-1E1.12
CDR-H1

GYTFTDYVMH

1326
hBDI-1E1.12
CDR-H2

TIIPLIDTTSYNQKFKG

1327
hBDI-1E1.12
CDR-H3

TSPYYYSSYDVMDA

1328
hBDI-1E1.12 VL

EIVLTQSPATLSLSPGERATLSCKGSQNINNYLAWY

QQKPGQAPRLLIYKTNNLQTGIPARFSGSGSGTDYT

LTISSLEPEDFATYYCYQYDNGYTFGQGTKLEIK

1329
hBDI-1E1.12
CDR-L1

KGSQNINNYLA

1330
hBDI-1E1.12
CDR-L2

KTNNLQT

1331
hBDI-1E1.12
CDR-L3

YQYDNGYT

1332
hBDI-1E1.2 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW

VRQAPGQGLEWMGTIIPLIDTTSYNQKFKGRVTITA

DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD

VMDAWGQGTTVTVSS

1333
hBDI-1E1.2
CDR-H1

GYTFTDYVMH

1334
hBDI-1E1.2
CDR-H2

TIIPLIDTTSYNQKFKG

1335
hBDI-1E1.2
CDR-H3

TSPYYYSSYDVMDA

1336
hBDI-1E1.2 VL

AIQLTQSPSSLSASVGDRVTITCKGSQNINNYLAWY

QQKPGKAPKLLIYKTNNLQTGIPSRFSGSGSGTDYT

LTISSLQPEDFATYYCYQYDNGYTFGQGTKLEIK

1337
hBDI-1E1.2
CDR-L1

KGSQNINNYLA

1338
hBDI-1E1.2
CDR-L2

KTNNLQT

1339
hBDI-1E1.2
CDR-L3

YQYDNGYT

1340
hBDI-1E1.3 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW

VRQAPGQGLEWMGTIIPLIDTTSYNQKFKGRVTITA

DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD

VMDAWGQGTTVTVSS

1341
hBDI-1E1.3
CDR-H1

GYTFTDYVMH

1342
hBDI-1E1.3
CDR-H2

TIIPLIDTTSYNQKFKG

1343
hBDI-1E1.3
CDR-H3

TSPYYYSSYDVMDA

1344
hBDI-1E1.3 VL

EIVLTQSPATLSLSPGERATLSCKGSQNINNYLAWY

QQKPGQAPRLLIYKTNNLQTGIPARFSGSGSGTDFT

LTISSLEPEDFAVYYCYQYDNGYTFGQGTKLEIK

1345
hBDI-1E1.3
CDR-L1

KGSQNINNYLA

1346
hBDI-1E1.3
CDR-L2

KTNNLQT

1347
hBDI-1E1.3
CDR-L3

YQYDNGYT

1348
hBDI-1E1.4 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW

VRQAPGQGLEWMGTIIPLIDTTSYNQKFKGRVTITA

DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD

VMDAWGQGTTVTVSS

1349
hBDI-1E1.4
CDR-H1

GYTFTDYVMH

1350
hBDI-1E1.4
CDR-H2

TIIPLIDTTSYNQKFKG

1351
hBDI-1E1.4
CDR-H3

TSPYYYSSYDVMDA

1352
hBDI-1E1.4 VL

EIVLTQSPATLSLSPGERATLSCKGSQNINNYLAWY

QQKPGQAPRLLIYKTNNLQTGIPARFSGSGSGTDYT

LTISSLEPEDFATYYCYQYDNGYTFGQGTKLEIK

1353
hBDI-1E1.4
CDR-L1

KGSQNINNYLA

1354
hBDI-1E1.4
CDR-L2

KTNNLQT

1355
hBDI-1E1.4
CDR-L3

YQYDNGYT

1356
hBDI-1E1.5 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW

VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRATLTA

DKSTNTAYMELSSLRSEDTAVYYCARTSPYYYSSYD

VMDAWGQGTTVTVSS

1357
hBDI-1E1.5
CDR-H1

GYTFTDYVMH

1358
hBDI-1E1.5
CDR-H2

TIIPLIDTTSYNQKFKG

1359
hBDI-1E1.5
CDR-H3

TSPYYYSSYDVMDA

1360
hBDI-1E1.5 VL

AIQLTQSPSSLSASVGDRVTITCKGSQNINNYLAWY

QQKPGKAPKLLIYKTNNLQTGVPSRFSGSGSGTDFT

LTISSLQPEDFATYYCYQYDNGYTFGQGTKLEIK

1361
hBDI-1E1.5
CDR-L1

KGSQNINNYLA

1362
hBDI-1E1.5
CDR-L2

KTNNLQT

1363
hBDI-1E1.5
CDR-L3

YQYDNGYT

1364
hBDI-1E1.6 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW

VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRATLTA

DKSTNTAYMELSSLRSEDTAVYYCARTSPYYYSSYD

VMDAWGQGTTVTVSS

1365
hBDI-1E1.6
CDR-H1

GYTFTDYVMH

1366
hBDI-1E1.6
CDR-H2

TIIPLIDTTSYNQKFKG

1367
hBDI-1E1.6
CDR-H3

TSPYYYSSYDVMDA

1368
hBDI-1E1.6 VL

AIQLTQSPSSLSASVGDRVTITCKGSQNINNYLAWY

QQKPGKAPKLLIYKTNNLQTGIPSRFSGSGSGTDYT

LTISSLQPEDFATYYCYQYDNGYTFGQGTKLEIK

1369
hBDI-1E1.6
CDR-L1

KGSQNINNYLA

1370
hBDI-1E1.6
CDR-L2

KTNNLQT

1371
hBDI-1E1.6
CDR-L3

YQYDNGYT

1372
hBDI-1E1.7 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW

VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRATLTA

DKSTNTAYMELSSLRSEDTAVYYCARTSPYYYSSYD

VMDAWGQGTTVTVSS

1373
hBDI-1E1.7
CDR-H1

GYTFTDYVMH

1374
hBDI-1E1.7
CDR-H2

TIIPLIDTTSYNQKFKG

1375
hBDI-1E1.7
CDR-H3

TSPYYYSSYDVMDA

1376
hBDI-1E1.7 VL

EIVLTQSPATLSLSPGERATLSCKGSQNINNYLAWY

QQKPGQAPRLLIYKTNNLQTGIPARFSGSGSGTDFT

LTISSLEPEDFAVYYCYQYDNGYTFGQGTKLEIK

1377
hBDI-1E1.7
CDR-L1

KGSQNINNYLA

1378
hBDI-1E1.7
CDR-L2

KTNNLQT

1379
hBDI-1E1.7
CDR-L3

YQYDNGYT

1380
hBDI-1E1.8 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW

VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRATLTA

DKSTNTAYMELSSLRSEDTAVYYCARTSPYYYSSYD

VMDAWGQGTTVTVSS

1381
hBDI-1E1.8
CDR-H1

GYTFTDYVMH

1382
hBDI-1E1.8
CDR-H2

TIIPLIDTTSYNQKFKG

1383
hBDI-1E1.8
CDR-H3

TSPYYYSSYDVMDA

1384
hBDI-1E1.8 VL

EIVLTQSPATLSLSPGERATLSCKGSQNINNYLAWY

QQKPGQAPRLLIYKTNNLQTGIPARFSGSGSGTDYT

LTISSLEPEDFATYYCYQYDNGYTFGQGTKLEIK

1385
hBDI-1E1.8
CDR-L1

KGSQNINNYLA

1386
hBDI-1E1.8
CDR-L2

KTNNLQT

1387
hBDI-1E1.8
CDR-L3

YQYDNGYT

1388
hBDI-1E1.9 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYVMHW

VRQAPGQGLEWIGTIIPLIDTTSYNQKFKGRVTITA

DKSTSTAYMELSSLRSEDTAVYYCARTSPYYYSSYD

VMDAWGQGTTVTVSS

1389
hBDI-1E1.9
CDR-H1

GYTFTDYVMH

1390
hBDI-1E1.9
CDR-H2

TIIPLIDTTSYNQKFKG

1391
hBDI-1E1.9
CDR-H3

TSPYYYSSYDVMDA

1392
hBDI-1E1.9 VL

AIQLTQSPSSLSASVGDRVTITCKGSQNINNYLAWY

QQKPGKAPKLLIYKTNNLQTGVPSRFSGSGSGTDFT

LTISSLQPEDFATYYCYQYDNGYTFGQGTKLEIK

1393
hBDI-1E1.9
CDR-L1

KGSQNINNYLA

1394
hBDI-1E1.9
CDR-L2

KTNNLQT

1395
hBDI-1E1.9
CDR-L3

YQYDNGYT

1396
hBDI-5H1.1 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQVVLTMTNMDPVDTATYYCARISTGISSYY

VMDAWGQGTTVTVSS

1397
hBDI-5H1.1
CDR-H1

GFSLSTFGMGVG

1398
hBDI-5H1.1
CDR-H2

NIWWDDDKYYNPSLKN

1399
hBDI-5H1.1
CDR-H3

ISTGISSYYVMDA

1400
hBDI-5H1.1 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDTYVSW

YQQRPGSSPTTVIYGNDQRPSGVPDRFSGSIDSSSN

SASLTISGLKTEDEADYYCQSYDSDIDIVFGGGTKL

TVL

1401
hBDI-5H1.1
CDR-L1

ERSSGDIGDTYVS

1402
hBDI-5H1.1
CDR-L2

GNDQRPS

1403
hBDI-5H1.1
CDR-L3

QSYDSDIDIV

1404
hBDI-5H1.10 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAVLTITNMDPVDTATYYCARISTGISSYY

VMDAWGQGTTVTVSS

1405
hBDI-5H1.10
CDR-H1

GFSLSTFGMGVG

1406
hBDI-5H1.10
CDR-H2

NIWWDDDKYYNPSLKN

1407
hBDI-5H1.10
CDR-H3

ISTGISSYYVMDA

1408
hBDI-5H1.10 VL

DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVS

WYQQKPGKAPKNVIYGNDQRPSGVPSRFSGSGSGNS

ATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVE

IK

1409
hBDI-5H1.10
CDR-L1

ERSSGDIGDTYVS

1410
hBDI-5H1.10
CDR-L2

GNDQRPS

1411
hBDI-5H1.10
CDR-L3

QSYDSDIDIV

1412
hBDI-5H1.11 VH

EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTFGMGV

GWIRQAPGKGLEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAYLQINSLRAEDTAVYYCARISTGISSYY

VMDAWGQGTLVTVSS

1413
hBDI-5H1.11
CDR-H1

GFSLSTFGMGVG

1414
hBDI-5H1.11
CDR-H2

NIWWDDDKYYNPSLKN

1415
hBDI-5H1.11
CDR-H3

ISTGISSYYVMDA

1416
hBDI-5H1.11 VL

DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVS

WYQQKPGQPPKNVIYGNDQRPSGVPDRFSGSGSGNS

ATLTISSLQAEDVAVYFCQSYDSDIDIVFGGGTKVE

IK

1417
hBDI-5H1.11
CDR-L1

ERSSGDIGDTYVS

1418
hBDI-5H1.11
CDR-L2

GNDQRPS

1419
hBDI-5H1.11
CDR-L3

QSYDSDIDIV

1420
hBDI-5H1.12 VH

EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTFGMGV

GWIRQAPGKGLEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAYLQINSLRAEDTAVYYCARISTGISSYY

VMDAWGQGTLVTVSS

1421
hBDI-5H1.12
CDR-H1

GFSLSTFGMGVG

1422
hBDI-5H1.12
CDR-H2

NIWWDDDKYYNPSLKN

1423
hBDI-5H1.12
CDR-H3

ISTGISSYYVMDA

1424
hBDI-5H1.12 VL

DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVS

WYQQKPGKAPKNVIYGNDQRPSGVPSRFSGSGSGNS

ATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVE

IK

1425
hBDI-5H1.12
CDR-L1

ERSSGDIGDTYVS

1426
hBDI-5H1.12
CDR-L2

GNDQRPS

1427
hBDI-5H1.12
CDR-L3

QSYDSDIDIV

1428
hBDI-5H1.13 VH

EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAVLTITNMDPVDTATYYCARISTGISSYY

VMDAWGQGTTVTVSS

1429
hBDI-5H1.13
CDR-H1

GFSLSTFGMGVG

1430
hBDI-5H1.13
CDR-H2

NIWWDDDKYYNPSLKN

1431
hBDI-5H1.13
CDR-H3

ISTGISSYYVMDA

1432
hBDI-5H1.13 VL

DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVS

WYQQKPGKAPKNVIYGNDQRPSGVPSRFSGSGSGNS

ATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVE

IK

1433
hBDI-5H1.13
CDR-L1

ERSSGDIGDTYVS

1434
hBDI-5H1.13
CDR-L2

GNDQRPS

1435
hBDI-5H1.13
CDR-L3

QSYDSDIDIV

1436
hBDI-5H1.16 VH

EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTIS

KDTSNSQAVLTITNMDPVDTATYYCARISTGISSYY

VMDAWGQGTTVTVSS

1437
hBDI-5H1.16
CDR-H1

GFSLSTFGMGVG

1438
hBDI-5H1.16
CDR-H2

NIWWDDDKYYNPSLKN

1439
hBDI-5H1.16
CDR-H3

ISTGISSYYVMDA

1440
hBDI-5H1.16 VL

EFVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVS

WYQQKPGQPPRNVIYGNDQRPSGVPDRFSGSGSGTD

FTLTISRLEPEDFAVYFCQSYDSDIDIVFGGGTKVE

IK

1441
hBDI-5H1.16
CDR-L1

ERSSGDIGDTYVS

1442
hBDI-5H1.16
CDR-L2

GNDQRPS

1443
hBDI-5H1.16
CDR-L3

QSYDSDIDIV

1444
hBDI-5H1.17 VH

EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTIS

KDTSNSQAVLTITNMDPVDTATYYCARISTGISSYY

VMDAWGQGTTVTVSS

1445
hBDI-5H1.17
CDR-H1

GFSLSTFGMGVG

1446
hBDI-5H1.17
CDR-H2

NIWWDDDKYYNPSLKN

1447
hBDI-5H1.17
CDR-H3

ISTGISSYYVMDA

1448
hBDI-5H1.17 VL

EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVS

WYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGSGTD

FTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVE

IK

1449
hBDI-5H1.17
CDR-L1

ERSSGDIGDSYVS

1450
hBDI-5H1.17
CDR-L2

ADDQRPS

1451
hBDI-5H1.17
CDR-L3

QSYDINIDIV

1452
hBDI-5H1.2 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQVVLTMTNMDPVDTATYYCARISTGISSYY

VMDAWGQGTTVTVSS

1453
hBDI-5H1.2
CDR-H1

GFSLSTFGMGVG

1454
hBDI-5H1.2
CDR-H2

NIWWDDDKYYNPSLKN

1455
hBDI-5H1.2
CDR-H3

ISTGISSYYVMDA

1456
hBDI-5H1.2 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDTYVSW

YQQRPGSPPTNVIYGNDQRPSGVPDRFSGSIDSSSN

SASLTISGLKTEDEADYFCQSYDSDIDIVFGGGTKL

TVL

1457
hBDI-5H1.2
CDR-L1

ERSSGDIGDTYVS

1458
hBDI-5H1.2
CDR-L2

GNDQRPS

1459
hBDI-5H1.2
CDR-L3

QSYDSDIDIV

1460
hBDI-5H1.3 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQVVLTMTNMDPVDTATYYCARISTGISSYY

VMDAWGQGTTVTVSS

1461
hBDI-5H1.3
CDR-H1

GFSLSTFGMGVG

1462
hBDI-5H1.3
CDR-H2

NIWWDDDKYYNPSLKN

1463
hBDI-5H1.3
CDR-H3

ISTGISSYYVMDA

1464
hBDI-5H1.3 VL

EIVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVS

WYQQKPGQAPRLLIYGNDQRPSGIPDRFSGSGSGTD

FTLTISRLEPEDFAVYYCQSYDSDIDIVFGGGTKVE

IK

1465
hBDI-5H1.3
CDR-L1

ERSSGDIGDTYVS

1466
hBDI-5H1.3
CDR-L2

GNDQRPS

1467
hBDI-5H1.3
CDR-L3

QSYDSDIDIV

1468
hBDI-5H1.4 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQVVLTMTNMDPVDTATYYCARISTGISSYY

VMDAWGQGTTVTVSS

1469
hBDI-5H1.4
CDR-H1

GFSLSTFGMGVG

1470
hBDI-5H1.4
CDR-H2

NIWWDDDKYYNPSLKN

1471
hBDI-5H1.4
CDR-H3

ISTGISSYYVMDA

1472
hBDI-5H1.4 VL

EFVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVS

WYQQKPGQAPRLVIYGNDQRPSGIPDRFSGSGSGTD

FTLTISRLEPEDFAVYYCQSYDSDIDIVFGGGTKVE

IK

1473
hBDI-5H1.4
CDR-L1

ERSSGDIGDTYVS

1474
hBDI-5H1.4
CDR-L2

GNDQRPS

1475
hBDI-5H1.4
CDR-L3

QSYDSDIDIV

1476
hBDI-5H1.5 VH

EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAVLTITNMDPVDTATYYCARISTGISSYY

VMDAWGQGTTVTVSS

1477
hBDI-5H1.5
CDR-H1

GFSLSTFGMGVG

1478
hBDI-5H1.5
CDR-H2

NIWWDDDKYYNPSLKN

1479
hBDI-5H1.5
CDR-H3

ISTGISSYYVMDA

1480
hBDI-5H1.5 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDTYVSW

YQQRPGSSPTTVIYGNDQRPSGVPDRFSGSIDSSSN

SASLTISGLKTEDEADYYCQSYDSDIDIVFGGGTKL

TVL

1481
hBDI-5H1.5
CDR-L1

ERSSGDIGDTYVS

1482
hBDI-5H1.5
CDR-L2

GNDQRPS

1483
hBDI-5H1.5
CDR-L3

QSYDSDIDIV

1484
hBDI-5H1.6 VH

EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAVLTITNMDPVDTATYYCARISTGISSYY

VMDAWGQGTTVTVSS

1485
hBDI-5H1.6
CDR-H1

GFSLSTFGMGVG

1486
hBDI-5H1.6
CDR-H2

NIWWDDDKYYNPSLKN

1487
hBDI-5H1.6
CDR-H3

ISTGISSYYVMDA

1488
hBDI-5H1.6 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDTYVSW

YQQRPGSPPTNVIYGNDQRPSGVPDRFSGSIDSSSN

SASLTISGLKTEDEADYFCQSYDSDIDIVFGGGTKL

TVL

1489
hBDI-5H1.6
CDR-L1

ERSSGDIGDTYVS

1490
hBDI-5H1.6
CDR-L2

GNDQRPS

1491
hBDI-5H1.6
CDR-L3

QSYDSDIDIV

1492
hBDI-5H1.7 VH

EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAVLTITNMDPVDTATYYCARISTGISSYY

VMDAWGQGTTVTVSS

1493
hBDI-5H1.7
CDR-H1

GFSLSTFGMGVG

1494
hBDI-5H1.7
CDR-H2

NIWWDDDKYYNPSLKN

1495
hBDI-5H1.7
CDR-H3

ISTGISSYYVMDA

1496
hBDI-5H1.7 VL

EIVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVS

WYQQKPGQAPRLLIYGNDQRPSGIPDRFSGSGSGTD

FTLTISRLEPEDFAVYYCQSYDSDIDIVFGGGTKVE

IK

1497
hBDI-5H1.7
CDR-L1

ERSSGDIGDTYVS

1498
hBDI-5H1.7
CDR-L2

GNDQRPS

1499
hBDI-5H1.7
CDR-L3

QSYDSDIDIV

1500
hBDI-5H1.8 VH

EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAVLTITNMDPVDTATYYCARISTGISSYY

VMDAWGQGTTVTVSS

1501
hBDI-5H1.8
CDR-H1

GFSLSTFGMGVG

1502
hBDI-5H1.8
CDR-H2

NIWWDDDKYYNPSLKN

1503
hBDI-5H1.8
CDR-H3

ISTGISSYYVMDA

1504
hBDI-5H1.8 VL

EFVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVS

WYQQKPGQAPRLVIYGNDQRPSGIPDRFSGSGSGTD

FTLTISRLEPEDFAVYYCQSYDSDIDIVFGGGTKVE

IK

1505
hBDI-5H1.8
CDR-L1

ERSSGDIGDTYVS

1506
hBDI-5H1.8
CDR-L2

GNDQRPS

1507
hBDI-5H1.8
CDR-L3

QSYDSDIDIV

1508
hBDI-5H1.9 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAVLTITNMDPVDTATYYCARISTGISSYY

VMDAWGQGTTVTVSS

1509
hBDI-5H1.9
CDR-H1

GFSLSTFGMGVG

1510
hBDI-5H1.9
CDR-H2

NIWWDDDKYYNPSLKN

1511
hBDI-5H1.9
CDR-H3

ISTGISSYYVMDA

1512
hBDI-5H1.9 VL

DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVS

WYQQKPGQPPKNVIYGNDQRPSGVPDRFSGSGSGNS

ATLTISSLQAEDVAVYFCQSYDSDIDIVFGGGTKVE

IK

1513
hBDI-5H1.9
CDR-L1

ERSSGDIGDTYVS

1514
hBDI-5H1.9
CDR-L2

GNDQRPS

1515
hBDI-5H1.9
CDR-L3

QSYDSDIDIV

1516
hBDI-9E8.1 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYS

FDYWGQGTMVTVSS

1517
hBDI-9E8.1
CDR-H1

GFSLSTYGMGVG

1518
hBDI-9E8.1
CDR-H2

NIWWDDDKYYNPSLKN

1519
hBDI-9E8.1
CDR-H3

IESIGTTYSFDY

1520
hBDI-9E8.1 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDSYVSW

YQQRPGSSPTTVIYADDQRPSGVPDRFSGSIDSSSN

SASLTISGLKTEDEADYYCQSYDINIDIVFGGGTKL

TVL

1521
hBDI-9E8.1
CDR-L1

ERSSGDIGDSYVS

1522
hBDI-9E8.1
CDR-L2

ADDQRPS

1523
hBDI-9E8.1
CDR-L3

QSYDINIDIV

1524
hBDI-9E8.10 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYS

FDYWGQGTTVTVSS

1525
hBDI-9E8.10
CDR-H1

GFSLSTYGMGVG

1526
hBDI-9E8.10
CDR-H2

NIWWDDDKYYNPSLKN

1527
hBDI-9E8.10
CDR-H3

IESIGTTYSFDY

1528
hBDI-9E8.10 VL

DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVS

WYQQKPGKAPKNVIYADDQRPSGVPSRFSGSGSGNS

ASLTISSLQPEDFATYYCQSYDINIDIVFGQGTKVE

IK

1529
hBDI-9E8.10
CDR-L1

ERSSGDIGDSYVS

1530
hBDI-9E8.10
CDR-L2

ADDQRPS

1531
hBDI-9E8.10
CDR-L3

QSYDINIDIV

1532
hBDI-9E8.11 VH

EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTYGMGV

GWIRQAPGKGLEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAYLQINSLRAEDTAVYYCARIESIGTTYS

FDYWGQGTLVTVSS

1533
hBDI-9E8.11
CDR-H1

GFSLSTYGMGVG

1534
hBDI-9E8.11
CDR-H2

NIWWDDDKYYNPSLKN

1535
hBDI-9E8.11
CDR-H3

IESIGTTYSFDY

1536
hBDI-9E8.11 VL

DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVS

WYQQKPGQPPKNVIYADDQRPSGVPDRFSGSGSGNS

ASLTISSLQAEDVAVYFCQSYDINIDIVFGGGTKVE

IK

1537
hBDI-9E8.11
CDR-L1

ERSSGDIGDSYVS

1538
hBDI-9E8.11
CDR-L2

ADDQRPS

1539
hBDI-9E8.11
CDR-L3

QSYDINIDIV

1540
hBDI-9E8.12 VH

EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTYGMGV

GWIRQAPGKGLEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAYLQINSLRAEDTAVYYCARIESIGTTYS

FDYWGQGTLVTVSS

1541
hBDI-9E8.12
CDR-H1

GFSLSTYGMGVG

1542
hBDI-9E8.12
CDR-H2

NIWWDDDKYYNPSLKN

1543
hBDI-9E8.12
CDR-H3

IESIGTTYSFDY

1544
hBDI-9E8.12 VL

DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVS

WYQQKPGKAPKNVIYADDQRPSGVPSRFSGSGSGNS

ASLTISSLQPEDFATYYCQSYDINIDIVFGQGTKVE

IK

1545
hBDI-9E8.12
CDR-L1

ERSSGDIGDSYVS

1546
hBDI-9E8.12
CDR-L2

ADDQRPS

1547
hBDI-9E8.12
CDR-L3

QSYDINIDIV

1548
hBDI-9E8.13 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYS

FDYWGQGTMVTVSS

1549
hBDI-9E8.13
CDR-H1

GFSLSTYGMGVG

1550
hBDI-9E8.13
CDR-H2

NIWWDDDKYYNPSLKN

1551
hBDI-9E8.13
CDR-H3

IESIGTTYSFDY

1552
hBDI-9E8.13 VL

DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVS

WYQQKPGKAPKNVIYADDQRPSGVPSRFSGSGSGNS

ASLTISSLQPEDFATYYCQSYDINIDIVFGQGTKVE

IK

1553
hBDI-9E8.13
CDR-L1

ERSSGDIGDSYVS

1554
hBDI-9E8.13
CDR-L2

ADDQRPS

1555
hBDI-9E8.13
CDR-L3

QSYDINIDIV

1556
hBDI-9E8.2 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYS

FDYWGQGTMVTVSS

1557
hBDI-9E8.2
CDR-H1

GFSLSTYGMGVG

1558
hBDI-9E8.2
CDR-H2

NIWWDDDKYYNPSLKN

1559
hBDI-9E8.2
CDR-H3

IESIGTTYSFDY

1560
hBDI-9E8.2 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDSYVSW

YQQRPGSPPTNVIYADDQRPSGVPDRFSGSIDSSSN

SASLTISGLKTEDEADYFCQSYDINIDIVFGGGTKL

TVL

1561
hBDI-9E8.2
CDR-L1

ERSSGDIGDSYVS

1562
hBDI-9E8.2
CDR-L2

ADDQRPS

1563
hBDI-9E8.2
CDR-L3

QSYDINIDIV

1564
hBDI-9E8.3 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYS

FDYWGQGTMVTVSS

1565
hBDI-9E8.3
CDR-H1

GFSLSTYGMGVG

1566
hBDI-9E8.3
CDR-H2

NIWWDDDKYYNPSLKN

1567
hBDI-9E8.3
CDR-H3

IESIGTTYSFDY

1568
hBDI-9E8.3 VL

EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVS

WYQQKPGQAPRLLIYADDQRPSGIPDRFSGSGSGTD

FTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVE

IK

1569
hBDI-9E8.3
CDR-L1

ERSSGDIGDSYVS

1570
hBDI-9E8.3
CDR-L2

ADDQRPS

1571
hBDI-9E8.3
CDR-L3

QSYDINIDIV

1572
hBDI-9E8.4 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYS

FDYWGQGTMVTVSS

1573
hBDI-9E8.4
CDR-H1

GFSLSTYGMGVG

1574
hBDI-9E8.4
CDR-H2

NIWWDDDKYYNPSLKN

1575
hBDI-9E8.4
CDR-H3

IESIGTTYSFDY

1576
hBDI-9E8.4 VL

EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVS

WYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGSGTD

FTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVE

IK

1577
hBDI-9E8.4
CDR-L1

ERSSGDIGDSYVS

1578
hBDI-9E8.4
CDR-L2

ADDQRPS

1579
hBDI-9E8.4
CDR-L3

QSYDINIDIV

1580
hBDI-9E8.5 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYS

FDYWGQGTMVTVSS

1581
hBDI-9E8.5
CDR-H1

GFSLSTYGMGVG

1582
hBDI-9E8.5
CDR-H2

NIWWDDDKYYNPSLKN

1583
hBDI-9E8.5
CDR-H3

IESIGTTYSFDY

1584
hBDI-9E8.5 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDSYVSW

YQQRPGSSPTTVIYADDQRPSGVPDRFSGSIDSSSN

SASLTISGLKTEDEADYYCQSYDINIDIVFGGGTKL

TVL

1585
hBDI-9E8.5
CDR-L1

ERSSGDIGDSYVS

1586
hBDI-9E8.5
CDR-L2

ADDQRPS

1587
hBDI-9E8.5
CDR-L3

QSYDINIDIV

1588
hBDI-9E8.6 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYS

FDYWGQGTMVTVSS

1589
hBDI-9E8.6
CDR-H1

GFSLSTYGMGVG

1590
hBDI-9E8.6
CDR-H2

NIWWDDDKYYNPSLKN

1591
hBDI-9E8.6
CDR-H3

IESIGTTYSFDY

1592
hBDI-9E8.6 VL

NFMLTQPHSVSESPGKTVTISCERSSGDIGDSYVSW

YQQRPGSPPTNVIYADDQRPSGVPDRFSGSIDSSSN

SASLTISGLKTEDEADYFCQSYDINIDIVFGGGTKL

TVL

1593
hBDI-9E8.6
CDR-L1

ERSSGDIGDSYVS

1594
hBDI-9E8.6
CDR-L2

ADDQRPS

1595
hBDI-9E8.6
CDR-L3

QSYDINIDIV

1596
hBDI-9E8.7 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYS

FDYWGQGTMVTVSS

1597
hBDI-9E8.7
CDR-H1

GFSLSTYGMGVG

1598
hBDI-9E8.7
CDR-H2

NIWWDDDKYYNPSLKN

1599
hBDI-9E8.7
CDR-H3

IESIGTTYSFDY

1600
hBDI-9E8.7 VL

EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVS

WYQQKPGQAPRLLIYADDQRPSGIPDRFSGSGSGTD

FTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVE

IK

1601
hBDI-9E8.7
CDR-L1

ERSSGDIGDSYVS

1602
hBDI-9E8.7
CDR-L2

ADDQRPS

1603
hBDI-9E8.7
CDR-L3

QSYDINIDIV

1604
hBDI-9E8.8 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYS

FDYWGQGTMVTVSS

1605
hBDI-9E8.8
CDR-H1

GFSLSTYGMGVG

1606
hBDI-9E8.8
CDR-H2

NIWWDDDKYYNPSLKN

1607
hBDI-9E8.8
CDR-H3

IESIGTTYSFDY

1608
hBDI-9E8.8 VL

EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVS

WYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGSGTD

FTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVE

IK

1609
hBDI-9E8.8
CDR-L1

ERSSGDIGDSYVS

1610
hBDI-9E8.8
CDR-L2

ADDQRPS

1611
hBDI-9E8.8
CDR-L3

QSYDINIDIV

1612
hBDI-9E8.9 VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYS

FDYWGQGTTVTVSS

1613
hBDI-9E8.9
CDR-H1

GFSLSTYGMGVG

1614
hBDI-9E8.9
CDR-H2

NIWWDDDKYYNPSLKN

1615
hBDI-9E8.9
CDR-H3

IESIGTTYSFDY

1616
hBDI-9E8.9 VL

DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVS

WYQQKPGQPPKNVIYADDQRPSGVPDRFSGSGSGNS

ASLTISSLQAEDVAVYFCQSYDINIDIVFGGGTKVE

IK

1617
hBDI-9E8.9
CDR-L1

ERSSGDIGDSYVS

1618
hBDI-9E8.9
CDR-L2

ADDQRPS

1619
hBDI-9E8.9
CDR-L3

QSYDINIDIV

1620
hBDI-9E8.4E VH

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTIS

KDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYS

FDYWGQGTMVTVSS

1621
hBDI-9E8.4E
CDR-H1

GFSLSTYGMGVG

1622
hBDI-9E8.4E
CDR-H2

NIWWDDDKYYNPSLKN

1623
hBDI-9E8.4E
CDR-H3

IESIGTTYSFDY

1624
hBDI-9E8.4E VL

EFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVS

WYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGSGTD

FTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVE

IK

1625
hBDI-9E8.4E
CDR-L1

ERSSGDIGESYVS

1626
hBDI-9E8.4E
CDR-L2

ADDQRPS

1627
hBDI-9E8.4E
CDR-L3

QSYDINIDIV

1628
hBFU-3E2.1 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYW

VKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTA

DKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPM

DAWGQGTTVTVSS

1629
hBFU-3E2.1
CDR-H1

GYTFTESYMY

1630
hBFU-3E2.1
CDR-H2

RIDPEDGSTDYVEKFKN

1631
hBFU-3E2.1
CDR-H3

FGARSYFYPMDA

1632
hBFU-3E2.1 VL

ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWY

QQKPGQQPRLLIYGASNLESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIK

1633
hBFU-3E2.1
CDR-L1

RASESVSTLMH

1634
hBFU-3E2.1
CDR-L2

GASNLES

1635
hBFU-3E2.1
CDR-L3

QQSWNDPWT

1636
hBFU-3E2.2 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYW

VRQAPGQGLELIGRIDPEDGSTDYVEKFKNRVTLTA

DKSTSTAYMELSSLRSEDTAVYYCARFGARSYFYPM

DAWGQGTTVTVSS

1637
hBFU-3E2.2
CDR-H1

GYTFTESYMY

1638
hBFU-3E2.2
CDR-H2

RIDPEDGSTDYVEKFKN

1639
hBFU-3E2.2
CDR-H3

FGARSYFYPMDA

1640
hBFU-3E2.2 VL

ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWY

QQKPGQQPRLLIYGASNLESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIK

1641
hBFU-3E2.2
CDR-L1

RASESVSTLMH

1642
hBFU-3E2.2
CDR-L2

GASNLES

1643
hBFU-3E2.2
CDR-L3

QQSWNDPWT

1644
hBFU-3E2.3 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYW

VKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTA

DKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPM

DAWGQGTTVTVSS

1645
hBFU-3E2.3
CDR-H1

GYTFTESYMY

1646
hBFU-3E2.3
CDR-H2

RIDPEDGSTDYVEKFKN

1647
hBFU-3E2.3
CDR-H3

FGARSYFYPMDA

1648
hBFU-3E2.3 VL

ATQLTQSPSSLSASVGDRVTISCRASESVSTLMHWY

QQKPGKQPRLLIYGASNLESGVPSRFSGSGSGTDFT

LTISSLQPEDFATYFCQQSWNDPWTFGGGTKVEIK

1649
hBFU-3E2.3
CDR-L1

RASESVSTLMH

1650
hBFU-3E2.3
CDR-L2

GASNLES

1651
hBFU-3E2.3
CDR-L3

QQSWNDPWT

1652
hBFU-3E2.4 VH

EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYW

VRQAPGQGLELIGRIDPEDGSTDYVEKFKNRVTLTA

DKSTSTAYMELSSLRSEDTAVYYCARFGARSYFYPM

DAWGQGTTVTVSS

1653
hBFU-3E2.4
CDR-H1

GYTFTESYMY

1654
hBFU-3E2.4
CDR-H2

RIDPEDGSTDYVEKFKN

1655
hBFU-3E2.4
CDR-H3

FGARSYFYPMDA

1656
hBFU-3E2.4 VL

ATQLTQSPSSLSASVGDRVTISCRASESVSTLMHWY

QQKPGKQPRLLIYGASNLESGVPSRFSGSGSGTDFT

LTISSLQPEDFATYFCQQSWNDPWTFGGGTKVEIK

1657
hBFU-3E2.4
CDR-L1

RASESVSTLMH

1658
hBFU-3E2.4
CDR-L2

GASNLES

1659
hBFU-3E2.4
CDR-L3

QQSWNDPWT

TABLE 29

VH and VL Amino Acid Sequences of Humanized Versions of

Rat Anti-Human VEGFR II Monoclonal Antibodies (CDRs in bold)

SEQ ID

Protein
V Region

NO:
Clone
Region
12345678901234567890123456

1660
hBCU-6B1.1 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY

WVKQAPGQGLEFMGWINTETGQPTYADDFKGRFVF

SLDTSVSTAYLQISSLKAEDTAVYFCARLGNNYGI

WFAYWGQGTLVTVSS

1661
hBCU-6B1.1
CDR-H1

GYTFTNYGMY

1662
hBCU-6B1.1
CDR-H2

WINTETGQPTYADDFKG

1663
hBCU-6B1.1
CDR-H3

LGNNYGIWFAY

1664
hBCU-6B1.1 VL

DIQMTQSPSSLSASVGDRVTIECRASDDLYSTLAW

YQQKPGKSPKLLIFDANRLAAGVPSRFSGSGSGTD

YSLTISSLQPEDVATYFCQQYNKFPWTFGGGTKVE

IK

1665
hBCU-6B1.1
CDR-L1

RASDDLYSTLA

1666
hBCU-6B1.1
CDR-L2

DANRLAA

1667
hBCU-6B1.1
CDR-L3

QQYNKFPWT

1668
hBCU-6B1.2 VH

EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMY

WVKQAPGQGLEFMGWINTETGQPTYADDFKGRFTF

TLDTSTSTAYMELRSLRSDDTAVYFCARLGNNYGI

WFAYWGQGTLVTVSS

1669
hBCU-6B1.2
CDR-H1

GYTFTNYGMY

1670
hBCU-6B1.2
CDR-H2

WINTETGQPTYADDFKG

1671
hBCU-6B1.2
CDR-H3

LGNNYGIWFAY

1672
hBCU-6B1.2 VL

DIQMTQSPSSLSASVGDRVTIECRASDDLYSTLAW

YQQKPGKSPKLLIFDANRLAAGVPSRFSGSGSGTD

YSLTISSLQPEDVATYFCQQYNKFPWTFGGGTKVE

IK

1673
hBCU-6B1.2
CDR-L1

RASDDLYSTLA

1674
hBCU-6B1.2
CDR-L2

DANRLAA

1675
hBCU-6B1.2
CDR-L3

QQYNKFPWT

1676
hBCU-6B1.3 VH

EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMY

WVRQAPGQGLEFMGWINTETGQPTYADDFKGRFTF

TLDTSTSTAYMELRSLRSDDTAVYYCARLGNNYGI

WFAYWGQGTLVTVSS

1677
hBCU-6B1.3
CDR-H1

GYTFTNYGMY

1678
hBCU-6B1.3
CDR-H2

WINTETGQPTYADDFKG

1679
hBCU-6B1.3
CDR-H3

LGNNYGIWFAY

1680
hBCU-6B1.3 VL

DIQMTQSPSSLSASVGDRVTIECRASDDLYSTLAW

YQQKPGKSPKLLIFDANRLAAGVPSRFSGSGSGTD

YSLTISSLQPEDVATYFCQQYNKFPWTFGGGTKVE

IK

1681
hBCU-6B1.3
CDR-L1

RASDDLYSTLA

1682
hBCU-6B1.3
CDR-L2

DANRLAA

1683
hBCU-6B1.3
CDR-L3

QQYNKFPWT

1684
hBCU-6B1.4 VH

EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMY

WVRQAPGQGLEFMGWINTETGQPTYADDFKGRFTF

TLDTSTSTAYMELRSLRSDDTAVYYCARLGNNYGI

WFAYWGQGTLVTVSS

1685
hBCU-6B1.4
CDR-H1

GYTFTNYGMY

1686
hBCU-6B1.4
CDR-H2

WINTETGQPTYADDFKG

1687
hBCU-6B1.4
CDR-H3

LGNNYGIWFAY

1688
hBCU-6B1.4 VL

DIQMTQSPSSLSASVGDRVTITCRASDDLYSTLAW

YQQKPGKSPKLLIFDANRLAAGVPSRFSGSGSGTD

YTLTISSLQPEDVATYFCQQYNKFPWTFGGGTKVE

IK

1689
hBCU-6B1.4
CDR-L1

RASDDLYSTLA

1690
hBCU-6B1.4
CDR-L2

DANRLAA

1691
hBCU-6B1.4
CDR-L3

QQYNKFPWT

TABLE 30

VH and VL Amino Acid Sequences of Humanized Versions of

Rat Anti-Human PDGFR b Monoclonal Antibodies (CDRs in bold)

SEQ ID

Protein
V Region

NO:
Clone
Region
123456789012345678901234567890

1692
hBDE-3C9.1 VH

EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGMA

WVRQAPGKGLEWVASITNSGGNTYYRDSVKGRFTI

SRDNAKNTQYLQMNSLRAEDTAVYFCARHTPGANY

FDYWGQGTMVTVSS

1693
hBDE-3C9.1
CDR-H1

GFTFSNYGMA

1694
hBDE-3C9.1
CDR-H2

SITNSGGNTYYRDSVKG

1695
hBDE-3C9.1
CDR-H3

HTPGANYFDY

1696
hBDE-3C9.1 VL

DIQMTQSPSSLSASVGDRVTITCQASQSIKNYIAW

YQLKPGKAPRLLMRYTSTLESGTPSRFSGSGSGRD

YTFTISSLQPEDIATYYCVQYANLYTFGGGTKVEI

K

1697
hBDE-3C9.1
CDR-L1

QASQSIKNYIA

1698
hBDE-3C9.1
CDR-L2

YTSTLES

1699
hBDE-3C9.1
CDR-L3

VQYANLYT

1700
hBDE-3C9.2 VH

EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGMA

WVRQAPGKGLEWVASITNSGGNTYYRDSVKGRFTI

SRDNAKNSLYLQMNSLRAEDTAVYYCARHTPGANY

FDYWGQGTMVTVSS

1701
hBDE-3C9.2
CDR-H1

GFTFSNYGMA

1702
hBDE-3C9.2
CDR-H2

SITNSGGNTYYRDSVKG

1703
hBDE-3C9.2
CDR-H3

HTPGANYFDY

1704
hBDE-3C9.2 VL

DIQMTQSPSSLSASVGDRVTITCQASQSIKNYIAW

YQQKPGKAPRLLIRYTSTLESGVPSRFSGSGSGRD

YTFTISSLQPEDIATYYCVQYANLYTFGGGTKVEI

K

1705
hBDE-3C9.2
CDR-L1

QASQSIKNYIA

1706
hBDE-3C9.2
CDR-L2

YTSTLES

1707
hBDE-3C9.2
CDR-L3

VQYANLYT

Generation of Humanized Antibodies

All variants were cloned into pHybE vectors and were transiently transfected into 50 mls of HEK 2936e suspension cell cultures in a ratio of 60% to 40% light to heavy chain construct. 1 mg/ml PEI was used to transfect the cells. Cell supernatants were harvested after six days in shaking flasks, spun down to pellet cells, and filtered through 0.22 μm filters to separate IgG from culture contaminates. All were batch purified by adding 1 supernatant volume of protein A IgG binding buffer (Thermo Scientific 21001) and 1 ml of rProteinA sepharose fast flow beads (GE Healthcare, 17-1279-04). Supernatants, with beads and buffer added, were rocked overnight at 4° C., and the day after beads were collected by gravity over poly prep chromatography columns (Bio Rad, 731-1550). Once supernatants had passed through the columns the beads were washed with 10 column volumes of binding buffer, and IgG was eluted with Immunopure IgG elution buffer (Pierce, 185 1520) and collected in 1 ml aliquots. Fractions containing IgG were pooled and dialyzed in 15 mM Histidine pH 6 overnight at 4° C.

Purified variants were further characterized for their affinities for recombinant human target proteins by binding ELISA, by Biacore, and by cell-based potency assays.

TABLE 31

Summary of Protein Expression and Purification for

Humanized Anti-Human VEGF-A And Humanized

Anti-Human PDGF-BB Monoclonal Antibodies

Octet Titer
~Yield
SEC

Name
(mg/L)¹
(mg/L)²
(% monomer)³

hBDB-4G8.1
19.9
19.7
100.0

hBDB-4G8.2
105.3
95.8
100.0

hBDB-4G8.3
34.8
31.9
100.0

hBDB-4G8.4
45.8
34.2
100.0

hBDB-4G8.5
24.7
27.4
100.0

hBDB-4G8.6
28.6
34.2
100.0

hBDB-4G8.7
75.8
63.4
100.0

hBDB-4G8.8
145.9
101.4
100.0

hBDB-4G8.9
38.8
39.0
100.0

hBDB-4G8.10
40.7
32.9
89.1

hBDB-4G8.11
47.9
38.0
87.2

hBDB-4G8.12
37.5
38.3
100.0

hBDB-4G8.13
44.8
35.1
100.0

hBDB-4G8.14
73.0
47.0
100.0

hBDB-4G8.15
161.2
94.9
100.0

hBDI-5H1.1
49.8
38.7
100.0

hBDI-5H1.2
63.4
62.0
100.0

hBDI-5H1.3
94.2
86.5
99.1

hBDI-5H1.4
109.0
123.1
99.2

hBDI-5H1.5
23.0
27.7
100.0

hBDI-5H1.6
41.2
46.0
100.0

hBDI-5H1.7
9.6
9.6
88.1

hBDI-5H1.8
36.0
41.5
100.0

hBDI-5H1.9
56.0
60.2
85.6

hBDI-5H1.10
34.2
31.1
85.2

hBDI-5H1.11
41.0
34.4
96.3

hBDI-5H1.12
37.7
30.2
100.0

hBDI-9E8.1
90.0
72.4
100.0

hBDI-9E8.2
89.9
89.1
99.3

hBDI-9E8.3
28.8
24.4
97.1

hBDI-9E8.4
52.8
54.8
98.2

hBDI-9E8.5
78.0
57.7
100.0

hBDI-9E8.6
60.6
61.4
100.0

hBDI-9E8.7
30.4
27.9
88.1

hBDI-9E8.8
37.1
38.0
98.4

hBDI-9E8.9
50.3
44.9
94.6

hBDI-9E8.10
93.0
56.2
94.7

hBDI-9E8.11
78.4
52.7
99.1

hBDI-9E8.12
92.3
68.5
100.0

hBDI-5H1.13
13.6
10.5
88.1

hBDI-9E8.13
53.5
66.9
100.0

hBDI-1E1.1
133.5
ND
ND

hBDI-1E1.2
115.6
ND
ND

hBDI-1E1.3
83.4
ND
ND

hBDI-1E1.4
137.6
ND
ND

hBDI-1E1.5
97.4
ND
ND

hBDI-1E1.6
70.6
ND
ND

hBDI-1E1.7
91.9
ND
ND

hBDI-1E1.8
71.2
ND
ND

hBDI-1E1.9
94.3
ND
ND

hBDI-1E1.10
72.7
ND
ND

hBDI-1E1.11
57.4
ND
ND

hBDI-1E1.12
151.6
ND
ND

hBEW-9A8.1
0.2
ND
ND

hBEW-9A8.2
0.2
ND
ND

hBEW-9A8.3
0.2
ND
ND

hBEW-9A8.4
0.2
ND
ND

hBEW-9A8.5
0.5
ND
ND

hBEW-9A8.6
0.2
ND
ND

hBEW-9A8.7
0.3
ND
ND

hBEW-9A8.8
3.5
ND
ND

hBEW-9A8.9
15.3
18.6
ND

hBEW-9A8.10
5.2
ND
ND

hBEW-9A8.11
30.6
18.9
ND

hBEW-9A8.12
38.3
28.4
ND

hBEW-9A8.13
0.4
ND
ND

hBEW-9A8.14
0.3
ND
ND

hBEW-9A8.15
0.3
ND
ND

hBEW-9A8.16
3.2
ND
ND

hBEW-6C2.1
5.4
ND
ND

hBEW-6C2.2
1.5
ND
ND

hBEW-6C2.3
14.8
7.8
ND

hBEW-6C2.4
79.6
29.5
ND

hBEW-6C2.5
4.7
ND
ND

hBEW-6C2.6
3.9
ND
ND

hBEW-6C2.7
140.8
39.7
ND

hBEW-6C2.8
75.3
24.8
ND

hBDI-5H1.16
ND
23.9
93.4

hBDI-5H1.17
ND
21.0
92.1

hBFU-3E2.1
ND
40.2
88.1

hBFU-3E2.2
ND
34.6
93.6

hBFU-3E2.3
ND
33.6
84.2

hBFU-3E2.4
ND
38.4
94.7

hBEW-9A8.17
ND
20.0
98.7

hBEW-9A8.20
ND
17.6
86.6

hBEW-9A8.21
ND
13.3
97.5

hBEW-5C3.1
ND
20.8
85.0

hBEW-5C3.2
ND
17.7
74.6

hBEW-5C3.3
ND
6.9
93.7

hBEW-5C3.4
ND
32.0
88.7

hBEW-5C3.5
ND
30.6
85.1

hBEW-5C3.6
ND
19.4
75.4

hBEW-9E10.1
ND
42.7
98.0

hBEW-9E10.2
ND
46.1
98.0

hBEW-9E10.3
ND
45.9
97.6

hBEW-9E10.4
ND
47.1
98.0

hBEW-9E10.5
ND
56.2
97.9

hBEW-9E10.6
ND
52.9
97.6

hBEW-1B10.1
ND
34.1
97.8

hBEW-1B10.2
ND
45.3
98.1

hBEW-1E3.1
ND
29.6
95.5

hBEW-1E3.2
ND
20.9
98.3

hBEW-1E3.3
ND
22.0
98.5

hBEW-1E3.4
ND
48.0
98.1

hBEW-1E3.5
ND
23.8
98.5

hBEW-1E3.6
ND
17.0
98.7

ND = Not Determined

¹Octet titer is the amout of IgG in the unpurified supernatant as determined by protein A binding compared to a standard curve using an Octet instrument.

²Yield is determined by the total amount of purified protein in mg divided by the total cell culture volume in liters.

³SEC % monomer is determined using HPLC size exclusion chromatography.

Humanized anti-VEGF antibodies were tested for their binding to human VEGF-A according to the method described in Example 1.1. The on-rate, off-rate and binding kinetics are summarized in Table 32 below.

TABLE 32

Biacore Binding of Humanized Anti-VEGF Antibodies

Antibody
k_on(M−1 s−1)
k_off(M−1)
K_D(M)

hBDB-4G8.1
1.8E+07
1.0E−04
5.8E−12

hBDB-4G8.2
1.7E+07
6.2E−05
3.6E−12

hBDB-4G8.3
1.0E+07
4.8E−05
4.8E−12

hBDB-4G8.4
2.7E+07
1.5E−04
5.5E−12

hBDB-4G8.5
2.5E+07
4.0E−05
1.6E−12

hBDB-4G8.6
2.6E+07
3.7E−05
1.4E−12

hBDB-4G8.7
3.7E+07
1.3E−03
3.4E−11

hBDB-4G8.8
1.8E+07
8.6E−04
4.7E−11

hBDB-4G8.9
1.4E+07
8.8E−04
6.2E−11

hBDB-4G8.10
2.7E+07
2.2E−04
8.1E−12

hBDB-4G8.11
2.6E+07
3.4E−05
1.3E−12

hBDB-4G8.12
2.6E+07
3.2E−05
1.2E−12

hBDB-4G8.13
2.2E+07
1.7E−04
7.6E−12

hBDB-4G8.14
1.5E+07
5.6E−05
3.7E−12

hBDB-4G8.15
2.0E+07
8.7E−05
4.4E−12

hBEW-9A8.9
1.0E+07
8.2E−03
8.2E−10

hBEW-9A8.11
1.5E+07
1.1E−03
7.4E−11

hBEW-9A8.12
9.6E+06
1.4E−04
1.5E−11

hBEW-9A8.17
7.9E+06
1.4E−05
1.7E−12

hBEW-9A8.20
7.6E+06
1.2E−05
1.6E−12

hBEW-9A8.21
5.8E+06
3.9E−05
6.7E−12

hBEW-5C3.1
1.1E+07
6.9E−05
6.0E−12

hBEW-5C3.4
9.9E+06
8.5E−05
8.6E−12

hBEW-5C3.5
1.2E+07
9.7E−05
8.5E−12

hBEW-9E10.1
1.2E+07
2.5E−05
2.1E−12

hBEW-9E10.2
1.6E+07
1.9E−04
1.2E−11

hBEW-9E10.3
1.3E+07
4.2E−05
3.2E−12

hBEW-9E10.4
1.2E+07
2.5E−05
2.1E−12

hBEW-9E10.5
1.6E+07
2.3E−04
1.5E−11

hBEW-9E10.6
1.5E+07
4.0E−05
2.6E−12

hBEW-1B10.1
7.6E+06
1.4E−04
1.8E−11

hBEW-1B10.2
7.5E+06
1.5E−04
2.0E−11

hBEW-1E3.1
1.1E+07
8.5E−05
7.7E−12

hBEW-1E3.2
1.1E+07
1.0E−04
9.2E−12

hBEW-1E3.4
9.8E+06
9.6E−05
9.7E−12

hBEW-1E3.5
1.0E+07
1.0E−04
1.0E−11

Humanized anti-VEGF-A antibodies were tested for potency against hVEGF₁₆₅-induced cell proliferation in one of two cellular assay formats. The HMVEC-d bioassay utilizes cells which natively express VEGFR2 (Example 1.10). The VEGFR2-3T3 cells are stably transfected with VEGFR2 (Example 1.7). The data is summarized in Table 33 below.

TABLE 33

Summary of Characterization of Humanized

Anti-Human VEGF-A Monoclonal Antibodies.

hVEGF₁₆₅IC50 (nM)

VEGFR2-

Humanized Molecules
HMVEC-d
3T3

hBDB-4G8.1
NT
0.847

hBDB-4G8.2
NT
0.603

hBDB-4G8.3
NT
0.665

hBDB-4G8.3 half-body
NT
>10

hBDB-4G8.4
NT
0.918

hBDB-4G8.5
NT
0.620

hBDB-4G8.6
NT
0.488

hBDB-4G8.7
NT
>10

hBDB-4G8.8
NT
>10

hBDB-4G8.9
NT
>10

hBDB-4G8.10
NT
>10

hBDB-4G8.11
NT
0.385

hBDB-4G8.12
NT
0.563

hBDB-4G8.13
NT
0.791

hBDB-4G8.14
NT
0.499

hBDB-4G8.15
NT
0.963

hBEW-1B10.1
0.168
NT

hBEW-1B10.2
0.222
NT

hBEW-1E3.1
0.138
NT

hBEW-1E3.4
0.212
NT

hBEW-1E3.2
0.161
NT

hBEW-1E3.3
0.205
NT

hBEW-1E3.5
0.184
NT

hBEW-1E3.6
0.26
NT

hBEW-5C3.1
0.071
NT

hBEW-5C3.2
0.162
NT

hBEW-5C3.3
>2
NT

hBEW-5C3.4
0.098
NT

hBEW-5C3.5
0.123
NT

hBEW-5C3.6
>2
NT

hBEW-9A8.9
NT
>10

hBEW-9A8.11
NT
>10

hBEW-9A8.12
NT
0.598

hBEW-9A8.17
0.059
NT

hBEW-9A8.20
0.064
NT

hBEW-9A8.21
0.09
NT

hBEW-9E10.1
0.064
NT

hBEW-9E10.2
0.181
NT

hBEW-9E10.3
0.062
NT

hBEW-9E10.4
0.071
NT

hBEW-9E10.5
0.229
NT

hBEW-9E10.6
0.068
NT

NT = Not tested

Humanized anti-PDGF-BB antibodies were tested for their binding to human PDGF-BB according to the method described in Example 1.1. The on-rate, off-rate and binding kinetics are summarized in Table 34 below.

TABLE 34

Biacore Binding of Humanized Anti-PDGF Antibodies

Antibody
k_on(M−1 s−1)
k_off(M−1)
K_D(M)

hBDI-9E8.1
≧1.0E+07
5.6E−03
≦5.6E−10

hBDI-9E8.2
≧1.0E+07
5.1E−03
≦5.1E−10

hBDI-9E8.3
≧1.0E+07
6.5E−04
≦6.5E−11

hBDI-9E8.4
>1.0E+07
2.1E−04
≦2.1E−11

hBDI-9E8.5
≧1.0E+07
2.1E−03
≦2.1E−10

hBDI-9E8.6
≧1.0E+07
2.1E−03
≦2.1E−10

hBDI-9E8.7
≧1.0E+07
4.5E−04
≦4.5E−11

hBDI-9E8.8
≧1.0E+07
1.7E−04
≦1.7E−11*

hBDI-9E8.9
≧1.0E+07
1.5E−03
≦1.5E−10

hBDI-9E8.10
≧1.0E+07
1.8E−03
≦1.8E−10

hBDI-9E8.11
≧1.0E+07
7.4E−04
≦7.4E−11

hBDI-9E8.12
≧1.0E+07
2.1E−03
≦2.1E−10

hBDI-9E8.13
≧1.0E+07
1.0E−03*
≦1.0E−10*

hBDI-5H1.1
≧1.0E+07
4.1E−03
≦4.1E−10

hBDI-5H1.2
≧1.0E+07
1.9E−03
≦1.9E−10

hBDI-5H1.3
≧1.0E+07
4.5E−03
≦4.5E−10

hBDI-5H1.4
≧1.0E+07
1.4E−02
≦1.4E−09

hBDI-5H1.5
≧1.0E+07
1.7E−03
≦1.7E−10

hBDI-5H1.6
≧1.0E+07
8.2E−04
≦8.2E−11

hBDI-5H1.7
≧1.0E+07
2.9E−02*
≦2.9E−09*

hBDI-5H1.8
≧1.0E+07
7.2E−01*
≦7.2E−08*

hBDI-5H1.9
≧1.0E+07
3.1E−03
≦3.1E−10

hBDI-5H1.10
≧1.0E+07
2.3E−03
≦2.3E−10

hBDI-5H1.11
≧1.0E+07
3.7E−03
≦3.7E−10

hBDI-5H1.12
≧1.0E+07
2.3E−03
≦2.3E−10

hBDI-5H1.13
≧1.0E+07
4.9E−03*
≦4.9E−10*

*Heterogeneous off-rate

Humanized anti-PDGF-BB antibodies were tested for potency against hPDGF-BB in functional assays. The ability to neutralize hPDGF-BB-induced cell proliferation was assessed (Example 1.15) as well as the ability to block binding of hPDGF-BB to hPDGF-Rβ in a competition ELISA format (Example 1.13). The data is summarized in Table 35 below.

TABLE 35

Summary of Characterization of Humanized

Anti-Human PDGF-BB Monoclonal Antibodies

hPDGF-

BB/hPDGFRβ

hPDGF-BB
Competition

Humanized Molecules
IC50 (nM)
IC50 (nM)

hBDI-9E8.1
>5
+

hBDI-9E8.2
>5
+

hBDI-9E8.3
1.583
+

hBDI-9E8.4
0.061
4.301

hBDI-9E8.4 half body
>5
NT

hBDI-9E8.5
>5
+

hBDI-9E8.6
>5
+

hBDI-9E8.7
0.350
+

hBDI-9E8.8
0.105
+

hBDI-9E8.9
0.574
+

hBDI-9E8.10
0.562
+

hBDI-9E8.11
0.309
1.730

hBDI-9E8.12
0.525
+

hBDI-5H1.1
<10
+

hBDI-5H1.2
<10
+

hBDI-5H1.3
<10
−

hBDI-5H1.4
<10
−

hBDI-5H1.9
<10
+

hBDI-5H1.10
<10
−

hBDI-5H1.11
<10
−

hBDI-5H1.12
<10
−

hBDI-5H1.5
<10
+

hBDI-5H1.6
<10
+

hBDI-5H1.7
<10
−

hBDI-5H1.8
<10
−

hBDI-5H1.13
<10
+

hBDI-5H1.16
<10
NT

hBDI-5H1.17
<10
NT

hBFU-3E2.1
0.183
NT

hBFU-3E2.2
0.659
NT

hBFU-3E2.3
0.335
NT

hBFU-3E2.4
0.571
NT

NT—Not tested

Humanized anti-VEGFR2 antibodies were tested for potency against hVEGFR2 in functional assay formats. The antibodies were characterized for the ability to block VEGFR2 binding to hVEGF₁₆₅in a competition ELISA format (Example 1.22). The antibodies were also tested for the ability to bind exogeneous hVEGFR2 and allow signaling in response to hVEGF₁₆₅(Example 1.23). The data is summarized in Table 36 below.

TABLE 36

Summary of Characterization of Humanized

Anti-Human VEGFR II Monoclonal Antibodies.

Potency (nM)

hVEGF₁₆₅/
hVEGF₁₆₅/

Humanized
hVEGFR2-Fc
Tyr1054

Molecules
Competition
phospho-assay

hBCU-6B1.1
0.474
NT

hBCU-6B1.2
0.340
NT

hBCU-6B1.3
0.319
NT

hBCU-6B1.4
0.335
NT

NT—Not tested

Humanized anti-PDGF-Rβ antibodies were characterized for activity in functional assays. Antibodies were assessed for the ability to bind hPDGF-Rβ (Example 1.26) and block binding of hPDGF-Rβ to hPDGF-BB in a competition ELISA format (Example 1.27). They were also tested for the ability to bind exogenoeous hPDGF-Rβ and allow signaling in response to hPDGF-BB (Example 1.28). The data is summarized in Table 37 below.

TABLE 37

Summary of Characterization of Humanized

Anti-Human PDGFR-B Monoclonal Antibodies

Potency (nM)

hPDGF-BB/
hPDGF-BB

hPDGFRβ-Fc
hPDGFRβ-Fc
Tyr751

Humanized Molecules
Binding
Competition
phospho-assay

hBDE-3C9.1
NT
0.217
1.053

hBDE-3C9.2
NT
0.260
0.882

NT—Not tested

Example 7
Affinity Maturation of Anti-Human VEGF-A Antibody 4G8
Library Designs And Strategy

Two different hBDB-4G8.3 parental sequences were made: One with “DT” and another with “EI” at the beginning of VL. Both parentals were tested as scFv, and the “EI” was chosen as the template for the libraries. Two libraries were made by dope primers: HC and LC. After library selection and diversity reduction, libraries were combined into one recombined library (rHC+LC). Final selected clones from each of 3 libraries were converted to IgG.

HC Library

- Doping (X) 11 residues at 76080808: 30, 31, 33, 53, 56, 58, 95, 96, 100, 100a and 100c
- Co-evolve (1): D61Q/D62G/K64T. Library will contain DDFKG (SEQ ID NO: 1708) or QGFTG (SEQ ID NO: 1709)

A 10⁹library will be able to sample mutants carrying up to 4 doped residues at least 4 times. On average, library members will have 5 doped residues.

LC Library

- Doping (X) 10 residues at 76080808: 30, 31, 32, 50, 53, 91-94 and 96
- Germline toggle (Z): E27Q, V58I and F87Y
- Co-evolve (1): M33L/H34A. Library will contain HMHW (SEQ ID NO: 1710) or YLAW (SEQ ID NO: 1711)

A 10⁹library will be able to sample mutants carrying up to 4 doped residues at least 4 times. On average, library members will have 5 doped residues.

Recombined Library

H1+H2 library is recombined with H3 library into a HC library. HC library is combined with LC library for a total recombined library rHC+LC.

Codons Specified for Residues To Be Doped

For instance, if a proline is to be doped, the doping oligo will have C_(5-85-5-5)C_(5-85-5-5)S codon regardless of the original codon in the antibody sequence. These codons are selected based on the following criteria: Increase non-synonymous mutation; increase coverage of more amino acids when mutated; and uses high frequency codons and avoid SSS and WWW codons

Doping Order is A-C-G-T

A_{(70-10-10-10)}
C_{(10-70-10-10)}
G_{(10-10-70-10)}
T_{(10-10-10-70)}

Alanine (A):

GCN
G_{(10-10-70-10)}C_{(10-70-10-10)}S

Threonine (T):

ACN
A_{(70-10-10-10)}C_{(10-70-10-10)}S

Proline (P):

CCN
C_{(10-70-10-10)}C_{(10-70-10-10)}S

Serine (S):

TCN
T_{(10-10-10-70)}C_{(10-70-10-10)}S

AGY
A_{(70-10-10-10)}G_{(10-10-70-10)}C_{(10-70-10-10)}

Valine (V):

GTN
G_{(10-10-70-10)}T_{(10-10-10-70)}S

Glycine (G):

GGN
G_{(10-10-70-10)}G_{(10-10-70-10)}S

Leucine (L):

CTN
C_{(10-70-10-10)}T_{(10-10-10-70)}S

TTR
T_{(10-10-10-70)}T_{(10-10-10-70)}G_{(10-10-70-10)}

Arginine (R):

CGN
C_{(10-70-10-10)}G_{(10-10-70-10)}S

AGR
A_{(70-10-10-10)}G_{(10-10-70-10)}G_{(10-10-70-10)}

Methionine (M):

ATG
A_{(70-10-10-10)}T_{(10-10-10-70)}G_{(10-10-70-10)}

Tryptophan (W):

TGG
T_{(10-10-10-70)}G_{(10-10-70-10)}G_{(10-10-70-10)}

Pheylalanine (F):

TTY
T_{(10-10-10-70)}T_{(10-10-10-70)}C_{(10-70-10-10)}

Isoleucine (I):

50% ATY
A_{(70-10-10-10)}T_{(10-10-10-70)}C_{(10-70-10-10)}

50% ATA
A_{(70-10-10-10)}T_{(10-10-10-70)}A_{(70-10-10-10)}

Tyrosine (Y):

TAY
T_{(10-10-10-70)}A_{(70-10-10-10)}C

Histidine (H):

CAY
C_{(10-70-10-10)}A_{(70-10-10-10)}C_{(10-70-10-10)}

Glutamine (Q):

CAR
C_{(10-70-10-10)}A_{(70-10-10-10)}G_{(10-10-70-10)}

Asparagine (N):

AAY
A_{(70-10-10-10)}A_{(70-10-10-10)}C_{(10-70-10-10)}

Lysine (K):

AAR
A_{(70-10-10-10)}A_{(70-10-10-10)}G_{(10-10-70-10)}

Aspartic Acid (D):

GAY
G_{(10-10-70-10)}A_{(70-10-10-10)}C_{(10-70-10-10)}

Glutamic acid (E):

GAR
G_{(10-10-70-10)}A_{(70-10-10-10)}G_{(10-10-70-10)}

Cysteine (C):

TGY
NNS

List of Amino Acid Sequences of Affinity Matured H4g8.3 VH Variants.

Table 38 provides a list of amino acid sequences of unique, functional VH regions of affinity matured humanized anti-VEGF antibodies derived from hBDB-4G8.3. Amino acid residues of individual CDRs of each VH sequence are indicated in bold.

TABLE 38

List of Amino Acid Sequences of

Affinity Matured H4g8.3 VH Variants

Clone
SEQ ID NO:
VH

CL-27663
1712
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYRMYWVRQAPGQGL

EWMGWINTETGXPAYADDFKRRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTKYYYSSYIFYFDYWGQGTMVTVSS

CL-27664
1713
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYSMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTKYYYRFYLFYFDYWGQGTMVTVSS

CL-27665
1714
EVQLVQSGSELKKPGASVKVSCKASGYTFTYYGMYWVRQAPGQGL

EWMGWINTKTGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYGSYIFYFDYWGQGTMVTVSS

CL-27666
1715
EVQLVQSGSELKKPGASVKVSCKASGYTFINYRMYWVRQAPGQGL

EWMGWINTETGKPVYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYKFYFDYWGQGTMVTVSS

CL-27667
1716
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYAMYWVRQAPGQGL

EWMGWINTETGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTIYYYXKYIFYFDYWGQGTMVTVSS

CL-27668
1717
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARPTYYYWIYIFYFDYWGQGTMVTVSS

CL-27669
1718
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYCMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARRNYYYXCYIFYFDYWGQGTMVTVSS

CL-27670
1719
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYDMYWVRQAPGQGL

EWMGWINTVTGSPAYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTTYYYCSYTFYFDYWGQGTMVTVSS

CL-27671
1720
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTGTGXPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARXNYYYXSYXFYFDYWGQGTMVTVSS

CL-27672
1721
EVQLVQSGSELKKPGASVKVSCKASGYTFSKYGMYWVRQAPGQGL

EWMGWINTYTGKPLYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYMGYRFYFDYWGQGTMVTVSS

CL-27673
1722
EVQLVQSGSELKKPGASVKVSCKASGYTFTPYGMYWVRQAPGQGL

EWMGWINTETGVPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYRSYRFYFDYWGQGTMVTVSS

CL-27674
1723
EVQLVQSGSELKKPGASVKVSCKASGYTFINYVMYWVRQAPGQGL

EWMGWINTATGXPSYAQGFTGRFVFSFDTSVSTTYLQISSLKAED

TAVYYCARTTYYYRRYIFYFDYWGQGTMVTVSS

CL-27675
1724
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYDMYWVRQAPGQGL

EWMGWINTATGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTLYYYRRYIFYFDYWGQGTMVTVSS

CL-27676
1725
EVQLVQSGSELKKPGASVKVSCKASGYTFIKYGMYWVRQAPGQGL

EWMGWINTETGRPAYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARIRYYYGSYIFYFDYWGQGTMVTVSS

CL-27677
1726
EVQLVQSGSELKKPGASVKVSCKASGYTFKNYEMYWVRQAPGQGL

EWMGWINTETGKPRYADDFKGRFVFSLDTSVNTAYLQISSLKAED

TAVYYCARTNYYYRSYVFYFDYWGQGTMVTVSS

CL-27678
1727
EVQLVQSGSELKKPGASVKVSCKASGYTFPLYSMYWVRQAPGQGL

EWMGWINTHTGNPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYTFYFDYWGQGTMVTVSS

CL-27679
1728
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTATGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARMNYYYRSYIFYFDYWGQGTMVTVSS

CL-27680
1729
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYCMYWVRQAPGQGL

EWMGWINTETGKPLYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARRNYYYGGYIFYFDYWGQGTMVTVSS

CL-27681
1730
EVQLVQSGSELKKPGASVKVSCKASGYTFTXYGMYWVRQAPGQGL

EWMGWINTQTGPPPYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTYYYYRWYIFYFDYWGQGTMVTVSS

CL-27682
1731
EVQLVQSGSELKKPGASVKVSCKASGYTFTIYEMYWVRQAPGQGL

EWMGWINTETGTPPYAXDFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARXXYYYXSYIFYFDYWGQGTMVTVSS

CL-27683
1732
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYVMYWVRQAPGQGL

EWMGWINTDTGNPAYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTTYYYRVYMFYFDYWGQGTMVTVSS

CL-27685
1733
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYCMYWVRQAPGQGL

EWMGWINTATGNPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYASYIFYFDYWGQGTMVTVSS

CL-27686
1734
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYAMYWVRQAPGQGL

EWMGWINTPTGMPNYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTSYYYSSYLFYFDYWGQGTMVTVSS

CL-27687
1735
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTDTGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTEYYYRSYIFYFDYWGQGTMVTVSS

CL-27688
1736
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYEMYWVRQAPGQGL

EWMGWINTATGKPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTIYYYVRYIFYFDYWGQGTMVTVSS

CL-27689
1737
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGTPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTVYYYRSYLFYFDYWGQGTMVTVSS

CL-27690
1738
EVQLVQSGSELKKPGASVKVSCKASGYTFATYGMYWVGQAPGQGL

EWMGWINTETGMPAYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARIRYYYGRYLFYFDYWGQGTMVTVSS

CL-27691
1739
EVQLVQSGSELKKPGASVKVSCKASGYTFSIYYMYWVRQAPGQGL

EWMGWINTGTGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTSYYYRSYLFYFDYWGQGTMVTVSS

CL-27692
1740
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYAMYWVRQAPGQGL

EWMGWINTQTGKPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARPQYYYTSYIFYFDYWGQGTMVTVSS

CL-27694
1741
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTXTGXPTYAXDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARXXYYYRSYXFYFDYWGQGTMVTVSS

CL-27695
1742
EVQLVQSGSELKKPGASVKVSCKASGYTFTYYNMYWVRQAPGQGL

EWMGWINTATGSPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSTYYYRSYIFYFDYWGQGTMVTVSS

CL-27696
1743
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYGMYWVRQAPGQGL

EWMGWINTQTGKPRYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYWSYIFYFDYWGQGTMVTVSS

CL-27697
1744
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYPMYWVRQAPGQGL

EWMGWINTETGXPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARXXYYYXRYIFYFDYWGQGTMVTVSS

CL-27699
1745
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYDMYWVRQAPGQGL

EWMGWINTATGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRSYLFYFDYWGQGTMVTVSS

CL-27700
1746
EVQLVQSGSELKKPGASVKVSCKASGYTFAHYGMYWVRQAPGQGL

EWMGWINTETGNPDYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRCYIFYFDYWGQGTMVTVSS

CL-27701
1747
EVQLVQSGSELKKPGASVKVSCKASGYTFTIYGMYWVRQAPGQGL

EWMGWINTETGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRCYMFYFDYWGQGTMVTVSS

CL-27702
1748
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTVTGAPIYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYWGYRFYFDYWGQGTMVTVSS

CL-27703
1749
EVQLVQSGSELKKPGASVKVSCKASGYTFRSYVMYWVRQAPGQGL

EWMGWINTDTGTPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARPYYYYRRYIFYFDYWGQGTMVTVSS

CL-27704
1750
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYCMYWVRQAPGQGL

EWMGWINTKTGNPAYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARXIYYYRRYVLYFDYWGQGTMVTVSS

CL-27705
1751
EVQLVQSGSELKKPGASVKVSCKASGYTFANYSMYWVRQAPGQGL

EWMGWINTETGKPKYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRRYSFYFDYWGQGTMVTVSS

CL-27706
1752
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYCMYWVRQAPGQGL

EWMGWINTTTGKPNYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYRRYLFYFDYWGQGTMVTVSS

CL-27708
1753
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTMTGKPNYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTDYYYRSYDFYFDYWGQGTMVTVSS

CL-27709
1754
EVQLVQSGSELKKPGASVKVSCKASGYTFPKYAMYWVRQAPGQGL

EWMGWINTETGXPRYAHDFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRGYIFYFDYWGQGTMVTVSS

CL-27710
1755
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYVMYWVRQAPGQGL

EWMGWINTETGTPMYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARRDYYYRRYVFYFDYWGQGTMVTVSS

CL-27711
1756
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYDMYWVRQVPGQGL

EWMGWVNTDTGKPPYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSKYYYWTYVFYFDYWGQGTMVTVSS

CL-27712
1757
EVQLVQSGSELKKPGASVKVSCKASGYTFTYYDMYWVRQAPGQGL

EWMGWINTXTGKPIYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTIYYYGRYSFYFDYWGQGTMVTVSS

CL-27713
1758
EVQLVQSGSELKKPGASVKVSCKASGYTFPFYVMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRRYIFYFDYWGQGTMVTVSS

CL-27714
1759
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYSMYWVRQAPGQGL

EWMGWINTKTGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTIYYYMCYVFYFDYWGQGTMVTVSS

CL-27715
1760
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGNPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARKHYYYGSYLFYFDYWGQGTMVTVSS

CL-27716
1761
EVQLVQSGSELKKPGASVKVSCKASGYTFPDYDMYWVRQAPGQGL

EWMGWINTETGMPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRGYIFYFDYWGQGTMVTVSS

CL-27717
1762
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTDTGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTYYYYKKYIFYFDYWGQGTMVTVSS

CL-27718
1763
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTGTGRPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTQYYYRRYIFYFDYWGQGTMVTVSS

CL-27719
1764
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL

EWMGWINTKTGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARKNYYYKSYVFYFDYWGQGTMVTVSS

CL-27721
1765
EVQLVQSVSELKKPGASVKVSCKASGYTFTKYTMYWVRQAPGQGL

EWMGWINTETGNPMYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRIYIFYFDYWGQGTMVTVSS

CL-27722
1766
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTATGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSSYYYRNYIFYFDYWGQGTMVTVSS

CL-27723
1767
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTVTGKPDYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARQKYYYRSYFFYFDYWGQGTMVTVSS

CL-27725
1768
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYDMYWVRQAPGQGL

EWMGWINTDTGKPAYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARPSYYYVXYIFYFDYWGQGTMVTVSS

CL-27726
1769
EVQLVQSGSELKKPGASVKVSCKASGYTFTLYXMYWVRQAPGQGL

EWMGWINTATGKPTYAHDFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTXYYYRSYIFYFDYWGQGTMVTVSS

CL-27727
1770
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYGMYWVRQAPGQGL

EWMGWINTHTGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRCYIFYFDYWGQGTMVTVSS

CL-27728
1771
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGKPEYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARPNYYYRSYFFYFDYWGQGTMVTVSS

CL-27729
1772
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGRPGYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARLWYYYWMYIFYFDYWGQGTMVTVSS

CL-27730
1773
EVQLVQSGSELKKPGASVKVSCKASGYTFTYYGMYWVRQAPGQGL

EWMGWINTETGTPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARVYYYYGSYSFYFDYWGQGTMVTVSS

CL-27731
1774
EVQLVQSGSELKKPGASVKVSCKASGYTFVNYAMYWVRQAPGQGL

EWMGWINTXTGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARKTYYYRGYIFYFDYWGQGTMVTVSS

CL-27733
1775
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYYMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSKYYYRSYTFYFDYWGQGTMVTVSS

CL-27734
1776
EVQLVQSGSELKKPGASVKVSCKASGYTFLHYGMYWVRQAPGQGL

EWMGWINTETGWPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTSYYYVSYIFYFDYWGQGTMVTVSS

CL-27735
1777
EVQLVQSGSELKKPGASVKVSCKASGYTFTIYGMYWVRQAPGQGL

EWMGWINTATGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTXYYYRSYVFYFDYWGQGTMVTVSS

CL-27736
1778
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGNPIYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARAHYYYRTYXFYFDYWGQGTMVTVSS

CL-27737
1779
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGNPIYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARAHYYYRTYNFYFDYWGQGTMVTVSS

CL-27738
1780
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYWMYWVRQAPGQGL

EWMGWINTETGRPRYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARVYYYYRCYSFYFDYWGQGTMVTVSS

CL-27739
1781
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYWMYWVRQAPGQGL

EWMGWINTETGTPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTTYYYRSYIFYFDYWGQGTMVTVSS

CL-27741
1782
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYGMYWVRQAPGQGL

EWMGWINTNTGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARAYYYYWSYIFYFDYWGQGTMVTVSS

CL-27742
1783
EVQLVQSGSELKKPGASVKVSCKASGYTFTSYVMYWVRQAPGQGL

EWMGWINTKTGMPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTTYYYMSYIFYFDYWGQGTMVTVSS

CL-27744
1784
EVQLVQSGSELKKPGASVKVSCKASGYTFTQYGMYWVRQAPGQGL

EWMGWINTETGKPKYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYWSYKFYFDYWGQGTMVTVSS

CL-27747
1785
EVQLVQSGSELKKPGASVKVSCKASGYTFSTYMMYWVRQAPGQGL

EWMGWINTETGXPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYRSYIFYFDYWGQGTMVTVSS

CL-27750
1786
EVQLVQSGSELKKPGASVKVSCKASGYTFMNYVMYWVRQAPGQGL

EWMGWINTKTGMPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYMRYIFYFDYWGQGTMVTVSS

CL-27751
1787
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYGMYWVRQAPGQGL

EWMGWINTQTGEPPYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTGYYYWNYLFYFDYWGQGTMVTVSS

CL-27752
1788
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYRMYWVRQAPGQGL

EWMGWINTETGKPPYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYMSYIFYFDYWGQGTMVTVSS

CL-27753
1789
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGSPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYVSYIFYFDYWGQGTMVTVSS

CL-27755
1790
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGXPTYAHDFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARXNYYYXXYIFYFDYWGQGTMVTVSS

CL-27756
1791
EVQLVQSGSELKKPGASVKVSCKASGYTFTIYGMYWVRQAPGQGL

EWMGWINTDTGRPIYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARIIYYYCSYIFYFDYWGQGTMVTVSS

CL-27757
1792
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL

EWMGWINTETGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS

CL-27758
1793
EVQLVQSGSELKKPGASVKVSCKASGYTFSLYAMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGQFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYNFYFDYWGQGTMVTVSS

CL-27760
1794
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS

CL-27824
1795
EVQLVQSGSELNXPGASLKVSCKASGYTFXNYGXYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS

CL-27833
1796
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGIYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS

CL-29884
1797
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRLYMFYFDYWGQGTMVTVSS

CL-29885
1798
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYQSYMFYFDYWGQGTMVTVSS

CL-29887
1799
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL

EWMGWINTETGEPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-29888
1800
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRTYMFYFDYWGQGTMVTVSS

CL-29889
1801
EVQLVQSGSELKKPGASVKVSCKASGYTFADYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYRTYMFYFDYWGQGTMVTVSS

CL-29890
1802
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYGMYWVRQAPGQGL

EWMGWINTETGXPTYAXDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARRXYYYXSYXFYFDYWGQGTMVTVSS

CL-29891
1803
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-29892
1804
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTETGQPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-29893
1805
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARVNYYYRNYMFYFDYWGQGTMVTVSS

CL-29895
1806
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARVNYYYMSYMFYFDYWGQGTMVTVSS

CL-29896
1807
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRMYMFYFDYWGQGTMVTVSS

CL-29897
1808
EVQLVQSGSELKKPGASVKVSCKASGYTFLNYGMYWVRQAPGQGL

EWMGWINTETGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTKYYYWRYIFYFDYWGQGTMVTVSS

CL-29898
1809
EVQLVQSGSELKKPGASVKVSCKASGYTFNDYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-29899
1810
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARINYYYRSYMFYFDYWGQGTMVTVSS

CL-29901
1811
EVQLVQSGSELKKPGASVKVSCKASGYTFMNYGMYWVRQAPGQGL

EWMGWIDTETGXXXYAHDFTGRFVFSLDTSVSTAYLEISSLKAED

TAVYYCARXNYYYXXYMFYFDYWGQGTMVTVSS

CL-29902
1812
EVQLVQSGSELKKPGASVKVSCKASGYTFTSYGMYWVRQAPGQGL

EWMGWINTETGQPMYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARRIYYYRCYLFYFDYWGQGTMVTVSS

CL-29904
1813
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTDTGMPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS

CL-29906
1814
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS

CL-29907
1815
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGEPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYRSYMFYFDYWGQGTMVTVSS

CL-29908
1816
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS

CL-29909
1817
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS

CL-29910
1818
EVQLVQSGSELKKPGASVKVSCKASGYTFNYYGMYWVRQAPGQRL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYESYMFYFDYWGQGTMVTVSS

CL-29912
1819
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-29913
1820
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYRMYWVRQAPGQGL

EWMGWINTVTGKPKYADDFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARFKYYYGSYFFYFDYWGQGTMVTVSS

CL-29914
1821
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-29915
1822
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS

CL-29916
1823
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-29917
1824
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL

EWMGWIDTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPRYMFYFDYWGQGTMVTVSS

CL-29918
1825
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTDTGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYASYMFYFDYWGQGTMVTVSS

CL-29919
1826
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYQSYMFYFDYWGQGTMVTVSS

CL-29921
1827
EVQLVQSGSELKKPGASVKVSCKASGYTFSHYGMYWVRQAPGQGL

EWMGWINTETGSPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-29922
1828
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-29924
1829
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-29925
1830
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTETGEPTYAXGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-29926
1831
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYTSYMFYFDYWGQGTMVTVSS

CL-29927
1832
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRMYMFYFDYWGQGTMVTVSS

CL-29928
1833
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGEPYYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPKYMFYFDYWGQGTMVTVSS

CL-29929
1834
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYWMYWVRQAPGQGL

EWMGWINTETGKPAYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYIYYLFYFDYWGQGTMVTVSS

CL-29931
1835
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL

EWMGWINTGTGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS

CL-29932
1836
EVQLVQSGSELKKPGASVKVSCKASGYTFTPYGMYWVRQAPGQGL

EWMGWINTDTGXPPYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYTCYIFYFDYWGQGTMVTVSS

CL-29934
1837
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYWVRQAPGQGL

EWMGWINTETGXPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPRYMFYFDYWGQGTMVTVSS

CL-29935
1838
EVQLVQSGSELKKPGASVKVSCKASGYTFPDYGMYWVRQAPGQGL

EWMGWIDTETGMPXYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS

CL-29936
1839
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-29937
1840
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARXNYYYRXYMFYFDYWGQGTMVTVSS

CL-29938
1841
EVQLVQSGSELKKPGASVKVSCKASGYTFNKYDMYWVRQAPGQGL

EWMGWINTKTGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTAYYYRNYKSTLITGGQGTMVTVSS

CL-29939
1842
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYKGYMFYFDYWGQGTMVTVSS

CL-29940
1843
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTYYYYRTYIFYFDYWGQGTMVTVSS

CL-29941
1844
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS

CL-29942
1845
EVQLVQSGSELKKPGASVKVSCKASGYNFTKYEMYWVRQAPGQGL

EWMGWINTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTKYYYRSYVFYFDYWGQGTMVTVSS

CL-29943
1846
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYLSYMFYFDYWGQGTMVTVSS

CL-29946
1847
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYWVRQAPGQGL

EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-29947
1848
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTDTGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRTYMFYFDYWGQGTMVTVSS

CL-29948
1849
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-29949
1850
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARVNYYYRSYMFYFDYWGQGTMVTVSS

CL-29950
1851
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTQTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYRLYMFYFDYWGQGTMVTVSS

CL-29951
1852
EVQLVQSGSELKKPGASVKVSCKASGYTFPDYGMYWVRQAPGQGL

EWMGWIDTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARADYYYPTYMFYFDYWGQGTMVTVSS

CL-29952
1853
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPTYMFYFDYWGQGTMVTVSS

CL-29955
1854
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYRSYMFYFDYWGQGTMVTVSS

CL-29957
1855
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTVTGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTHYYYRTYLFYFDYWGQGTMVTVSS

CL-29958
1856
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-29959
1857
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS

CL-29960
1858
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYSMYWVRQAPGQGL

EWMGWINTXTGKPIYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTKYYYRTYRFYFDYWGQGTMVTVSS

CL-29961
1859
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWIDTETGTPVYADDFKGRFVFSLDTSVNTAYLQISSLKAED

TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS

CL-29962
1860
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYSSYMFYFDYWGQGTMVTVSS

CL-29963
1861
EVQLVQSGSELKKPGASVKVSCKASGYTFSEYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-29966
1862
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARVNYYYRWYMFYFDYWGQGTMVTVSS

CL-29967
1863
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL

EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-29968
1864
EVQLVQSGSELKKPGASVKVSCKAYGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYEKYMFYFDYWGQGTMVTVSS

CL-29969
1865
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYRGYMFYFDYWGQGTMVTVSS

CL-29970
1866
EVQLVQSGSELKKPGASVKVSCKASGYTFMTYVMYWVRQAPGQGL

EWMGWINTETGKPSYAHDFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARMXYYYXIYMFYFDYWGQGTMVTVSS

CL-29971
1867
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-29972
1868
EVQLVQSGSELKKPGASVKVSCNASGXTFTNYGMYWVRQAPGQGL

EWMGWINTETGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARINYYYRSYIFYFDYWGQGTMVTVSS

CL-29973
1869
EVQLVQSGSELKKPGASVKVSCKASGYTFNDYGMYWVRQAPGQGL

EWMGWINTETGEPTYAXXFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYEGYMFYFDYWGQGTMVTVSS

CL-29974
1870
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-29975
1871
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS

CL-29976
1872
EVQLVQSGSELRKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL

EWMGWIDTETGRPWYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYQGYMFYFDYWGQGTMVTVSS

CL-29980
1873
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMHWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS

CL-30036
1874
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSHIFYFDYWGQGTMVTVSS

CL-30060
1875
EVQLVQSGSELKKPGASVRVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS

CL-30075
1876
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTXTGKPTYAXGFTGRFVFSLDTSVSTAYLQIXXLXAXD

TAVYYCARXKYYYXSYIFYFDYWGQGTMVTVSS

CL-30076
1877
EVQLVQSGSELKKPGASVKVSCKASGYTFYNYCMYWVRQAPGQGL

EWMGWINTETGIPKYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARINYYYKRYIFYFDYWGQGTMVTVSS

CL-30077
1878
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYYMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTXYYYXRYXFYFDYWGQGTMVTVSS

CL-30078
1879
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVFS

CL-30079
1880
EVQLVQSGSELKKPGASVKVSCKASGYTFIHYGMYWVRQAPGQGL

EWMGWINTETGRPTYADDFKGRFVFSLDTSVSTAYLQISSLKXED

TAVYYCARTVYYYPRYTFYFDYWGQGTMVTVSS

CL-30082
1881
EVQLVQSGSELKKPGASVKVSCKASGYTFMNYGMYWVRQAPGQGL

EWMGWINTETGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPGYIFYFDYWGQGTMVTVSS

CL-30083
1882
EVQLVQSGSELKKPGASVKVSCKASGYTFTLYGMYWVRQAPGQGL

EWMGWINTDTGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYXSYIFYFDYWGQGTMVTVSS

CL-30084
1883
EVQLVQSGSELKKPGASVKVSCKASGYTFNKYGMYWVRQAPGQGL

EWMGWINTETGKPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARAKYYYRSYIFYFDYWGQGTMVTVSS

CL-30086
1884
EVQLVQSGSELKKPGASVKVSCKASGYTFLNYGMYWVRQAPGQGL

EWMGWINTETGRPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRIYRFYFDYWGQGTMVTVSS

CL-30087
1885
EVQLVQSGSELKKPGASVKVSCKASGYTFYNYGMYWVRQAPGQGL

EWMGWINTATGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARXKYYYXSXXFYFDYWGQGTMVTVSS

CL-30091
1886
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYDMYWVRQAPGQGL

EWMGWINTVTGLPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTIYYYKSYIFYFDYWGQGTMVTVSS

CL-30092
1887
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTGTGIPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTSYYYRNYLFYFDYWGQGTMVTVSS

CL-30093
1888
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYGMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTTYYYRRYIFYFDYWGQGTMVTVSS

CL-30096
1889
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYAMYWVRQAPGQGL

EWMGWINTETGKPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRSYIFYFDYWGQGTMVTVSS

CL-30097
1890
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQIXXLKTED

TAVYYCARSNYYYRGYIFYFDYWGQGTMVTVSS

CL-30103
1891
EVQLVQSGSELKKPGASVKVSCKASGYTFAIYRMYWVRQAPGQGL

EWMGWINTDTGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSKYYYGFYMFYFDYWGQGTMVTVSS

CL-30107
1892
EVQLVQSGSELKKPGASVKVSCKASGYTFMNYGMYWVRQAPGQGL

EWMGWINTETGRPVYAQGFTGRFVFSLDTSVSTAYLQISSLKAXD

TAVYYCARTNYYYLRYVFYFDYWGQGTMVTVSS

CL-30108
1893
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTGTGMPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARNKYYYRSYMFYFDYWGQGTMVTVSS

CL-30110
1894
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYDMYWVRQAPGQGL

EWMGWINTETGKPPYADGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS

CL-30113
1895
EVQLVQSGSELKKPGASVKVSCKASGYTFTSYGMYWVRQAPGQGL

EWMGWINTETGIPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARWDYYYTSYKFYFDYWGQGTMVTVSS

CL-30114
1896
EVQLVQSGSELKKPGASVKVSCKASGYTFTIYGMYWVRQAPGQGL

EWMGWINTVTGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTEYYYMNYIFYFDYWGQGTMVTVSS

CL-30116
1897
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYDMYWVRQAPGQGL

EWMGWINTGTGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYSRYDFYFDYWGQGTMVTVSS

CL-30119
1898
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYGMYWVRQAPGQGL

EWMGWINTQTGKPAYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARAIYYYRIYIFYFDYWGQGTMVTVSS

CL-30124
1899
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYAMYWVRQAPGQGL

EWMGWINTQTGEPSYAQGFTGXFVFSLDTSASTEYLXISILXDXD

TAVYYCARXTYYYXNYIFYFDYWGXGTMVTVSS

CL-30127
1900
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYGMYWVRQAPGQGL

EWMGWINTETGRPTYADDFNGWFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRIYIFYFDYWGQGTMVTVSS

CL-30128
1901
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS

CL-30129
1902
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL

EWMGWINTGTGKPTYAQGFTGRFVFSLDTSVSTAYLQIXSLKAED

TAVYYCARPIYYYIRYIFYFDYWGQGTMVTVSS

CL-30130
1903
EVQLVQSGSELKKPGASVKVSCKASGYTFADYPMYWVRQAPGQGL

EWMGWINTXTGQPLYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTSYYYRSYIFYFDYWGQGTMVTVSS

CL-30135
1904
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAXD

TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS

CL-30136
1905
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYSMYWVRQAPGQGL

EWMGWINTETGKPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTSYYYRSYIFYFDYWGQGTMVTVSS

CL-30138
1906
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYWMYWVRQAPGQGL

EWMGWINTETGEPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTEYYYKSYNFYFDYWGQGTMVTVSS

CL-30140
1907
EVQLVQSGSELKKPGASVKVSCKASGYTFTAYGMYWVRQAPGQGL

EWMGWINTETGMPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTKYYYRSYMFYFDYWGQGTMVTVSS

CL-30141
1908
EVQLVQSGSELKKPGASVKVSCKASGYTFHNYGMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTSYYYRSYFFYFDYWGQGTMVTVSS

CL-30142
1909
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYVMYWVRQAPGQGL

EWMGWINTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARLIYYYXTYIFYFDYWGQGTMVTVSS

CL-30145
1910
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYAMYWVRQAPGQGL

EWMGWINTETGKPPYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTLYYYRTYIFYFDYWGQGTMVTVSS

CL-30147
1911
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRRYIFYFDYWGQGTMVTVXS

CL-30148
1912
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTETGQPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRCYIFYFDYWGQGTMVTVSS

CL-30151
1913
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGKPNYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARPNYYYRSYIFYFDYWGQGTMVTVSS

CL-30154
1914
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYAMYWVRQAPGQGL

EWMGWINTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYGIYLFYFDYWGQGTMVTVSS

CL-30156
1915
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYDMYWVRQAPGQGL

EWMGWINTVTGRPAYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARITYYYRMYRFYFDYWGQGTMVTVSS

CL-30159
1916
EVQLVQSGSELKKPGASVKVSCKASGYTFIDYLMYWVRQAPGQGL

EWMGWINTVTGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTHYYYRSYAFYFDYWGQGTMVTVSS

CL-30161
1917
EVQLVQSGSELKKPGASVKVSCKASGYTFAKYEMYWVRQAPGQGL

EWMGWINTETGNPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRDYTFYFDYWGQGTMVTVSS

CL-30162
1918
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYRMYWVRQAPGQGL

EWMGWINTVTGRPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARNIYYYRSYIFYFDYWGQGTMVTVSS

CL-30164
1919
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS

CL-30165
1920
EVQLVQSGSELKKPGASVKVSCKASGYTFRNYVMYWVRQAPGQGL

EWMGWINTQTGEPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYGIYIFYFDYWGQGTMVTVSS

CL-30166
1921
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLQAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS

CL-30168
1922
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGMPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYRGYIFYFDYWGQGTMVTVSS

CL-30169
1923
EVQLVQSGSELKKPGASVKVSCKASGYTFLGYSMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARKFYYYESYIFYFDYWGQGTMVTVSS

CL-30170
1924
EVQLVQSGSELKKPGASVKVSCKASGYTFTYYCMYWVRQAPGQGL

EWMGWINTHTGKPMYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARKKYYYRSYIFYFDYWGQGTMVTVSS

CL-30593
1925
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL

EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYMSYMFYFDYWGQGTMVTVSS

CL-30594
1926
EVQLVQSGSELKKPGASVKVSCKASGYTFMNYGMYWVRQAPGQGL

EWMGWINTETGKPMYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTIYYYPRYIFYFDYWGQGTMVTVSS

CL-30595
1927
EVQLVQSGSELKKPGASVKVSCKASGYTFAMYKMYWVRQAPGQGL

EWMGWINTQTGGPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTKYYYWRYVFYFDYWGQGTMVTVSS

CL-30597
1928
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTETGQPMYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-30599
1929
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYSSYMFYFDYWGQGTMVTVSS

CL-30600
1930
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTATGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYMYYLFYFDYWGQGTMVTVSS

CL-30602
1931
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRLYMFYFDYWGQGTMVTVSS

CL-30604
1932
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL

EWMGWINTWTGKPTYAXDFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-30605
1933
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRTYMFYFDYWGQGTMVTVSS

CL-30606
1934
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYRMYWVRQAPGQGL

EWMGWINTETGKPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS

CL-30608
1935
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYDMYWVRQAPGQGL

EWMGWINTVTGXPTYAXXFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSXYYYRSYIFYFDYWGQGTMVTVSS

CL-30609
1936
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL

EWMGWINTETGKPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTDYYYRRYTFYFDYWGQGTMVTVSS

CL-30611
1937
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTYTGIPSYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARVNYYYSTYIFYFDYWGQGTMVTVSS

CL-30613
1938
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGIYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYRGYMFYFDYWGQGTMVTVSS

CL-30614
1939
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYRSYMFYFDYWGQGTMVTVSS

CL-30615
1940
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL

EWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARVNYYYRSYMFYFDYWGQGTMVTVSS

CL-30616
1941
EVQLVQSGSELKKPGASVKVSCKASGYTFTTYGMYWVRQAPGQGL

EWMGWINTLTGAPMYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYIFYFDYWGQGTMVTVSS

CL-30617
1942
EVQLVQSGSELKKPGASVKVSCKASGYTFKNYSMYWVRQAPGQGL

EWMGWINTDTGMPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRFYIFYFDYWGQGTMVTVSS

CL-30618
1943
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARVNYYYRSYMFYFDYWGQGTMVTVSS

CL-30619
1944
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS

CL-30620
1945
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS

CL-30623
1946
EVQLVQSGSELKKPGASVKVSCKASGYTFANYGMYWVRQAPGQGL

EWMGWINTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYQSYMFYFDYWGQGTMVTVSS

CL-30624
1947
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTDTGTPAYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYTRYNFYFDYWGQGTMVTVSS

CL-30626
1948
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-30628
1949
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS

CL-30629
1950
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYDMYWVRQAPGQGL

EWMGWINTETGNPTYAXXFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARXNYYYSSYIFYFDYWGQGTMVTVSS

CL-30630
1951
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARSNYYYRTYMFYFDYWGQGTMVTVSS

CL-30631
1952
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL

EWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-30632
1953
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-30634
1954
EVQLVQSGSELKKPGASVKVSCKASGYTFTYYGMYWVRQAPGQGL

EWMGWINTETGKPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTIYYYTTYIFYFDYWGQGTMVTVSS

CL-30635
1955
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL

EWMGWIDTETGEPIYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARINYYYPNYMFYFDYWGQGTMVTVSS

CL-30636
1956
EVQLVQSGSELKKPGASVKVSCKTSGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS

CL-30637
1957
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-30638
1958
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWIDTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS

CL-30639
1959
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-30640
1960
EVQLVQSGSELKKPGASVKVSCKASGYTFSSYGMYWVRQAPGQGL

EWMGWIDTETGEPKYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-30642
1961
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARYNYYYRIYLFYFDYWGQGTMVTVSS

CL-30643
1962
EVQLVQSGSELKKPGASVKVSCKASGYTFPYYSMYWVRQAPGQGL

EWMGWINTDTGTPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTTYYYWSYIFYFDYWGQGTMVTVSS

CL-30644
1963
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-30645
1964
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTXTGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTSYYYRCYIFYFDYWGQGTMVTVSS

CL-30647
1965
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGQPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-30649
1966
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWIDTDTGKPTYAXDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYTGYMFYFDYWGQGTMVTVSS

CL-30651
1967
EVQLVQSGSELEKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL

EWMGWIDTDTGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS

CL-30653
1968
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL

EWMGWIDTETGDPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYLSYMFYFDYWGQGTMVTVSS

CL-30654
1969
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSS

CL-30655
1970
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGEPSYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-30657
1971
EVQLVQSGSELKKPGASVKVSCKASGYTFANYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS

CL-30658
1972
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-30659
1973
EVQLVQSGSELKKPGASVKVSCKASGYTFPYYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRMYMFYFDYWGQGTMVTVSS

CL-30660
1974
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS

CL-30662
1975
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGSPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARIIYYYLSYLFYFDYWGQGTMVTVSS

CL-30663
1976
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWINTETGDPTYAQGFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-30664
1977
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYSGYMFYFDYWGQGTMVTVSS

CL-30665
1978
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRYYMFYFDYWGQGTMVTVSS

CL-30666
1979
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-30669
1980
EVQLVQSGSELKKPGASVKVSCKASGYTFTKYAMYWVRQAPGQGL

EWMGWINTYTGVPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARGHYYYMMYIFYFDYWGQGTMVTVSS

CL-30670
1981
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWIDTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARYKYYYRSYKFYFDYWGQGTMVTVSS

CL-30671
1982
EVQLVQSGSELKKPGASVKVSCKASGYTFPDYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS

CL-30674
1983
EVQLVQSGSELKKPGASVKVSCKASGYTFSHYGMYWVRQAPGQGL

EWMGWINTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-30675
1984
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL

EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-30676
1985
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGYPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRTYMFYFDYWGQGTMVTVSS

CL-30677
1986
EVQLVQSGSELKKPGASVKVSCKASGYTFNNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRTYMFYFDYWGQGTMVTVSS

CL-30678
1987
EVQLVQSGSELKKPGASVKVSCKASGYTFSHYGMYWVRQAPGQGL

EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS

CL-30679
1988
EVQLVQSGSELKKPGASVKVSCKASGYTFTSYRMYWVRQAPGQGL

EWMRWINTETGWPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTSYYYRNYMFYFDYWGQGTMVTVSS

CL-30682
1989
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGNPMYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-30684
1990
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS

CL-30685
1991
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCVRTNYYYRTYMFYFDYWGQGTMVTVSS

CL-32447
1992
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWXRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-32466
1993
EVQLVQSGSELKKPGASVKVSCKASGYTFHDYGMYWVRQAPGQGL

EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS

CL-32470
1994
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGXPTYAXXFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-32507
1995
EVQLVQSGSELKKPGASVKVSCKASGYTFNDYGMYWVRQAPGQGL

EWMGWIDTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS

CL-34445
1996
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-34457
1997
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYAHDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARXNYYYRSYMFYFDYWGQGTMVTVSS

CL-34458
1998
EVQLVQSGSELKKPGAPVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-34465
1999
EVQLVQSGSELKKPGASVKVSCKASGYTFPDYGMYWVRQAPGQGL

EWMGWIDTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRTYMFYFDYWGQGTMVTVSS

CL-34466
2000
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPIYAQGFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYNSYMFYFDYWGQGTMVTVSS

CL-34468
2001
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPRYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-34478
2002
EVQLVQSGSELKKPGASVKVSCKASGYTFPHYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS

CL-34480
2003
EVQLVQSGSELKKPGASVKVSCKASGYTFEDYGMYWVRQAPGQGL

EWMGWINTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS

CL-34482
2004
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRTYMFYFDYWGQGTMVTVSS

CL-34488
2005
EVQLVQSGSELKKPGASVKVSCKASGYTFDDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-34490
2006
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGTPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-34493
2007
EVQLVQSGSELKKPGASVKVSCKASGYTFGDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARVNYYYRNYMFYFDYWGQGTMVTVSS

CL-34495
2008
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS

CL-34496
2009
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS

CL-34499
2010
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL

EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-34502
2011
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-34503
2012
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL

EWMGWIDTETGTPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS

CL-34505
2013
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-34510
2014
EVQLVQSGSELKKPGASVKVSCKASGYTFSHYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYMSYMFYFDYWGQGTMVTVSS

CL-34512
2015
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTDTGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPKYMFYFDYWGQGTMVTVSS

CL-34527
2016
EVQLVQSGSELKKPGASVKVSCKASGYTFANYGMYWVRQAPGQGL

EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-34528
2017
EVHLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWIDTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-34529
2018
EVQLVQSGSELNKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPSYADDFKGRFVFSLDTXVSTAYXQISSLKAED

XAVYXCARTNYYYSSYMFYFDYWGQGTXVTVSS

CL-34534
2019
EVQLVQSGSELKKPGASVKVSCKASGYTFNDYGMYWVRQAPGQGL

EWMGWIDTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS

CL-34539
2020
EVQLVPSGSHFNNPGASXKVSCSASGYTFSDYGMYWVRQAPGQGL

EWMGWIDTETGDPTYADDFKGXFVFSLDTSVXXAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-34548
2021
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-34562
2022
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGKPTYADDFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRTYMFYFDYWGQGTMVTVSS

CL-34568
2023
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGQPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-34577
2024
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYESYMFYFDYWGQGTMVTVSS

CL-34582
2025
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-34586
2026
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYAXXFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-34590
2027
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-34592
2028
EVQLVQSGSELKKPGASVKVSCKASGYTFNDYGMYWVRQAPGQGL

EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS

CL-34595
2029
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRTYMFYFDYWGQGTMVTVSS

CL-34596
2030
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS

CL-34597
2031
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-34599
2032
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-34600
2033
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISNLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-34617
2034
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPRYMFYFDYWGQGTMVTVSS

CL-40631
2035
EVQLVQSGSELKKPGASVKVSCXASGYTFSDYGMYWVRQAPGQGL

EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS

CL-40642
2036
RVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-40646
2037
EVQLVQSGSELKKPGASVKVSCEASGYTFSDYGMYWVRQAPGQGL

EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS

CL-40665
2038
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTSLQ

CL-40668
2039
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKVED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-40671
2040
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS

CL-40687
2041
ASAAVQSGSELKKPGASVKVSCKASGYTFENYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS

CL-40688
2042
EVQLVQSGSELKKPGASVKVSCKASGYTFENYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS

CL-40694
2043
EVQLVQSGSELKKPGASVKVSCKASGYTFENYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLGTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS

CL-40708
2044
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS

CL-40716
2045
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL

EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARANYYYRSYMFYFDYWGQGTMVTVSS

CL-40717
2046
EVQLVQSGSELKKPGASVKVSCKASGYTFDDYGMYWVRQAPGQGL

EWMGWIDTETGTPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS

CL-40721
2047
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-40722
2048
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-40723
2049
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-40736
2050
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYXVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-40740
2051
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL

EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-40741
2052
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGP

EWMGWIDTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-40742
2053
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEN

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-40745
2054
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-40746
2055
EVQLVQSGSXLKXPGXSXKVSCXVSGYTFQNYGMYCVRPAPGQWL

XWMGWIDXXTGEPTYAYDFKGWFLFSLHTSVSMSSLQNXSLKXDD

TAVYYCAKTNYYYNSYMFYFDYWGQGTXXTVSS

CL-40747
2056
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS

CL-40753
2057
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRNYMFYFDYWGQGTMVTVSS

CL-40758
2058
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED

TAVHYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-40760
2059
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS

CL-40763
2060
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-40764
2061
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGNPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-40765
2062
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGQPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-40766
2063
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEG

TAVYYCARTNYYYSSYMFCFDYWGQGTMVTVSS

CL-40768
2064
EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYMFYFDYWGQGAMVTVSS

CL-40770
2065
EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYWVRRAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-40774
2066
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKVED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-40779
2067
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-40780
2068
EVQLVQSGSELEKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRGYMFYFDYWGQGTMVTSLQ

CL-40788
2069
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDAETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS

CL-40790
2070
EGHLGQSGSELKNPGASVKVSCXASGYTFXNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYAXDFKGRFVFSLGTSVSTAYLQIXSLRAED

TAVYYCEXTNYYYSRYMFYFXYWGQGTMVTVSS

CL-40791
2071
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGXIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS

CL-40793
2072
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVFS

CL-40795
2073
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRGYMLYFDYWGQGTMVTVSS

CL-40796
2074
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS

CL-40800
2075
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRRAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS

CL-40801
2076
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRLVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS

CL-40805
2077
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYSSYMFYFDYWGQGTMVTVSS

CL-40806
2078
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRGYMFYFDYWGQGTMVTVSS

CL-40811
2079
EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

CL-40812
2080
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYXSYMFYFDYWGQGTMVTVSS

CL-40815
2081
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYKSYMFYFDYWGQGTMVTVSS

CL-40816
2082
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGQFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSYMFYFDYWGQGTMVTVSS

CL-40817
2083
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYPSHMFYFDYWGQGTMVTVSS

CL-40819
2084
EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYWVRQAPGQGL

EWMGWIDTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAED

TAVYYCARTNYYYRSYMFYFDYWGQGTMVTVSS

List of Amino Acid Sequences of Affinity Matured h4G8.3 VL Variants

Table 39 provides a list of amino acid sequences of unique, functional VL regions of affinity matured humanized VEGF antibodies derived from hBDB-4G8.3. Amino acid residues of individual CDRs of each VL sequence are indicated in bold.

TABLE 39

List of Amino Acid Sequences of Affinity Matured

H4g8.3 VL Variants

Clone
SEQ ID NO:
VL

CL-27686
2085
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGXA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPFTFGQGTKLEIK

CL-27698
2086
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSRSGTDFTLTISSLEPEDFAVY

FCQQSWNDPFTFGQGTKLEIK

CL-27717
2087
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPFTFGQGAKLEIK

CL-27741
2088
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPFTFGLGTKLEIK

CL-27758
2089
EIVLTQFPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPFTFGQGTKLEIK

CL-27762
2090
EIVLTQSPATLSLSPGERATLSCRASQSVTPHMHWYQQKPGQA

PRLLIYGASTLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSCNDPFTFGQGTKLEIK

CL-27763
2091
EIVLTQSPATLSLSPGERATLSGRASESVDKYMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSRNDPLTFGQGTKLEIK

CL-27764
2092
EIVLTQSPATLSLSPGERATLSCRASQSVKTDMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSRNEPFTFGQGTKLEIK

CL-27765
2093
EIVLTQSPATLSLSPGERATLSCRASQSVSTHLAWYQQKPGQA

PRLLIYRASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQNWNDPLTFGQGTKLEIK

CL-27766
2094
EIVLTQSPATLSLSPGERATLSCRASQSVRTHMHWYQQKPGQA

PRLLIYGASALESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQGCNXPFTFGQGTKLEIK

CL-27767
2095
EIVLTQSPATLSLSPGERATLSCRASQSVRTHMHWYQQKPGQA

PRLLIYEASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSCNDPFTFGQGTKLEIK

CL-27768
2096
EIVLTQSPATLSLSPGERATLSCRASQSVSTDMHWYQQKPGQA

PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPFTFGQGTKLEIK

CL-27770
2097
EIVLTQSPATLSLSPGERATLSCRASQSVSPHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTSNEPFTFGQGTKLEIK

CL-27771
2098
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASDLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSXIDPVTFGQGTKLEIK

CL-27772
2099
EIVLTQSPATPSLSPGERATLSCRASESVNAHMHWYQQKPGQA

PRLLIYDASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWSDPFTFGQGTKLEIK

CL-27773
2100
EIVLTQSPATLSLSPGERATLSCRASESVRTQLAWYQQKPGQA

PRLLIYSASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSRTEPFTFGQGTKLEIK

CL-27774
2101
EIVLTQSPATLSLSPGERATLSCRASQSVSTPMHWYQQKPGQA

PRLLIYSASNLESGIPARFSDSGSGTDFTLTISSLEPEDFAVY

YCQQFWDDPYTFGQGTKLEIK

CL-27775
2102
EIVLTQSPATLSLSPGERATLSCRASESVITHLAWYQQKPGQA

PRLLIYSASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQCCIDPFTFGQGTKLEIK

CL-27776
2103
EIVLTQSPATLSLSPGERATLSCRASQSVRSQLAWYQQKPGQA

PRLLIYVASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSXNDPFTFGQGTKLEIK

CL-27779
2104
EIVLTQSPATLSLSPGERATLSCRASESVRTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWIDPFTFGQGTKLEIK

CL-27780
2105
EIVLTQSPATLSLSPGERATLSCRASESVSIHLAWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPFTFGQGTKLEIK

CL-27781
2106
EIVLTQSPATLSLSPGERATLSCRASQSVSTPMHWYQQKPGQA

PRLLIYGASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNEPYTFGQGTKLEIK

CL-27782
2107
EIVLTQSPATLSLSPGERATLSCRASESVSAHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWIYPFTFGQGTKLEIK

CL-27783
2108
EIVLTQSPATLSLSPGERATLSCRASQSVRTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGIDFTLTISSLEPEDFAVY

YCQQSXRYPFTFGQGTKLEIK

CL-27784
2109
EIVLTQSPATLSLSPGERATLSCRASQSVRTHMHWYQQKPGQA

PRLLIYRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQRSNEPFTFGQGTKLEIK

CL-27785
2110
EIVLTQSPATLSLSPGERATLSCRASQSVRSHMHWYQQKPGQA

PRLLIYGASGLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQRWNEPSTFGQGTKLEIK

CL-27786
2111
EIVLTQSPATLSLSPGERATLSCRASQSVRFHMHWYQQKPGQA

PRLLIYGASPLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSRRHPFTFGQGTKLEIK

CL-27787
2112
EIVLTQSPATLSLSPGERATLSCRASQSVSIQMHWYQQKPGQA

PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQQWNVPFTFGQGTKLEIK

CL-27788
2113
EIVLTQSPATLSLSPGERATLSCRASQSVSTPMHWYQQKPGQA

PRLLIYRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQGGNDPYTFGQGTKLEIK

CL-27790
2114
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYWASDLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQCWNGPLTFGQGTKLEIK

CL-27791
2115
EIVLTQSPATLSLSPGERATFSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGCGTDFTLTISSLEPEDFAVY

XCQQSGNDPFTFGQGTKLEIK

CL-27792
2116
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQGGNVPCTFGQGTKLEIK

CL-27794
2117
EIVLTQSPATLSLSPGERATLSCRASESVSWHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQIRADPFTFGQGTKLEIK

CL-27795
2118
EIVLTQSPATLSLSPGERATLSCRASESVCAHMHWYQQKPGQA

PRLLIYWASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSGLDPVTFGQGTKLEIK

CL-27796
2119
EIVLTQSPATLSLSPGERATLSCRASESVSTQMHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSGNNPFTFGQGTKLEIK

CL-27797
2120
EIVLTQSPATLSLSPGERATLSCRASQSVSTLMHWYQQKPGQA

PRLLIYRASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQGWNKPFTFGQGTKLEIK

CL-27798
2121
EIVLTQSPATLSLSPGERATLSCRASQSVTTHLAWYQQKPGQA

PRLLIYWASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSSKNPFTFGQGTKLEIK

CL-27799
2122
EIVLTQSPATLSLSPGERATLSCRASESVSXHMHWYQQKPGQA

PRLLIYWASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPPTFGQGTKLEIK

CL-27800
2123
EIVLTQSPATLSLSPGERATLSCRASQSVSSHLAWYQQKPGQA

PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSSRDPFTFGQGTKLEIK

CL-27801
2124
EIVLTQSPATLSLSPGERATLSCRASQSVTTNMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQRWNDPFTFGQGTKLEIK

CL-27802
2125
EIVLTQSPATLSLSPGERATLSCRASQSVSTHLAWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQKSNXPFTFGQGTKLEIK

CL-27803
2126
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYRASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWKDPYTFGQGTKLEIK

CL-27805
2127
EIVLTQSPATLSLSPGERATLSCRASQSVSAHLAWYQQKPGQA

PRLLIYEASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNVPFTFGQGTKLEIK

CL-27806
2128
EIVLTQSPATLSLSPGERATLSCRASESVLILMHWYQQKPGQA

PRLLIYEASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSSNDPFTFGQGTKLEIK

CL-27807
2129
EIVLTQSPATLSLSPGERATLSCRASQSVSSLMHWYQQKPGQA

PRLLIYGASCLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQYXNDPYTFGQGTKLEIK

CL-27809
2130
EIVLTQSPATLSLSPGERATLSCRASQSVITHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQRWKFPFTFGQGTKLEIK

CL-27810
2131
EIVLTQSPATLSLSPGERATLSCRASESVSTQLAWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQNWNNPLTFGQGTKLEIK

CL-27811
2132
EIVLTQSPATLSLSPGERATLSCRASQSVSRDMHWYQQKPGQA

PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQRWKEPFTFGQGTKLEIK

CL-27812
2133
EIVLTQSPATLSLSPGERATLSCRASQSVTTLMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQGCNDPLTFGQGTKLEIK

CL-27813
2134
EIVLTQSPATLSLSPGERATLSCRASESVVTHMHWYQQKPGQA

PRLLIYRASGLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWQHPFTFGQGTKLEIK

CL-27814
2135
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSGNDPCTFGQGTKLEIK

CL-27815
2136
EIVLTQSPATLSLSPGERATLSCRASQSVNSYLAWYQQKPGQA

PRLLIYWASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQAWNDPSTFGQGTKLEIK

CL-27816
2137
EIVLTQSPATLSLSPGERATLSCRASQSVSNPMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPFTFGQGTKLEIK

CL-27818
2138
EIVLTQSPATLSLSPGERATLSCRASQSVSTLMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQGLTDPFTFGQGTKLEIK

CL-27819
2139
EIVLTQSPATLSLSPGERATLSCRASESVSPPLAWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSENDPLTFGQGTKLEIK

CL-27820
2140
EIVLTQSPATLSLSPGERATLSCRASESVNTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWNHPFTFGQGTKLEIK

CL-27821
2141
EIVLTQSPATLSLSPGERATLSCRASESVSYPMHWYQQKPGQA

PRLLIYGASRLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQRWSDPFTFGQGTKLEIK

CL-27822
2142
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYIASFLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSXFEPSTFGQGTKLEIK

CL-27823
2143
EIVLTQSPATLSLSPGERATLSCRASESVSTQMHWYQQKPGQA

PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWKDPFTFGQGTKLEIK

CL-27824
2144
EIVLTQSPATLSLSPGERATLSCRASQSVSTKMHWYQQKPGQA

PRLLIYRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWIDPFTFGQGTKLEIK

CL-27826
2145
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYRASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWKDPFTFGQGTKLEIK

CL-27827
2146
EIVLTQSPATLSLSPGERATLSCRASQSVMTHLAWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNEPFTFGQGTKLEIK

CL-27828
2147
EIVLTQSPATLSLSPGERATLSCRASQSVXTHLAWYQQKPGQA

PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWQDPITFGQGTKLEIK

CL-27833
2148
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYAASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

XXQQSWNDPFTFGQGTKLEIK

CL-27838
2149
EIVLTQSPATLSLSPGERATLSCRASQSVSSLMHWYQQKPGQA

PRLLIYVASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNYPFTFGQGTKLEIK

CL-27840
2150
EIVLTQSPATLSLSPGERATLSCRASQSVITPLAWYQQKPGQA

PRLLIYGASRLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQIWNDPFTFGQGTKLEIK

CL-27841
2151
EIVLTQSPATLSLSPGERATLSCRASQSVSPLLAWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQRWNEPFTFGQGTKLEIK

CL-27842
2152
EIVLTQSPATLSLSPGERATLSCRASQSVNPHLAWYQQKPGQA

PRLLIYWASSLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQNWNDPFTFGQGTKLEIK

CL-27843
2153
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASRLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQGWNYPFTFGQGTKLEIK

CL-27844
2154
EIVLTQSPATLSLSPGERATLSCRASQSVSTRMHWYQQKPGQA

PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTRYDPFTFGQGTKLEIK

CL-27845
2155
EIVLTQSPATLSLSPGERATLSCRASESVSSHMHWYQQKPGQA

PRLLIYGASRLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPFTFGQGTKLEIK

CL-27846
2156
EIVLTQSPATLSLSPGERATLSCRASQSVTTHMHWYQQKPGQA

PRLLIYAASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNHPFTFGQGTKLEIK

CL-27847
2157
EIVLTQSPATLSLSPGERATLSCRASQSVKTQLAWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQRCNGPFTFGQGTKLEIK

CL-27848
2158
EIVLTQSPATLSLSPGERATLSCRASQSVSTQLAWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTGNDPFTFGQGTKLEIK

CL-27849
2159
EIVLTQSPATLSLSPGERATLSCRASESVSPLMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWKDPFTFGQGTKLEIK

CL-27850
2160
EIVLTQSPATLSLSPGERATLSCRASESVSAHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQWWNNPFTFGQGTKLEIK

CL-27851
2161
EIVLTQSPATLSLSPGERATLSCRASQSVNTHMHWYQQKPGQA

PRLLIYRASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNEPLTFGQGTKLEIK

CL-29979
2162
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWQDPLTFGQGTKLEIK

CL-29980
2163
EIVLTQSPATLSLSPGERATLSCRASQSVNTNMHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWNVPFTFGQGTKLEIK

CL-29981
2164
EIVLTQSPATLSLSPGERATLSCRASESVSTAMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWNVPITFGQGTKLEIK

CL-29982
2165
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASMLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-29983
2166
EIVLTQSPATLSLSPGERATLSCRASESVNDHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNNPITFGQGTKLEIK

CL-29984
2167
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPLTFGQGTKLEIK

CL-29985
2168
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWDDPITFGQGTKLEIK

CL-29986
2169
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSFLDPITFGQGTKLEIK

CL-29987
2170
EIVLTQSPATLSLSPGERATLSCRASESVSTNMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQGWSDPLTFGQGTKLEIK

CL-29988
2171
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWIDPLTFGQGTKLEIK

CL-29989
2172
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWIDPITFGQGTKLEIK

CL-29990
2173
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGCGTDFTLTISSLEPEDFAVY

FCQQSWHDPLTFGQGTKLEIK

CL-29991
2174
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWDDPITFGQGTKLEIK

CL-29992
2175
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASELESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWNDPITFGQGTKLEIK

CL-29993
2176
EIVLTQSPATLSLSPGERATLSCRASESVNTLMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWNEPITFGQGTKLEIK

CL-29994
2177
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWSDPLTFGQGTKLEIK

CL-29995
2178
EIVLTQSPATLSLSPGERATLSCRASQSVSKHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNNPITFGQGTKLEIK

CL-29996
2179
EIVLTQSPATLSLSPGERATLSCRASQSVDTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWHDPITFGQGTKLEIK

CL-29997
2180
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWTDPLTFGQGTKLEIK

CL-29998
2181
EIVLTQSPATLSLSPGERATLSCRASQSVSSHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPLTFGQGTKLEIK

CL-29999
2182
EIVLTQSPATLSLSPGERATLSCRASESVSTNMHWYQQKPGQA

PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNEPFTFGQGTKLEIK

CL-30000
2183
EIVLTQSPATLSLSPGERATLSCRASQSVDTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWGDPLTFGQGTKLEIK

CL-30001
2184
EIVLTQSPATLSLSPGERATLSCRASESVSNNLAWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWNDPITFGQGTKLEIK

CL-30002
2185
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPITFGQGTKLEIK

CL-30003
2186
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNEPWTFGQGTKLEIK

CL-30004
2187
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWIDPLTFGQGTKLEIK

CL-30005
2188
EIVLTQSPATLSLSPGERATLSCRASQSVGNNMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30006
2189
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFGGSGSGTDFTLTISSLEPEDFAVY

YCQQSWTDPLTFGQGTKLEIK

CL-30007
2190
EIVLTQSPATLSLSPGERATLSCRASESVYTXLAWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQILNDPFTFGQGTKLEIK

CL-30009
2191
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30010
2192
EIVLTQSPATLSLSPGERATLSCRASQSVGTNMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPITFGQGTKLEIK

CL-30011
2193
EIVLTQSPATLSLSPGERATLSCRASESVATHMHWYQQKPGQA

PRLLIYGASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30012
2194
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30013
2195
EIVLTQSPATLSLSPGERATLSCRASESVMNHLAWYQQKPGQA

PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWSDPLTFGQGTKLEIK

CL-30014
2196
EIVLTQSPATLSLSPGERATLSCRASQSVGTSMHWYQQKPGQA

PRLLIYAASELESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPFTFGQGTKLEIK

CL-30015
2197
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPLTFGQGTKLEIK

CL-30017
2198
EIVLTQSPATLSLSPGERATLSCRASESVSNNMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWSDPFTFGQGTKLEIK

CL-30018
2199
EIVLTQSPATLSLSPGERATLSCRASQSVSSHMHWYQQKPGQA

PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSFSDPITFGQGTKLEIK

CL-30019
2200
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWSDPLTFGQGTKLEIK

CL-30020
2201
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30021
2202
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNPPITFGQGTKLEIK

CL-30022
2203
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNEPFTFGQGTKLEIK

CL-30023
2204
EIVLTQSPATLSLSPGERATLSCRASQSVGTNMHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWNEPITFGQGTKLEIK

CL-30024
2205
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPVTFGQGTKLEIK

CL-30025
2206
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWNDPLTFGQGTKLEIK

CL-30026
2207
EIVLTQSPATLSLSPGERATLSCRASQSVSSHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-30027
2208
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-30028
2209
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWSDPLTFGQGTKLEIK

CL-30029
2210
EIVLTQSPATLSLSPGERATLSCRASESVSTHMNWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNVPYTFGQGTKLEIK

CL-30030
2211
EIVLTQSPATLSLSPGERATLSCRASESVTSNMHWYQQKPGQA

PRLLIYAASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWQNPITFGQGTKLEIK

CL-30031
2212
EIVLTQSPATLSLSPGERATLSCRASESVSDHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWTDPLTFGQGTKLEIK

CL-30032
2213
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30033
2214
EIVLTQSPATLSLSPGERATLSCRASESVSNYMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWTDPLTFGQGTKLEIK

CL-30034
2215
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWNDPITFGQGTKLEIK

CL-30035
2216
EIVLTQSPATLSLSPGERATLSCRASQSVGTAMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWDAPFTFGQGTKLEIK

CL-30036
2217
EIVLTQSPATLSLSPGERATLSCRASQSVRSHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWTPPITFGQGTKLEIK

CL-30037
2218
EIVLTQSPATLSLSPGERATLSCRASESVSTSMNWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWKDPITFGQGTKLEIK

CL-30038
2219
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNVPWTFGQGTKLEIK

CL-30039
2220
EIVLTQSPATLSLSPGERATLSCRASESVSNSMHWYQQKPGQA

PRLLIYGASTLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWTDPLTFGQGTKLEIK

CL-30040
2221
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWNDPSTFGQGTKLEIK

CL-30041
2222
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30042
2223
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASTLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWSDPLTFGQGTKLEIK

CL-30043
2224
EIVLTQSPATLSLSPGERATLSCRASESVDSNMHWYQQKPGQA

PRLLIYRASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWGDPITFGQGTKLEIK

CL-30044
2225
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30045
2226
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30046
2227
EIVLTQSPATLSLSPGERATLSCRASESVSDHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWTDPLTFGQGTKLEIK

CL-30047
2228
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30048
2229
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWSDPLTFGQGTKLEIK

CL-30049
2230
EIVLTQSPATLSLSPGERATLSCRASESVNTHLAWYQQKPGQA

PRLLIYGASMLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWSLPYTFGQGTKLEIK

CL-30050
2231
EIVLTQSPATLSLSPGERATLSCRASQSVSSHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30053
2232
EIVLTQSPATLSLSPGERATLSCRASESVSTHMNWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPFTFGQGTKLEIK

CL-30054
2233
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNEPYTFGQGTKLEIK

CL-30055
2234
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWGDPITFGQGTKLEIK

CL-30056
2235
EIVLTQSPATLSLSPGERATLSCRASQSVSTNMHWYQQKPGQA

PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWNEPITFGQGTKLEIK

CL-30057
2236
EIVLTQSPATLSLSPGERATLSCRASESVGKHMHWYQQKPGQA

PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWNDPITFGQGTKLEIK

CL-30058
2237
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASFLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWTNPITFGQGTKLEIK

CL-30059
2238
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWDDPLTFGQGTKLEIK

CL-30060
2239
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWTDPITFGQGTKLEIK

CL-30061
2240
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWIDPITFGQGTKLEIK

CL-30062
2241
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPITFGQGTKLEIK

CL-30063
2242
EIVLTQSPATLSLSPGERATLSCRASESVCTRMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPYTFGQGTKLEIK

CL-30064
2243
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTFDDPLTFGQGTKLEIK

CL-30066
2244
EIVLTQSPATLSLSPGERATLSCRASQSVGDSLAWYQQKPGQA

PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWNVPITFGQGTKLEIK

CL-30067
2245
EIVLTQSPATLSLSPGERATLSCRASESVANHLAWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPITFGQGTKLEIK

CL-30068
2246
EIVLTQSPATLSLSPGERATLSCRASESVSTHMNWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQGWYDPLTFGQGTKLEIK

CL-30069
2247
EIVLTQSPATLSLSPGERATLSCRASESVSSHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPITFGQGTKLEIK

CL-30070
2248
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNVPFTFGQGTKLEIK

CL-30071
2249
EIVLTQSPATLSLSPGERATLSCRASESVNKHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWIDPFTFGQGTKLEIK

CL-30072
2250
EIVLTQSPATLSLSPGERATLSCRASQSVGNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNMPITFGQGTKLEIK

CL-30073
2251
EIVLTQSPATLSLSPGERATLSCRASESVGEHMHWYQQKPGQA

PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-30074
2252
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWDVPLTFGQGTKLEIK

CL-30078
2253
ENVLTQSPATLSLSPGERATLSCRASESVITHMNWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPFTFGQGTKLEIK

CL-30090
2254
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-30095
2255
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASELESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWSDPLTFGQGTKLEIK

CL-30098
2256
EIVLTQSPATLSLSPGERATLSCRASQSVDTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWIDPITFGQGTKLEIK

CL-30099
2257
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWIDPLTFGQGTKLEIK

CL-30103
2258
EIVLTQSPATPSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPFTFGQGTKLEIK

CL-30104
2259
EIVLTQSPATLSLSPGERATLSCRASESVSSHMHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWNDPITFGQGTKLEIK

CL-30106
2260
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30109
2261
EIVLTQSPATLSLSPGERATLSCRASQSVITHMNWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWNDPITFGQGTKLEIK

CL-30115
2262
EIVLTQSPATLSLSPGERATLSCRASESVQTHMNWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPFTFGQGTKLEIK

CL-30120
2263
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-30121
2264
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPLTFGQGTKLEIK

CL-30123
2265
EIVLTQSPATLSLSPGERATLSCRASESVITHMNWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWDNPITFGQGTKLEIK

CL-30126
2266
EIVLTQSPATLSLSPGERATLSCRASQSVHKHMNWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQGWDDPLTFGQGTKLEIK

CL-30128
2267
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30131
2268
EIVLTQSPATLSLSPGERATLSCRASESVLTHMNWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYEPWTFGQGTKLEIK

CL-30132
2269
EIVLTQSPATLSLSPGERATLSCRASESVDTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPITFGQGTKLEIK

CL-30133
2270
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWSDPITFGQGTKLEIK

CL-30134
2271
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMNWYQQKPGQA

PRLLIYGASFLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWSDPITFGQGTKLEIK

CL-30135
2272
EIVLTQSPATLSLSPGERATLSCRASQSVGTPMHWYQQKPGQA

PRLLIYGASTLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-30137
2273
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPITFGQGTKLEIK

CL-30143
2274
EIVLTQSPATLSLSPGERATLSCRASESVDTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPITFGQGTKLEIK

CL-30144
2275
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASMLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWTDPITFGQGTKLEIK

CL-30147
2276
EIVLTQSPATLSLXPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLEYGVPARFSGSGCGTDFTLTISSIEHEDFAVY

FCQQSWNDPFTFGQGTKLEIK

CL-30150
2277
EIVLTQSPATLSLSPGERATLSCRASQSVANHLAWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWTDPITFGQGTKLEIK

CL-30152
2278
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASMLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNNPITFGQGTKLEIK

CL-30155
2279
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYAASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWDDPLTFGQGTKLEIK

CL-30158
2280
EIVLTQSPATLSLSPGERVTLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPITFGQGTKLEIK

CL-30160
2281
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30163
2282
EIVLTQSPATLSLSPGERATLSCRASQSVSSHMHWYQQKPGQA

PRLLIYAASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-30164
2283
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWMDPITFGQGTKLEIK

CL-30166
2284
EIVLTQSPATLSLSPGERATLSCRASESVSTNMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWSEPWTFGQGTKLEIK

CL-30167
2285
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWSDPLTFGQGTKLEIK

CL-30593
2286
EIVLTQSPATLSLSPGERATLSCRASQSVDTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-30594
2287
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNEPFTFGQGTKLEIK

CL-30595
2288
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPITFGQGTKLEIK

CL-30597
2289
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASTLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30598
2290
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASVLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWDDPLTFGQGTKLEIK

CL-30600
2291
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWLDPITFGQGTKLEIK

CL-30601
2292
EIVLTQSPATLSLSPGERATLSCRASQSVNTHLAWYQQKPGQA

PRLLIYAASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWTDPLTFGQGTKLEIK

CL-30602
2293
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWSDPLTFGQGTKLEIK

CL-30604
2294
EIVLTQSPATLSLSPGERATLSCRASQSVSNPMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNXPFTFGQGTKLEIK

CL-30606
2295
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWDDPFTFGQGTKLEIK

CL-30608
2296
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWSDPLTFGQGTKLEIK

CL-30609
2297
EIVLTQSPATLSLSPGERATLSCRASESVNSNMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-30610
2298
EIVLTQSPATLSLSPGERATLSCRASQSVRNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWDDPLTFGQGTKLEIK

CL-30611
2299
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWDDPLTFGQGTKLEIK

CL-30613
2300
EIVLTQSPATLSLSPGERATLSCRASQSVNTAMHWYQQKPGQA

PRLLIYGASSLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30614
2301
EIVLTQSPATLSLSPGERATLSCRASESVGSHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNLPLTFGQGTKLEIK

CL-30615
2302
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPITFGQGTKLEIK

CL-30616
2303
EIVLTQSPATLSLSPGERATLSCRASQSVITHMNWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWGDPWTFGQGTKLEIK

CL-30617
2304
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWIDPLTFGQGTKLEIK

CL-30618
2305
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASMLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWDDPLTFGQGTKLEIK

CL-30619
2306
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYAASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPITFGQGTKLEIK

CL-30620
2307
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPITFGQGTKLEIK

CL-30624
2308
EIVLTQSPATPSLSPGERATLSCRASESVGSCMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPLTFGQGTKLEIK

CL-30626
2309
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPLTFGQGTKLEIK

CL-30627
2310
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30628
2311
EIVLTQSPATLSLSPGERATLSCRASESVSRHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNNPLTFGQGTKLEIK

CL-30629
2312
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPATFGQGTKLEIK

CL-30630
2313
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30631
2314
EIVLTQSPATLSLSPGERATLSCRASQSVGRHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWTDPLTFGQGTKLEIK

CL-30632
2315
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWSDPITFGQGTKLEIK

CL-30634
2316
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30635
2317
EIVLTQSPATLSLSPGERATLSCRASESVSSNMNWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSFYDPITFGQGTKLEIK

CL-30636
2318
EIVLTQSPATLSLSPGERATLSCRASESVSSHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWSDPLTFGQGTKLEIK

CL-30637
2319
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWHDPLTFGQGTKLEIK

CL-30638
2320
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYAASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWIDPITFGQGTKLEIK

CL-30639
2321
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWTDPLTFGQGTKLEIK

CL-30640
2322
EIVLTQSPATLSLSPGERATLSCRASESVRSHLAWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSIEPEDFAVY

FCQQSWNAPFTFGQGTKLEIK

CL-30641
2323
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWSDPLTFGQGTKLEIK

CL-30642
2324
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWDDPITFGQGTKLEIK

CL-30643
2325
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNEPLTFGQGTKLEIK

CL-30644
2326
EIVLTQSPATLSLSPGERATLSCRASESVSTHMPWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30645
2327
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWSDPLTFGQGTKLEIK

CL-30647
2328
EIVLTQSPATLSLSPGERATLSCRASQSVSTAMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWFDPLTFGQGTKLEIK

CL-30648
2329
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWSDPITFGQGTKLEIK

CL-30649
2330
EIVLTQSPATLSLSPGERATLSCRASESVNSDMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-30650
2331
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNVPITFGQGTKLEIK

CL-30651
2332
EIVLTQSPATLSLSPGERATLSCRASESVSTNLAWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWNDPITFGQGTKLEIK

CL-30653
2333
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYAASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWTDPITFGQGTKLEIK

CL-30654
2334
EIVLTQSPATLSLSPGERATLSCRASESVSTHMNWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWTDPITFGQGTKLEIK

CL-30655
2335
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWDVPFTFGQGTKLEIK

CL-30657
2336
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWSDPITFGQGTKLEIK

CL-30658
2337
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQCRNDPFTFGQGTKLEIK

CL-30659
2338
EIVLTQSPATLSLSPGERATLSCRASESVSKHMNWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWTDPLTFGQGTKLEIK

CL-30660
2339
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASRLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30662
2340
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWDDPLTFGQGTKLEIK

CL-30663
2341
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNEPYTFGQGTKLEIK

CL-30664
2342
EIVLTQSPATLSLSPGERATLSCRASESVGMHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30665
2343
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMNWYQQKPGQA

PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSFNNPLTFGQGTKLEIK

CL-30666
2344
EIVLTQSPATLSLSPGERATLSCRASQSVNTHLHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWFDPLTFGQGTKLEIK

CL-30667
2345
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPLTFGQGTKLEIK

CL-30669
2346
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-30670
2347
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWLDPLTFGQGTKLEIK

CL-30671
2348
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASILESGVLARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30672
2349
EIVLTQSPATLSLSPGERATLSCRASESVSSHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWNYPITFGQGTKLEIK

CL-30673
2350
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPITFGQGTKLEIK

CL-30674
2351
EIVLTQSPATLSLSPGERATLSCRASESVGNHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWIDPLTFGQGTKLEIK

CL-30675
2352
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYAASKLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWVEPFTFGQGTKLEIK

CL-30676
2353
EIVLTQSPATLSLSPGERATLSCRASQSVETHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWRDPLTFGQGTKLEIK

CL-30677
2354
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMNWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWDDPLTFGQGTKLEIK

CL-30678
2355
EIVLTQSPATLSLSPGERATLSCRASQSVGSSMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPLTFGQGTKLEIK

CL-30679
2356
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30681
2357
EIVLTQSPATLSLSPGERATLSCRASQSVTNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWHDPLTFGQGTKLEIK

CL-30682
2358
EIVLTQSPATLSLSPGERATLSCRASESVSSHLAWYQQKPGQA

PRLLIYGASTLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWGDPFTFGQGTKLEIK

CL-30683
2359
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWSDPLTFGQGTKLEIK

CL-30684
2360
EIVLTQSPATLSLSPGERATLSCRASESVHDHMHWYQQKPGQA

PRLLIYAASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPLTFGQGTKLEIK

CL-30685
2361
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWADPLTFGQGTKLEIK

CL-34444
2362
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34445
2363
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPFTFGQGTKLEIK

CL-34446
2364
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSFYDPLTFGQGTKLEIK

CL-34447
2365
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34448
2366
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASMLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWMDPITFGQGTKLEIK

CL-34450
2367
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWMDPLTFGQGTKLEIK

CL-34451
2368
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34452
2369
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWHDPLTFGQGTKLEIK

CL-34453
2370
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSFTNPLTFGQGTKLEIK

CL-34454
2371
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34457
2372
EIVLTQSPATLSLSPGERATLSCRASXSVNTHMHWYQQKPGQA

PRLLIYGASXLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQXWYDPITFGQGTKLEIK

CL-34458
2373
EIVLTQSPATLSLSPGERATLSCRASESVRTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34459
2374
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-34460
2375
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34461
2376
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34462
2377
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASVLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34464
2378
EIVLTQSPATLSLSPGERATLSCRASQSVSRHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPITFGQGTKLEIK

CL-34465
2379
EIVLTQSPATLSLSPGERATLSCRASQSVSSHMHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWDDPITFGQGTKLEIK

CL-34467
2380
EIVLTQSPATLSLSPGERATLSCRASESVSTSMHWYQQKPGQA

PRLLIYGASQLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNVPFTFGQGTKLEIK

CL-34468
2381
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASRLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWTVPLTFGQGTKLEIK

CL-34472
2382
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-34473
2383
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASVLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-34474
2384
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASTLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-34478
2385
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPLTFGQGTKLEIK

CL-34479
2386
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASTLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-34480
2387
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34481
2388
EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34482
2389
EIVLTQSPATLSLSPGERATLSCRASQSVGEHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPITFGQGTKLEIK

CL-34485
2390
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-34487
2391
EIVLTQSPATLSLSPGERATLSCRASQSVSTNMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPITFGQGTKLEIK

CL-34488
2392
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASTLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34490
2393
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-34494
2394
EIVLTQSPATLSLSPGERATLSCRASQSVGSHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPITFGQGTKLEIK

CL-34496
2395
EIVLTQSPATLSLSPGERATLSCRASQSVGNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-34498
2396
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-34499
2397
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPITFGQGTKLEIK

CL-34500
2398
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPITFGQGTKLEIK

CL-34502
2399
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34504
2400
EIVLTQSPATLSLSPGERATLSCRASESVSRHMNWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPITFGQGTNLEIK

CL-34505
2401
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASYLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPITFGQGTKLEIK

CL-34506
2402
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPITFGQGTKLEIK

CL-34508
2403
EIVLTQSPATLSLSPGERATLSCRASESVDTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34509
2404
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPITFGQGTKLEIK

CL-34511
2405
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34512
2406
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34514
2407
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34515
2408
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPITFGQGTKLEIK

CL-34517
2409
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34520
2410
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-34521
2411
EIVLTQSPATLSLSPGERATLSCRASESVDRHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-34523
2412
EIVLTQSPATLSLSPGERATLSCRASQSVTNHMHWYQQKPGQA

PRLLIYGASVLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34524
2413
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPITFGQGTKLEIK

CL-34525
2414
EIVLTQSPATLSLSPGERATLSCRASESVSNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPITFGQGTKLEIK

CL-34526
2415
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-34529
2416
EIVLTQSPATLYLXPGERATLSCRASQSVSTHMHWYQQKPGQA

ARLVMYGASNLEFGVPARFSGSGSGTEFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34533
2417
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPITFGQGTKLEIK

CL-34534
2418
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34536
2419
EIVLTQSPATLSLSPGERATLSCRASQSVGAHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-34539
2420
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWSDPLTFGQGTKLEIK

CL-34541
2421
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPITFGQGTKLEIK

CL-34548
2422
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34556
2423
EIVLTQSPATLSLSPGERATLSCRASESVSXHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34558
2424
EIVLTQSPATLSLSPGERATLSCRASESVSTAMHWYQQKPGQA

PRLLIYAASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34561
2425
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPITFGQGTKLEIK

CL-34562
2426
EIVLTQSPATLSLSPGERATLSCRASQSVGSHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-34563
2427
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-34566
2428
EIVLTQSPATLSLSPGERATLSCRASQSVGTNMHWYQQKPGQA

PRLLIYGASVLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPITFGQGTKLEIK

CL-34568
2429
EIVLTQSPATLSLSPGERATLSCRASESVGKHMHWYQQKPGQA

PRLLIYGASHLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWMDPLTFGQGTKLEIK

CL-34573
2430
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASFLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34574
2431
EIVLTQSPATLSLSPGERATLSCRASESVGTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWGDPLTFGQGTKLEIK

CL-34577
2432
EIVLTQSPATLSLSPGERATLSCRASESVSKHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34580
2433
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASMLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWDDPLTFGQGTKLEIK

CL-34582
2434
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34585
2435
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-34586
2436
EIVLTQSPATLSLSPGERATLSCRASQSVXXHMHWYQQKPGQA

PRLLIYGASTLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWTDPXTFGQGTKLEIK

CL-34587
2437
EIVLTQSPATLSLSPGERATLSCRASESVSTHLHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34590
2438
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34591
2439
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPITFGQGTKLEIK

CL-34592
2440
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPITFGQGTKLEIK

CL-34593
2441
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASMLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34594
2442
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPITFGQGTKLEIK

CL-34598
2443
EIVLTQSPATLSLSPGERATLSCRASQSVSNHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWIEPYTFGQGTKLEIK

CL-34599
2444
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPITFGQGTKLEIK

CL-34600
2445
EIVLTQSPATLSLSPGERATLSCRASESVNTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWNDPFTFGQGTKLEIK

CL-34601
2446
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-34602
2447
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPGTFGQGTKLEIK

CL-34604
2448
EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-34610
2449
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-34612
2450
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMQWYQQKPGQA

PRLLIYGASILESGIPARFSGSGSGTDFTLTISSLEHEDFAVY

XCQQSWYDPLTFGQGTKLEIK

CL-34613
2451
EIVLTQSPATLSLSPGERATLSCRASESVGRHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPITFGQGTKLEIK

CL-34614
2452
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-34617
2453
EIVLTQSPATLSLSPGERATLSCRASESVDSSMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-34618
2454
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPITFGQGTKLEIK

CL-40245
2455
EIVLTQSPATLSLSPGERAALSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40250
2456
EIVLTQSPATLSLSPGERATLSYRASQSVGTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-40251
2457
EIVLTQSPGTLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40253
2458
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGADFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40255
2459
EIVLTQSPGTLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40258
2460
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASHPESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-40266
2461
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPMTFGQGTKLEIK

CL-40271
2462
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLGSN

CL-40272
2463
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLRSN

CL-40283
2464
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPMTFGQGTKLEIK

CL-40284
2465
EIVLTQSPATLSLSPGERAILSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLAFGQGTKLEIK

CL-40286
2466
EIVLPQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLEPGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPFTFGQGTKLEIK

CL-40287
2467
EIVLTQSPGTLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPFTFGQGTKLEIK

CL-40288
2468
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40299
2469
RNCVTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-40302
2470
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWCDPLTFGQGTKLEIK

CL-40303
2471
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLPIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40317
2472
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLGPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40324
2473
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-40327
2474
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPMTFGQGTKLEIK

CL-40328
2475
EIVLTQSPGTLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40331
2476
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQRTKLEIK

CL-40332
2477
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPMAFGQGTKLEIK

CL-40335
2478
RNCVDKSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASHLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-40336
2479
EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40337
2480
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQRSWYDPLTFGQGTKLEIK

CL-40338
2481
EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWNDPFTFGQGTKLEIK

CL-40339
2482
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40341
2483
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFVVY

YCQQSWYDPITFGQGTKLEIK

CL-40342
2484
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTCYDPLTFGQGTKLEIK

CL-40350
2485
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGADFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-40356
2486
EIVLTQSPATLSLSPGERATLSCRASESVGKHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPITFGQGTKLEIK

CL-40357
2487
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-40364
2488
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSFYDPLTFGQGTKLEIK

CL-40367
2489
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPLTFGQGTKLEIK

CL-40370
2490
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFILTISSLEPEDFAVY

YCQQSFYDPLTFGQGTKLEIK

CL-40373
2491
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-40381
2492
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAIY

FCQQTWYDPLTFGQGTKLEIK

CL-40382
2493
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGIDFTLTISSLEPEDFAVY

FCQQTWYDPLTFGQGTKLEIK

CL-40390
2494
EIVLTQSPATLSLSPGERATLSCRASGSVGKHMHWYQQKPGQA

PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40394
2495
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEEFAVY

FCQQTWYDPLTFGQGTKLEIK

CL-40399
2496
EIVLTQSPATLSLSPGERATLSCRASQSVSKHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDSTLTISSLEPEDFAVY

FCQQTWYDPITFGQGTKLEIK

CL-40408
2497
EIVLTQSPATLSLPPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSFYDPLTFGQGTKLEIK

CL-40414
2498
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFGGSGSGTDFTLTISSLEPEDFAVY

YCQQSFYDPLTFGQGTKLEIK

CL-40426
2499
EIVSTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTIGSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-40440
2500
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTNLEIK

CL-40441
2501
EIVLTQSPATLSLSPGERATFSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40443
2502
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAAY

FCQQTWYDPLTFGQGTKLEIK

CL-40445
2503
EIVLTQSPSTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPLTFGQGTKLEIK

CL-40447
2504
EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIX

CL-40453
2505
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWCQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPLTFGQGTKLEIK

CL-40463
2506
EIVLTQSPGTLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-40466
2507
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-40470
2508
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-40472
2509
EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40476
2510
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLRSN

CL-40479
2511
EIVLTQSPATLSLSPGERATLSCRASQSVATHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLRSN

CL-40480
2512
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQEPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40484
2513
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40485
2514
RNLLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPLTFGQGTKLEIK

CL-40489
2515
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPLTFGQGTKLVIK

CL-40494
2516
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGADFTLTISSLEPEDFAVY

FCQQTWYDPLTFGQGTKLEIK

CL-40498
2517
EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSRYDPLTFGQGTKLEIK

CL-40503
2518
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPLTFGQGTKLEIK

CL-40505
2519
EIVLTQSPGTLSLSPGERATLSCRASQSVATHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40511
2520
AIVLTQSPATLSLSPGERATLSCRASQSVATHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-40526
2521
EIVLTQSPAALSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPLTFGQGTKLEIK

CL-40531
2522
EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA

PRLLIYGASIPESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-41836
2523
AIVLTQSPGTLSLSPGERATLSCRASQSVATHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-41845
2524
EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-41849
2525
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASKLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-41850
2526
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

CL-41852
2527
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-41854
2528
EIVLTQSPATLSLSPGERATLSCRASQSVATHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-41855
2529
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPLTFGQGTKLEIK

CL-41885
2530
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTITSLEPEDFAVY

FCXQTWYDPLTFGQGTKLEIK

CL-41886
2531
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPITFGQGTKLRSN

CL-41888
2532
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-41920
2533
EIVLTQSPGTLSLSPGERASLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSFYDPLTFGRGTKLEIK

CL-41923
2534
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIN

CL-41928
2535
EIVLTQSPATLSLSPGERATLSCRTSESVGKHMHWYQQKPGQA

PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-41938
2536
EIVLTQSPATLSLSPGERATLSCRASESVGKHMHWYQQKPGQA

PRLLIYAASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPLTFGQGTKLEIK

CL-41940
2537
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSWYDPITFGQGTKLEIK

CL-41941
2538
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASILESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPLTFGQGTKLEIK

CL-41947
2539
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSFYDPLTFGQGTKLEIQ

CL-41949
2540
EIVLTQSPATLSLSPGERATLSCRASQSVSKHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQTWYDPITFGQGTKLEIK

CL-41950
2541
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQTWYDPLTFGQGTKLEIK

CL-41951
2542
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

YCQQSFYDPLTFGQGTKLEIK

CL-41952
2543
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQA

PRLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVY

FCQQSWYDPLTFGQGTKLEIK

TABLE 40

Amino Acid Residues Found In Each Position of the Heavy

Chain Variable Region During The Affinity Maturation Of

Humanized Anti-Human VEGF Antibody Hbdb-4G8.3

hBDB-4G8|Heavy Chain Variable Region

SEQ ID NO:
Sequence

2544
1 2 3 4 5 6

123456789012345678901234567890123456789012345678901234567890

EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTETGKPTY

R S S S Y N I

N QK D L D M

DY K V T K

ET C W P A

NM V A W N

AG E Q Y P

GA L H V L

HI W G S V

KL P K M W

ME Y N A D

LP M M I Y

RQ N T G G

IF T P R E

Y L

V

7 8 9 10 11 12

123456789012345678901234567890123456789012345678901234567890

ADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT

Y N T D H N L

H T YI ST N

GT NK T

ID EM V

S MY A

KF LC R

NL TI F

PE WF D

LV QL

WY GD S

MA IW

FG AX

RW CV

QQ V

R

123

VSS

SFQ

L

TABLE 41

Amino Acid Residues Found In Each Position of the Light

Chain Variable Region During The Affinity Maturation Of

Humanized Anti-Human VEGF Antibody Hbdb-4G8.3

hBDB-4G8|Light Chain Variable Region

SEQ ID NO:
Sequence

2545
1 2 3 4 5 6

123456789012345678901234567890123456789012345678901234567890

EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESGVPA

A NSA A W H Y

DRD P V Y

C I M

TAP E T

RER S F

HDY D V

EM R

IPL Q

LYQ A

QIK S

CW E

MF G

Y C

K D

V P

7 8 9 10

12345678901234567890123456789012345678901234567

RFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIK

CCIN M G

GLTY G

IGDA Y

W GL

REM A

NSSM W

A HP S

Y AG V

K RH C

Q VF P

F LK

F

K

Q

TABLE 42

Variable Region Sequences of hBDB-4G8.3 Affinity

Matured Clones Converted To IgG

SEQ ID

Protein
V Region

NO:
Clone
Region
123456789012345678901234567890

2546
CL-32416 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW

VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF

YFDYWGQGTMVTVSS

2547
CL-32416
CDR-H1

GYTFTDYGMY

2548
CL-32416
CDR-H2

WIDTETGEPTYADDFKG

2549
CL-32416
CDR-H3

TNYYYRSYMFYFDY

2550
CL-32416 VL

EIVLTQSPATLSLSPGERATLSCRASESVSTHMHWY

QQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIK

2551
CL-32416
CDR-L1

RASESVSTHMH

2552
CL-32416
CDR-L2

GASNLES

2553
CL-32416
CDR-L3

QQSWNDPFT

2554
CL-34449 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW

VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF

YFDYWGQGTMVTVSS

2555
CL-34449
CDR-H1

GYTFTDYGMY

2556
CL-34449
CDR-H2

WIDTETGEPTYADDFKG

2557
CL-34449
CDR-H3

TNYYYRSYMFYFDY

2558
CL-34449 VL

EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWY

QQKPGQAPRLLIYGASHLESGIPARFSGSGSGTDFT

LTISSLEPEDFAVYYCQQTWYDPLTFGQGTKLEIK

2559
CL-34449
CDR-L1

RASQSVGTHMH

2560
CL-34449
CDR-L2

GASHLES

2561
CL-34449
CDR-L3

QQTWYDPLT

2562
CL-34455 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYW

VRQAPGQGLEWMGWIDTETGEPTYAQGFTGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYPSYMF

YFDYWGQGTMVTVSS

2563
CL-34455
CDR-H1

GYTFTNYGMY

2564
CL-34455
CDR-H2

WIDTETGEPTYAQGFTG

2565
CL-34455
CDR-H3

TNYYYPSYMFYFDY

2566
CL-34455 VL

EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWY

QQKPGQAPRLLIYGASKLESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK

2567
CL-34455
CDR-L1

RASQSVGTHMH

2568
CL-34455
CDR-L2

GASKLES

2569
CL-34455
CDR-L3

QQSWYDPLT

2570
CL-34463 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW

VRQAPGQGLEWMGWIDTETGNPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYPSYMF

YFDYWGQGTMVTVSS

2571
CL-34463
CDR-H1

GYTFTDYGMY

2572
CL-34463
CDR-H2

WIDTETGNPTYADDFKG

2573
CL-34463
CDR-H3

TNYYYPSYMFYFDY

2574
CL-34463 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSKHMHWY

QQKPGQAPRLLIYGASNLESGIPARFSGSGSGTDFT

LTISSLEPEDFAVYFCQQTWYDPITFGQGTKLEIK

2575
CL-34463
CDR-L1

RASQSVSKHMH

2576
CL-34463
CDR-L2

GASNLES

2577
CL-34463
CDR-L3

QQTWYDPIT

2578
CL-34469 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYW

VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF

YFDYWGQGTMVTVSS

2579
CL-34469
CDR-H1

GYTFTNYGMY

2580
CL-34469
CDR-H2

WIDTETGEPTYADDFKG

2581
CL-34469
CDR-H3

TNYYYRSYMFYFDY

2582
CL-34469 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY

QQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK

2583
CL-34469
CDR-L1

RASQSVSTHMH

2584
CL-34469
CDR-L2

GASNLES

2585
CL-34469
CDR-L3

QQSWYDPLT

2586
CL-34475 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW

VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYSSYMF

YFDYWGQGTMVTVSS

2587
CL-34475
CDR-H1

GYTFTDYGMY

2588
CL-34475
CDR-H2

WIDTETGEPTYADDFKG

2589
CL-34475
CDR-H3

TNYYYSSYMFYFDY

2590
CL-34475 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY

QQKPGQAPRLLIYGASNLESGIPARFSGSGSGTDFT

LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK

2591
CL-34475
CDR-L1

RASQSVSTHMH

2592
CL-34475
CDR-L2

GASNLES

2593
CL-34475
CDR-L3

QQSWYDPLT

2594
CL-34483 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFPNYGMYW

VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF

YFDYWGQGTMVTVSS

2595
CL-34483
CDR-H1

GYTFPNYGMY

2596
CL-34483
CDR-H2

WIDTETGEPTYADDFKG

2597
CL-34483
CDR-H3

TNYYYRSYMFYFDY

2598
CL-34483 VL

EIVLTQSPATLSLSPGERATLSCRASQSVATHMHWY

QQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK

2599
CL-34483
CDR-L1

RASQSVATHMH

2600
CL-34483
CDR-L2

GASNLES

2601
CL-34483
CDR-L3

QQSWYDPLT

2602
CL-34489 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFSNYGMYW

VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYSSYMF

YFDYWGQGTMVTVSS

2603
CL-34489
CDR-H1

GYTFSNYGMY

2604
CL-34489
CDR-H2

WIDTETGEPTYADDFKG

2605
CL-34489
CDR-H3

TNYYYSSYMFYFDY

2606
CL-34489 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY

QQKPGQAPRLLIYGASNLESGIPARFSGSGSGTDFT

LTISSLEPEDFAVYFCQQSWYDPLTFGQGTKLEIK

2607
CL-34489
CDR-L1

RASQSVSTHMH

2608
CL-34489
CDR-L2

GASNLES

2609
CL-34489
CDR-L3

QQSWYDPLT

2610
CL-34501 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYW

VRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYPSYMF

YFDYWGQGTMVTVSS

2611
CL-34501
CDR-H1

GYTFSDYGMY

2612
CL-34501
CDR-H2

WIDTETGDPTYADDFKG

2613
CL-34501
CDR-H3

TNYYYPSYMFYFDY

2614
CL-34501 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY

QQKPGQAPRLLIYGASILESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYFCQQTWYDPLTFGQGTKLEIK

2615
CL-34501
CDR-L1

RASQSVSTHMH

2616
CL-34501
CDR-L2

GASILES

2617
CL-34501
CDR-L3

QQTWYDPLT

2618
CL-34513 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW

VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRGYMF

YFDYWGQGTMVTVSS

2619
CL-34513
CDR-H1

GYTFTDYGMY

2620
CL-34513
CDR-H2

WIDTETGEPTYADDFKG

2621
CL-34513
CDR-H3

TNYYYRGYMFYFDY

2622
CL-34513 VL

EIVLTQSPATLSLSPGERATLSCRASQSVNNHMHWY

QQKPGQAPRLLIYGASILESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYFCQQSWYDPLTFGQGTKLEIK

2623
CL-34513
CDR-L1

RASQSVNNHMH

2624
CL-34513
CDR-L2

GASILES

2625
CL-34513
CDR-L3

QQSWYDPLT

2626
CL-34518 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYW

VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYKSYMF

YFDYWGQGTMVTVSS

2627
CL-34518
CDR-H1

GYTFTNYGMY

2628
CL-34518
CDR-H2

WIDTETGEPTYADDFKG

2629
CL-34518
CDR-H3

TNYYYKSYMFYFDY

2630
CL-34518 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY

QQKPGQAPRLLIYGASKLESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK

2631
CL-34518
CDR-L1

RASQSVSTHMH

2632
CL-34518
CDR-L2

GASKLES

2633
CL-34518
CDR-L3

QQSWYDPLT

2634
CL-34522 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFENYGMYW

VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYSSYMF

YFDYWGQGTMVTVSS

2635
CL-34522
CDR-H1

GYTFENYGMY

2636
CL-34522
CDR-H2

WIDTETGEPTYADDFKG

2637
CL-34522
CDR-H3

TNYYYSSYMFYFDY

2638
CL-34522 VL

EIVLTQSPATLSLSPGERATLSCRASQSVGTHMHWY

QQKPGQAPRLLIYGASKLESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK

2639
CL-34522
CDR-L1

RASQSVGTHMH

2640
CL-34522
CDR-L2

GASKLES

2641
CL-34522
CDR-L3

QQSWYDPLT

2642
CL-34537 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYW

VRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARANYYYRSYMF

YFDYWGQGTMVTVSS

2643
CL-34537
CDR-H1

GYTFSDYGMY

2644
CL-34537
CDR-H2

WIDTETGDPTYADDFKG

2645
CL-34537
CDR-H3

ANYYYRSYMFYFDY

2646
CL-34537 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY

QQKPGQAPRLLIYGASNLESGIPARFSGSGSGTDFT

LTISSLEPEDFAVYFCQQSWYDPMTFGQGTKLEIK

2647
CL-34537
CDR-L1

RASQSVSTHMH

2648
CL-34537
CDR-L2

GASNLES

2649
CL-34537
CDR-L3

QQSWYDPMT

2650
CL-34538 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW

VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYPSYMF

YFDYWGQGTMVTVSS

2651
CL-34538
CDR-H1

GYTFTDYGMY

2652
CL-34538
CDR-H2

WIDTETGEPTYADDFKG

2653
CL-34538
CDR-H3

TNYYYPSYMFYFDY

2654
CL-34538 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY

QQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYFCQQTWYDPLTFGQGTKLEIK

2655
CL-34538
CDR-L1

RASQSVSTHMH

2656
CL-34538
CDR-L2

GASNLES

2657
CL-34538
CDR-L3

QQTWYDPLT

2658
CL-34540 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW

VRQAPGQGLEWMGWIDTETGQPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF

YFDYWGQGTMVTVSS

2659
CL-34540
CDR-H1

GYTFTDYGMY

2660
CL-34540
CDR-H2

WIDTETGQPTYADDFKG

2661
CL-34540
CDR-H3

TNYYYRSYMFYFDY

2662
CL-34540 VL

EIVLTQSPATLSLSPGERATLSCRASESVGKHMHWY

QQKPGQAPRLLIYAASNLESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK

2663
CL-34540
CDR-L1

RASESVGKHMH

2664
CL-34540
CDR-L2

AASNLES

2665
CL-34540
CDR-L3

QQSWYDPLT

2666
CL-34565 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW

VRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRNYMF

YFDYWGQGTMVTVSS

2667
CL-34565
CDR-H1

GYTFTDYGMY

2668
CL-34565
CDR-H2

WIDTETGDPTYADDFKG

2669
CL-34565
CDR-H3

TNYYYRNYMFYFDY

2670
CL-34565 VL

EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWY

QQKPGQAPRLLIYGASILESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIK

2671
CL-34565
CDR-L1

RASQSVSNHMH

2672
CL-34565
CDR-L2

GASILES

2673
CL-34565
CDR-L3

QQSWYDPIT

2674
CL-34570 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFDDYGMYW

VRQAPGQGLEWMGWIDTETGTPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYSSYMF

YFDYWGQGTMVTVSS

2675
CL-34570
CDR-H1

GYTFDDYGMY

2676
CL-34570
CDR-H2

WIDTETGTPTYADDFKG

2677
CL-34570
CDR-H3

TNYYYSSYMFYFDY

2678
CL-34570 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY

QQKPGQAPRLLIYGASNLESGIPARFSGSGSGTDFT

LTISSLEPEDFAVYYCQQSWYDPLTFGQGTKLEIK

2679
CL-34570
CDR-L1

RASQSVSTHMH

2680
CL-34570
CDR-L2

GASNLES

2681
CL-34570
CDR-L3

QQSWYDPLT

2682
CL-34603 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW

VRQAPGQGLEWMGWIDTETGEPTYAQGFTGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF

YFDYWGQGTMVTVSS

2683
CL-34603
CDR-H1

GYTFTDYGMY

2684
CL-34603
CDR-H2

WIDTETGEPTYAQGFTG

2685
CL-34603
CDR-H3

TNYYYRSYMFYFDY

2686
CL-34603 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY

QQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYYCQQTWYDPLTFGQGTKLEIK

2687
CL-34603
CDR-L1

RASQSVSTHMH

2688
CL-34603
CDR-L2

GASNLES

2689
CL-34603
CDR-L3

QQTWYDPLT

2690
CL-34605 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFTHYGMYW

VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF

YFDYWGQGTMVTVSS

2691
CL-34605
CDR-H1

GYTFTHYGMY

2692
CL-34605
CDR-H2

WIDTETGEPTYADDFKG

2693
CL-34605
CDR-H3

TNYYYRSYMFYFDY

2694
CL-34605 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY

QQKPGQAPRLLIYGASNLESGIPARFSGSGSGTDFT

LTISSLEPEDFAVYYCQQSFYDPLTFGQGTKLEIK

2695
CL-34605
CDR-L1

RASQSVSTHMH

2696
CL-34605
CDR-L2

GASNLES

2697
CL-34605
CDR-L3

QQSFYDPLT

2698
CL-34633 VH

EVQLVQSGSELKKPGASVKVSCKASGYTFSDYGMYW

VRQAPGQGLEWMGWIDTETGEPTYADDFKGRFVFSL

DTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYMF

YFDYWGQGTMVTVSS

2699
CL-34633
CDR-H1

GYTFSDYGMY

2700
CL-34633
CDR-H2

WIDTETGEPTYADDFKG

2701
CL-34633
CDR-H3

TNYYYRSYMFYFDY

2702
CL-34633 VL

EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWY

QQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFT

LTISSLEPEDFAVYFCQQSWYDPLTFGQGTKLEIK

2703
CL-34633
CDR-L1

RASQSVSTHMH

2704
CL-34633
CDR-L2

GASNLES

2705
CL-34633
CDR-L3

QQSWYDPLT

TABLE 43

Summary of Protein Expression and Purification Affinity

Matured Humanized Anti-Human VEGF-A Antibodies

Yield
SEC (%

Name
(mg/L)¹
monomer)²

CL-32416-IgG
28.5
100.0

CL-34449-IgG
16.1
100.0

CL-34455-IgG
34.1
100.0

CL-34469-IgG
21.3
100.0

CL-34475-IgG
33.6
100.0

CL-34522-IgG
18.4
100.0

CL-34538-IgG
40.8
100.0

CL-34540-IgG
80.0
100.0

CL-34565-IgG
133.6
100.0

CL-34570-IgG
28.3
100.0

CL-34633-IgG
49.9
100.0

¹Yield is determined by the total amount of purified protein in mg divided by the total cell culture volume in liters.

²SEC % monomer is determined using HPLC size exclusion chromatography.

TABLE 44

Biacore Binding of Affinity Matured Humanized

Anti-VEGF Antibodies

Antibody
k_on(M−1 s−1)
k_off(M−1)
K_D(M)

CL-28815-IgG
9.2E+06
1.1E−04
1.2E−11

(El version of

parent mAb)

CL-32416-IgG
2.0E+07
1.1E−05
5.4E−13

CL-34449-IgG
1.1E+07
9.1E−06
8.5E−13

CL-34455-IgG
2.2E+07
1.0E−05
4.6E−13

CL-34469-IgG
1.5E+07
9.5E−06
6.2E−13

CL-34475-IgG
2.7E+07
1.4E−05
5.2E−13

CL-34522-IgG
2.0E+07
1.0E−05
5.3E−13

CL-34538-IgG
3.3E+07
8.1E−06
2.4E−13

CL-34540-IgG
8.4E+06
7.1E−06
8.5E−13

CL-34565-IgG
2.0E+07
7.8E−06
4.0E−13

CL-34570-IgG
1.9E+07
5.5E−06
2.9E−13

CL-34633-IgG
1.7E+07
4.1E−06
2.4E−13

Affinity matured humanized anti-VEGF antibodies were characterized for hVEGF₁₆₅binding and potency. Binding affinity of these molecules to hVEGF₁₆₅was determined by Biacore analysis (Example 1.1). Potency was evaluated in both cell-based and ELISA formats. The ability to block binding of hVEGF₁₆₅to hVEGFR2 was evaluated in a competition ELISA (Example 1.4) Inhibition of hVEGF₁₆₅-induced cell proliferation was assessed using HMVEC-d cells (Example 1.10). The data is summarized in Table 45 below.

TABLE 45

Summary of Characterization of Affinity Matured Humanized

Anti-Human VEGF-A Antibodies

hVEGF₁₆₅IC50 (nM)

Affinity Matured
VEGFR2
Potency
Potency

Humanized IgG
Competition
HMVEC-d
VEGFR2-3T3

CL-32416-IgG
<0.1
0.117
NT

CL-34449-IgG
<0.1
0.077
NT

CL-34455-IgG
<0.1
0.105
NT

CL-34469-IgG
<0.1
0.094
NT

CL-34475-IgG
<0.1
0.106
NT

CL-34522-IgG
<0.1
0.116
NT

CL-34540-IgG
<0.1
0.139
NT

CL-34633-IgG
<0.1
0.138
NT

CL-34538-IgG
<0.1
0.127
NT

CL-34570-IgG
<0.1
0.11
NT

CL-34565-IgG
<0.1
0.126
NT

Example 8
Affinity Maturation of Anti-Human PDGF-BB Antibody hBDI-9E8

The PDGF-β antibody hBDI-9E8.4 was obtained from rat hybridomas generated at Aldevron and was humanized at AbbVie Bioresearch Center (100 Research Drive, Worcester, Mass. 01605). The human germlines for this clone are VH2-70 and IGKV3-20. To improve the affinity of hBDI-9E8.4, hypermutated CDR residues were identified from other human antibody sequences in the IgBLAST database that also shared high identity to germlines VHVH2-70 and IGKV3-20. The corresponding h9E8.4 CDR residues were then subjected to limited mutagenesis by PCR with primers having low degeneracy at these positions to create three antibody libraries in the scFv format suitable for surface display. To improve the affinity of hBDI-9E8.4 to PDGFβ we generated three antibody libraries in scFv format suitable for surface display. In the first library, residues 30, 32, 34, 35, and 35b in the VH CDR1 and residues 50, 52, 54, 56, 57, 58, 60, 61 and 65 (Kabat numbering) in the VH CDR2 were subjected to limited mutagenesis by primers. In the second library residues 95-100a, 100c and 102 (Kabat numbering) in the VH CDR3 were subjected to limited mutagenesis by primers. In the third library residues 24, 25, 27b, and 29-32 in the VL CDR1, residues 47, 50, 51, 53, 55, and 56 in the VL CDR2 and residues 90, 93-95a, 96 and 97 (Kabat numbering) in the VL CDR3 were subjected to limited mutagenesis by primers.

These hBDI-9E8.4 libraries were displayed to be selected against a low concentration of biotinylated PDGFβ by magnetic then fluorescence activated cell sorting. Selections for improved on-rate, off-rate, or both were carried out and antibody protein sequences of affinity-modulated hBDI-9E8.4 clones.

Table 46 provides a list of amino acid sequences of VH regions of affinity matured humanized PDGF antibodies derived from hBDI-9E8.4. Amino acid residues of individual CDRs of each VH sequence are indicated in bold.

TABLE 46

List of amino Acid Sequences Of Affinity Matured

hBDI-9E8.4 VH Variants

Clone
SEQ ID NO:
VH

CL-22556
2706
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVGVGWIRQPPGK

ALEWLANIWWVDEIFYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22557
2707
EVTLRESGPALVKPTQTLTLTCTFSGFSLWTSGMGVVWIRQPPGK

ALEWLALIDWADVKSYNPSLKNRLTISEDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22558
2708
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVSVGWIRQPPGK

ALEWLALIDWYDDMYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22559
2709
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVRVVWIRQPPGK

ALEWLANIWWDDYLDYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22560
2710
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMSVGWIRQPPGK

ALEWLALIDWADDTYYNPSLNNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22561
2711
EVTLRESGPALVKPTQTLTLTCTFSGFSLATYGMSVAWIRQPPGK

ALEWLALIDWYDDEYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22562
2712
EVTLRESGPALVKPTQTLTLTCTFSGFSLXTYGVGVGWIRQPPGK

ALEWLANIWWVDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22563
2713
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGK

ALEWLALIDWADDKYYNPSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22564
2714
EVTLRESGPALVKPTQTLTLTCTFSGFSLCTSGVRVRWIRQPPGK

ALEWLALIDWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22565
2715
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGK

ALEWLANIWWDDNXYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22567
2716
EVTLRESGPALVKPTQTLTLTCTFSGFSLATSGVSVGWIRQPPGK

ALEWLALIDWEDDKGYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22569
2717
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMRVGWIRQPPGK

ALEWLALIDWDDHKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22570
2718
EVTLRESGPALVKPTQTLTLTCTFSGFSLCTSGVGVGWIRQPPGK

ALEWLALIDWDDDNYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22571
2719
EVTLRESGPALVKPTQTLTLTCTFSGFSLFTYGMGVGWIRQPPGK

ALEWLALIDWVDDKFYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22572
2720
EVTLRESGPALVKPTQTLTLTCTFSGFSLCTSGVGVGWIRQPPGK

ALEWLANIWWDDDRYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22573
2721
EVTLRESGPALVKPTQTLTLTCTFSGFSLCTSGMSVGWIRQPPGK

ALEWLALICWDDDRYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22575
2722
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMRVGWIRQPPGK

ALEWLALIDWGDDMSYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22576
2723
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK

ALEWLALIDWEDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22578
2724
EVTLRESGPALVKPTQTLTLTCTFSGFSLLTYGVGVCWIRQPPGK

ALEGWLNIWWADGKCYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22581
2725
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVRVSWIRQPPGK

ALEWLALIDWDDEECYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22582
2726
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMSVSWIRQPPGK

ALEWLALIDWVDDMGYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22583
2727
EVTLRESGPALVKPTQTLTLTCTFSGFSLXTYGMGVGWIRQPPGK

ALEWLALIDWADYRSYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22584
2728
EVTLRESGPALVKPTQTLTLTCTFSGFSLATYGVGVGWIRQPPGK

ALEWLALIDWEDAVNYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22585
2729
EVTLRESGPALVKPTQTLTLTCTFSGFSLCTYGMGVCWIRQPPGK

ALEWLALIGWDDENYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22586
2730
EVTLRESGPALVKPTQTLTLTCTFSGFSLTTYGVRVGWIRQPPGK

ALEWLALIDWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22587
2731
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMSVCWIRQPPGK

ALEWLANIWWDDGCCYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22588
2732
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMRVGWIRQPPGK

ALEWLALIDWCDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22589
2733
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVSWIRQPPGK

ALEWLALIDWDDHXHYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22591
2734
EVTLRESGPALVKPTQTLTLTCTFSGFSLWTSGVGVGWIRQPPGK

ALEWLALIDWEDNKDYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22593
2735
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVRVGWIRQPPGK

ALEWLALIDWVDDMYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22595
2736
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVEWIRQPPGK

ALEWLALIDWDDDKDYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22596
2737
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK

ALEWLALIDWCDNRYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22597
2738
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMRVGWIRQPPGK

ALEWLALIDWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22598
2739
EVTLRESGPALVKPTQTLTLTCTFSGFSLRTYGVSVGWIRQPPGK

ALEWLALIDWYDGKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22599
2740
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVDWIRQPPGK

ALEWLALIDWEDDKSYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22600
2741
EVTLRESGPALVKPTQTLTLTCTFSGFSLWTYGVSVRWIRQPPGK

ALEWLALIDWDDVKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22601
2742
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGK

ALEWLALIDWDDDKFYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22602
2743
EVTLRESGPALVKPTQTLTLTCTFSGFSLPTYGVRVGWIRQPPGK

ALEWLANIWWVDNKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22603
2744
EVTLRESGPALVKPTQTLTLTCTFSGFSLXTSGVRVGWIRQPPGK

ALEWLALIDWDDYQYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22604
2745
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVSVGWIRQPPGK

ALEWLANIWWYDLKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22605
2746
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVGVGWIRQPPGK

ALEWLALIDWDDDKCYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22606
2747
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVGWIRQPPGK

ALEWLANIWWDDEKAYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22607
2748
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVSWIRQPPGK

ALEWLALIDWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22608
2749
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLALIDWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22609
2750
EVTLRESGPALVKPTQTLTLTCTFSGFSLPTSGVSVGWIRQPPGK

ALEWLANIWWADSKFYSTSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22610
2751
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVSVDWIRQPPGK

ALEWLALIDWGDQTNYNPSLKNRLTISKDTSKNQVVXTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22611
2752
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVGVEWIRQPPGK

ALEWLALIDWYDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22612
2753
EVTLRESGPALVKPTQTLTLTCTFSGFSLPTSGVGVGWIRQPPGK

ALEWLALIDWEDHMDYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22614
2754
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMRVGWIRQPPGK

ALEWLALIDWXDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22615
2755
EVTLRESGPALVKPTQTLTLTCTFSGFSLTTSGVGVGWIRQPPGK

ALEWLALIDWYDERFYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22617
2756
EVTLRESGPALVKPTQTLTLTXTFSGFSLSTYGMRVGWIRQPPGK

ALEWLANIWWADNXSYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22618
2757
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMSVGWIRQPPGK

ALEWLALIDWADDNYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22619
2758
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVGWIRQPPGK

ALEWLALIDWEDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22620
2759
EVTLRESGPALVKPTQTLTLTCTFSGFSLWTSGMGVGWIRQPPGK

ALEWLALIDWDDEKAYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22621
2760
EVTLRESGPALVKPTQTLTLTCTFSGFSLWTSGMRVGWIRQPPGK

ALEWLANIWWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22622
2761
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVSVGWIRQPPGK

ALEWLALIDWHDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22624
2762
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMSVGWIRQPPGK

ALEWLALIDWNDNKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22625
2763
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGK

ALEWLALIDWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22626
2764
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVRVCWIRQPPGK

ALEWLALIDWDDDKSYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22627
2765
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVSVTWIRQPPGK

ALEWLALIDWNDDNHYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22628
2766
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVVWIRQPPGK

ALEWLANIWWDDEKCYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22629
2767
EVTLRESGPALVKPTQTLTLTCTFTGFSLYTSGMGVGWIRQPPGK

ALEWLALIDWDDDKNYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22630
2768
EVTLRESGPALVKPTQTLTLTCTFSGFSLFTYGVGVDWIRQPPGK

ALEWLANIWWPDDNYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22631
2769
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGK

ALEWLALIDWDDDXCYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22633
2770
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVSVGWIRQPPGK

ALEWLALIDWDDEKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22634
2771
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGK

ALEWLALIDWIDDEDYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22635
2772
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVRWIRQPPGK

ALEWLANIWWDDNKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22636
2773
EVTLRESGPALVKPTQTLTLTCTFSGFSLCTSGMGVGWIRQPPGK

ALEWLANIWWDDDNYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22637
2774
EVTLRESGPALVKPTQTLTLTCTFSGFSLLTYGMGVGWIRQPPGK

ALEWLANIWWHDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22638
2775
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVAWIRQPPGK

ALEWLANIWWDDDKYYSTSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22639
2776
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVRVGWIRQPPGK

ALEWLALIDWEDYLCYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22640
2777
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGK

ALEWLALIDWDDDYYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22641
2778
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22642
2779
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK

ALEWLANIWWVDDNYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22643
2780
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVYWIRQPPGK

ALEWLALIDWDDDNYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22644
2781
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVGWIRQPPGK

ALEWLALIDWDDGKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22645
2782
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVRVVWIRQPPGK

ALEWLALIDWNDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22646
2783
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGVSVVWIRQPPGK

ALEWLANIWWHDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22648
2784
EVTLRESGPALVKPTQTLTLTCTFSGFSLMTSGMSVCWIRQPPGK

ALEWLANIWWYDHKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22649
2785
EVTLRESGPALVKPTQTLTLTCTFSGFSLRTYGVSVGWIRQPPGK

ALEWLANIWWDDAKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22650
2786
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVRVAWIRQPPGK

ALEWLANIWWDDVKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22651
2787
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIAASYSFDYWGQGTMVTVSS

CL-22652
2788
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARFEYLGAMYXFDYWGQGTMVTVSS

CL-22653
2789
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARXDSFRKPYSFDYWGQGTMVTVSS

CL-22654
2790
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIXSIGSTYWFDYWGQGTMVTVSS

CL-22655
2791
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARLVSIVTKYSFDYWGQGTMVTVSS

CL-22656
2792
XVTLXESGPALXKPTXTLTLTCTFSGFXLSTXGMGVGWIRQPPRK

ALXWLANXWWDDDKYYNPSLXNRLXISKDTSKNQVVLTMTNMDPV

DTAXYYCARXXXXXMXYSFDYWGQGTMVTXSX

CL-22658
2793
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARLEPIPMTYSFDYWGQGTMVTVSS

CL-22659
2794
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIEWSAITYSFDYWGQGTMVTVSS

CL-22660
2795
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIECTXNRYXFDYWGQGTMVTVSS

CL-22661
2796
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIECNSTTYSFDYWGQGTMVTVSS

CL-22664
2797
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARLASLCATYYFDYWGQGTMVTVSS

CL-22665
2798
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIGWRLRMYSFDYWGQGTMVTVSS

CL-22666
2799
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIVSIGGTYSFDYWGQGTMVTVSS

CL-22668
2800
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARVESIGTTYYFDYWGQGTMVTVSS

CL-22669
2801
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARYAPIGTTYWFDYWGQGTMVTVSS

CL-22670
2802
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTRTTYLFDYWGQGTMVTVSS

CL-22671
2803
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTGTAYSFDYWGQGTMVTVSS

CL-22672
2804
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIASVGTSYSFDYWGQGTMVTVSS

CL-22673
2805
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCAREESTCPTYYFDYWGQGTMVTVSS

CL-22675
2806
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARTESIDRAYSFDYWGQGTMVTVSS

CL-22677
2807
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIGSTGISYSFDYWGQGTMVTVSS

CL-22678
2808
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARRESIGTTYSFDYWGQGTMVTVSS

CL-22679
2809
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARKVTIETAYYFDYWGQGTMVTVSS

CL-22680
2810
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATXYCARFASIGTTYSFDYWGQGTMVTVSS

CL-22681
2811
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARMKSIATTYSFDYWGQGTMVTVSS

CL-22682
2812
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESRRATYSFDYWGQGTMVTVSS

CL-22683
2813
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIGXIGSAYTFDYWGQGTMVTVSS

CL-22685
2814
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARTGSGVTTYSFDYWGQGTMVTVSS

CL-22688
2815
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIGSIESAYSFDYWGQGTMVTVSS

CL-22689
2816
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARVYSKGTTYSFDYWGQGTMVTVSS

CL-22691
2817
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARFEALGLSYSFDYWGQGTMVTVSS

CL-22692
2818
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATXYCARRGTIRTTYSFDYWGQGTMVTVSS

CL-22694
2819
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIYWIGPTYCFDYWGQGTMVTVSS

CL-22695
2820
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESMRTTYSFDYWGQGTMVTVSS

CL-22696
2821
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIRSIVTTYSFDYWGQGTMVTVSS

CL-22698
2822
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARTQSSAMTYSFDYWGQGTMVTVSS

CL-22702
2823
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARNESMGTSYSFDYWGQGTMVTVSS

CL-22703
2824
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIEFVRAIYSFDYWGQGTMVTVSS

CL-22704
2825
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARFESLGETYSFDYWGQGTMVTVSS

CL-22705
2826
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIEAIGNQYSFDYWGQGTMVTVSS

CL-22706
2827
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARKDSMVTTYLFDYWGQGTMVTVSS

CL-22707
2828
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARVEWQGSTYSFDYWGQGTMVTVSS

CL-22708
2829
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYMFDYWGQGTMVTVSS

CL-22709
2830
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARCASVSTTYCFDYWGQGTMVTVSS

CL-22710
2831
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARILSIGNTYSFDYWGQGTMVTVSS

CL-22711
2832
EVTLRESGPALVKPTQTLTLTCTFFGFSLSTYGMGVGWIRQPPGK

ALEWLANIWCDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESNGNTYSFDYWGQGTMVTVSS

CL-22712
2833
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARRDSTGTPYSFDYWGQGTMVTVSS

CL-22713
2834
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARVESIVTTYYFDYWGQGTMVTVSS

CL-22714
2835
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARLEKFGRTYPFDYWGQGTMVTVSS

CL-22715
2836
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARFKSNRPSYSFDYWGQGTMVTVSS

CL-22716
2837
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSXKNRLXISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLDTTYXFDXXGQGXMXTVSS

CL-22717
2838
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIXATGMLYSFDYWGQGTMVTVSS

CL-22718
2839
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIETTYXFDYWGQGTMVTVSS

CL-22719
2840
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIEXMAPMYSFDYWGQGTMVTVSS

CL-22720
2841
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARVRPLVTIYSFDYWGQGTMVTVSS

CL-22721
2842
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIDSVWTTYSFDYWGQGTMVTVSS

CL-22722
2843
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARVEEIGNTYNFDYWGQGTMVTVSS

CL-22723
2844
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARRGLFRIRYSFDYWGQGTMVTVSS

CL-22724
2845
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRXTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22725
2846
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIEVIGTAYSFDYWGQGTMVTVSS

CL-22726
2847
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARLDVIGMLYAFDYWGQGTMVTVSS

CL-22728
2848
EVTLRESGPALVKPTKTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIMSIGSSYXFDYWGQGTMVTVSS

CL-22729
2849
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIDWIGTTYSFDYWGQGTMVTVSS

CL-22730
2850
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARNSSIGSTYSFDYWGQGTMVTVSS

CL-22731
2851
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESPGTWYSFDYWGQGTMVTVSS

CL-22732
2852
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIEWIGITYCFDYWGQGTMVTVSS

CL-22733
2853
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIEXLGTTYSFDYWGQGTMVTVSS

CL-22734
2854
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARKELTCSTYSFDYWGQGTMVTVSS

CL-22736
2855
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIEXIRMRYSFDYWGQGTMVTVSS

CL-22737
2856
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARKAAIATLYLFDYWGQGTMVTVSS

CL-22738
2857
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARRRPIVTTYSFDYWGQGTMVTVSS

CL-22740
2858
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTVYSFDYWGQGTMVTVSS

CL-22741
2859
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIASIGSMYSFDYWGQGTMVTVSS

CL-22742
2860
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESRATTYSFDYWGQGTMVTVSS

CL-22743
2861
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARNVWLGTTYSFDYWGQGTMVTVSS

CL-22744
2862
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIMSIGTAYSFDYWGQGTMVTVSS

CL-22745
2863
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIKWIWTTYSFDYWGQGTMVTVSS

CL-22746
2864
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIEXRGSTYIFDYWGQGTMVTVSS

CL-22759
2865
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCXRIESIGTTYSFDYWGQGTMVTVSS

CL-22763
2866
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNXDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-22806
2867
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYXFXYWGQGTMVTVSS

CL-22812
2868
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATXYCARIESIGTTYSFDYXGQGTMVTVSS

CL-22819
2869
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCAXIESIGTTYSFDYWGQGTMVTVSS

CL-22833
2870
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYXCARIESIGTTYSXDYWGQGTXVTVSS

CL-25629
2871
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRKPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25633
2872
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNVDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25645
2873
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ELEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25649
2874
EVTLRESGPALVKPTQTLTLTCTFSGFSLATSGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25656
2875
EVTLRESGPALVKPTQTLTLTCTFSGFRLSTYGMGVGWIRKPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25657
2876
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTANYYCARIASIPTMYAFDYWGQGTMVTVSS

CL-25676
2877
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWMANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25679
2878
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDHDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25684
2879
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25696
2880
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGVGVGWIRQPPGK

ALEWLANIWWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25697
2881
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRKPPGK

ALEWLANIWWDDDKYYNPSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25699
2882
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK

ALEWLANIWWDDDRYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25700
2883
EVTLRESGPALVKPTQTLTLTCTFSGFSLMTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25702
2884
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNTSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25710
2885
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLENIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25738
2886
EVTLKKSGPALVKPXQTLTLTCTFSGFSLSTYGMGVGWIRXPPGK

GLEWLANIWWDDDKYYNPSLKNRLTIXKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25739
2887
EVTLKESGPALVKPTXTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25745
2888
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSX

CL-25749
2889
EVTLRESGPALVKPTXTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25755
2890
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARMKSIGSTYSFDYWGQGTMVTVSS

CL-25763
2891
EVTLKESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25765
2892
EVTLRESGPALVKPTXTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGXMVTVSS

CL-25769
2893
EVTLKESGPALVKPTXTLTLTCTFSGFSLSTYGMGVGWIRHPPGK

ALEWLANIWWNNDNYYNPSLKNRLTINKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25773
2894
EVTLKESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEGLANIWWDDDKYYNPSLKNRLTINKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25789
2895
EVTLRESGPALVKPTHTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25791
2896
EVTLKESGPALVKPTQTLTLTCTFSGFRLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25797
2897
EVTLXESGPALVKPTXTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-25815
2898
EVTLKESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTINKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-28144
2899
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESGWTTYSFDYWGQGTMVTVSS

CL-28145
2900
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIWTSYSFDYWGQGTMVTVSS

CL-28146
2901
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIVSSWTIYSFDYWGQGTMVTVSS

CL-28147
2902
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIYSSGTVYSFDYWGQGTMVTVSS

CL-28148
2903
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGISYSFDYWGQGTMVTVSS

CL-28149
2904
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTGTSYSFDYWGQGTMVTVSS

CL-28151
2905
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGPSYSFDYWGQGTMVTVSS

CL-28152
2906
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGSSYSFDYWGQGTMVTVSS

CL-28155
2907
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIVSIGWSYSFDYWGQGTMVTVSS

CL-28156
2908
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIYSDWTIYSFDYWGQGTMVTVSS

CL-28157
2909
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWITYSFDYWGQGTMVTVSS

CL-28160
2910
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESEWTTYNFDYWGQGTMVTVSS

CL-28161
2911
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSPTTYSFDYWGQGTMVTVSS

CL-28162
2912
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGISYSFDYWGQGTMVTVSS

CL-28163
2913
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSATIYSFDYWGQGTMVTVSS

CL-28164
2914
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTGTTYSFDYWGQGTMVTVSS

CL-28167
2915
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTSYSFDYWGQGTMVTVSS

CL-28169
2916
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIVSTWTTYSFDYWGQGTMVTVSS

CL-28170
2917
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGTSYNFDYWGQGTMVTVSS

CL-28173
2918
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTWWTYSFDYWGQGTMVTVSS

CL-28175
2919
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSGWSYAFDYWGQGTMVTVSS

CL-28177
2920
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGYSYSFDYWGQGTMVTVSS

CL-28180
2921
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWMANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIETLGISYSFDYWGQGTMVTVSS

CL-28181
2922
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESMWSSYSFDYWGQGTMVTVSS

CL-28182
2923
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIETIGTSYSFDYWGQGTMVTVSS

CL-28186
2924
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIVSDVTTYSFDYWGQGTMVTVSS

CL-28187
2925
EVTLRESGPALVKPTKTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESFGTSYSFDYWGQGTMVTVSS

CL-28189
2926
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIKSIGWTYSFDYWGQGTMVTVSS

CL-28190
2927
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESNFWSYSFDYWGQGTMVTVSS

CL-28195
2928
EVTLRESGPALVKPTHTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIMSLETRYDFYYWGQGTMVTVSS

CL-28196
2929
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESVETSYNFDYWGQGTMVTVSS

CL-28198
2930
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESFWTTYSFDYWGQGTMVTVSS

CL-28204
2931
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESMGTSYSFDYWGQGTMVTVSS

CL-28205
2932
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIWSSYSFDYWGQGTMVTVSS

CL-28208
2933
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGFSYSFDYWGQGTMVTVSS

CL-28212
2934
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESVGPSYSFDYWGQGTMVTVSS

CL-28213
2935
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGWTYSFDYWGQGTMVTVSS

CL-28215
2936
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESDWTTYSFDYWGQGTMVTVSS

CL-28219
2937
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGPSYSFDYWGQGTMVTVSS

CL-28233
2938
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLVTSYDFDYWGQGTMVTVSS

CL-28235
2939
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESVGTSYNFDYWGQGTMVTVSS

CL-29595
2940
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTEASYSFDYWGQGTMVTVSS

CL-29596
2941
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESNGASYSFDYWGQGTMVTVSS

CL-29597
2942
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSVTTYSFDYWGQGTMVTVSS

CL-29598
2943
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDNYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARXESXWTSYSFDYWGQGTMVTVSS

CL-29600
2944
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGASYSFDYWGQGTMVTVSS

CL-29601
2945
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTGRSYGFDYWGQGTMVTVSS

CL-29607
2946
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIETLGTSYSFDYWGQGTMVTVSS

CL-29608
2947
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGTTYSFDYWGQGTMVTVSS

CL-29611
2948
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIPTAYSFDYWGQGTMVTVSS

CL-29612
2949
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGTTYSFDYWGQGTMVTVSS

CL-29613
2950
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARLESIATTYSFDYWGQGTMVTVSS

CL-29614
2951
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGPSYSFDYWGHGTMVTVSS

CL-29617
2952
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSYTSYSFDYWGQGTMVTVSS

CL-29618
2953
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTWTSYSFDYWGQGTMVTVSS

CL-29620
2954
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSVTNYQFDYWGQGTMVTVSS

CL-29621
2955
EVTLRESGPALVKPTQTLTLICTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTSYSFDYWGQGTMVTVSS

CL-29625
2956
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGPAYSFDYWGQGTMVTVSS

CL-29627
2957
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSNNQVVLTMTNMDPV

DTATYYCARIESFGSSYSFDYWGQGTMVTVSS

CL-29629
2958
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSETTYTFDYWGQGTMVTVSS

CL-29630
2959
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIWTTYSFDYWGQGTMVTVSS

CL-29631
2960
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNLLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESFGTSYSFDYWGQGTMVTVSS

CL-29632
2961
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIASXGTSYSFDYWGQGTMVTVSS

CL-29634
2962
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDEKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTSYSFDYWGQGTMVTVSS

CL-29635
2963
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSPTSYSFDYWGQGTMVTVSS

CL-29636
2964
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGWSYAFDYWGQGTMVTVSS

CL-29637
2965
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGWTYSFDYWGQGTMVTVSS

CL-29638
2966
EVTLRESGPALVKPTQTLTLTCTFSGFSLATSGVSVLWIRQPPGK

ALEWLANIWWDDGXYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESFGTSYSFDYWGQGTMVTVSS

CL-29639
2967
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLWTTYSFDYWGQGTMVTVSS

CL-29643
2968
EVTLRESGPALVKPTQTLTLTCTFSGFSLDTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSGYTYSFDYWGQGTMVTVSS

CL-29644
2969
EVTLRESGPALVKPTQTLTLTCTFSGFSLTTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSGSSYSFDYWGQGTMVTVSS

CL-29645
2970
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARVASSWVEYSFDYWGQGTMVTVSS

CL-29647
2971
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESFGTSYSFDYWGQGTMVTVSS

CL-29648
2972
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSGTTYSFDYWGQGTMVTVSS

CL-29649
2973
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRKPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESMGISYSFDYWGQGTMVTVSS

CL-29651
2974
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGIAYSFDYWGQGTMVTVSS

CL-29654
2975
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIXWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIVTTYSFDYWGQGTMVTVSS

CL-29658
2976
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESGWTIYSFDYWGQGTMVTVSS

CL-29662
2977
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGPTYSFDYWGQGTMVTVSS

CL-29663
2978
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESVGTSYSFDYWGQGTMVTVSS

CL-29665
2979
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK

ALEWLANIWWDDDQYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTTYSFDYWGQGTMVTVSS

CL-29667
2980
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESFGPSYSFDYWGQGTMVTVSS

CL-29668
2981
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSGTSYSFDYWGQGTMVTVSS

CL-29673
2982
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARXXSIVTTYSFDYWGQGTMVTVSS

CL-29674
2983
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTSYSFDYWGQGTMVTVSS

CL-29676
2984
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGLIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESVGTSYSFDYWGQGTMVTVSS

CL-29678
2985
EVTLKESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIGSSGTTYSFDYWGQGTMVTVSS

CL-29679
2986
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNTSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIDSFGAIYSFDYWGQGTMVTVSS

CL-29680
2987
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ELEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

ETATYYCARIESIGTAYNFDYWGQGTMVTVSS

CL-29683
2988
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGTSYSFDYWGQGTMFTVSS

CL-29688
2989
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGTSYSFDYWGQGTMVTVSS

CL-29689
2990
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIEAKGTTYSFDYWGQGTMVTVSS

CL-29699
2991
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESRGTSYSFDYWGQGTMVTVSS

CL-29706
2992
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESMGPTYSFDYWGQGTMVTVSS

CL-29707
2993
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIETSYSFDYWGQGTMVTVSS

CL-29709
2994
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYRARIESLGTTYSFDYWGQGTMVTVSS

CL-29711
2995
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRHPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESMGTSYSFDYWGQGTMVTVSS

CL-29713
2996
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESMGTTYSFDYWGQGTMVTVSS

CL-29714
2997
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCALIESSGTTYSFDYWGQGTMVTVSS

CL-29720
2998
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESKGVSYSFDYWGQGTMVTVSS

CL-29721
2999
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIPTTYSFDYWGQGTMVTVSS

CL-29727
3000
EVTLRESXPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ELEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGTTYSFDYWGQGTMVTVSS

CL-29728
3001
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGITYSFDYWGQGTMVTVSS

CL-29730
3002
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESMGRSYSFDYWGQGTMVTVSS

CL-29731
3003
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIATSYSFDYWGQGTMVTVSS

CL-29732
3004
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYNFDYWGQGTMVTVSS

CL-29735
3005
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESMGPMYSFDYWGQGTMVTVSS

CL-29736
3006
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTAYSFDYWGQGTMVTVSS

CL-29738
3007
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARMESSWTTYSFDYWGQGTMVTVSS

CL-29739
3008
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTGATYSFDYWGQGTMVTVSS

CL-29740
3009
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESMGPKYSFDYWGQGTMVTVSS

CL-29742
3010
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESMGMSYSFDYWGQGTMVTVSS

CL-29744
3011
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGLSYSFDYWGQGTMVTVSS

CL-29745
3012
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYRARIESLGMSYSFDYWGQGTMVTVSS

CL-29746
3013
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARLXSTGTNYSFDYWGQGTMVTVSS

CL-29748
3014
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSDTIYSFDYWGQGTMVTVSS

CL-29749
3015
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVDWIRQPPGK

ALEWLALIDWDDDIHYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-29751
3016
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESVGTTYSFDYWGQGTMVTVSS

CL-29753
3017
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWYDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTGTTYSFDYWGQGTMVTVSS

CL-29756
3018
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARNESFGRMYXFDYWGQGTMVTVSS

CL-29757
3019
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARXESIGTTYSFDYWGQGTMVTVSS

CL-29758
3020
EVTLRESGPSLVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESFGTTYSFDYWGQGTMVTVSS

CL-29759
3021
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIETLGTAYSFDYWGQGTMVTVSS

CL-29761
3022
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESFGSSYSFDYWGQGTMVTVSS

CL-29763
3023
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESGPTTYSFDYWGQGTMVTVSS

CL-29765
3024
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTMYSFDYWGQGTMVTVSS

CL-29771
3025
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTXTTYSXDYWGQGTMVTVSS

CL-29772
3026
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGITYSFDYWGQGTMVTVSS

CL-29773
3027
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESMETTYSFDYWGQGTMVTVSS

CL-29776
3028
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESNAITYSFDYWGQGTMVTVSS

CL-29777
3029
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSETTYMFDYWGQGTMVTVSS

CL-29780
3030
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLTNIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESMGTSYSFDYWGQGTMVTVSS

CL-29786
3031
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIYSIGTSYSFDYWGQGTMVTVSS

CL-33292
3032
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSPWTYSFDYWGQGTMVTVSS

CL-33332
3033
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESRPDTYSFDYWGQGTMVTVSS

CL-33361
3034
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIQSSASNYEFDYWGQGTMVTVSS

CL-33368
3035
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIQSGWTNXEFDYWGQGTMVTVSS

CL-33583
3036
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIQSIWTRYDFDYWGQGTMVTVSS

CL-33588
3037
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIQSFATNYEFDYWGQGTMVTVSS

CL-33591
3038
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESVPWSYSFDYWGQGTMVTVSS

CL-33592
3039
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTPFSYSFDYWGQGTMVTVSS

CL-33599
3040
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTSYDFDYWGQGTMVTVSS

CL-33601
3041
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIQSSSTNYEFDYWGQGTMVTVSS

CL-33612
3042
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIQSSWRRYEFDYWGQGTMVTVSS

CL-33616
3043
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIKTSATNYDFDYWGQGTMVTVSS

CL-33618
3044
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSAFSYNFDYWGQGTMVTVSS

CL-33626
3045
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVFLTMTNMDPV

DTATYYCARIVSSLTEYNFDYWGQGTMVTVSS

CL-33627
3046
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESRVDSYSFDYWGQGTMVTVSS

CL-33628
3047
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTWTSYDFDYWGQGTMVTVSS

CL-33654
3048
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESVAWRYDFDYWGQGTMVTVSS

CL-33657
3049
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLPTSYNFDYWGQGTMVTVSS

CL-33663
3050
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSPFTYSFDYWGQGTMVTVSS

CL-33665
3051
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESDYTKYDFDYWGQGTMVTVSS

CL-33667
3052
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLPTRYDFDYWGQGTMVTVSS

CL-33674
3053
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWMANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIPTSYSFDYWGQGTMVTVSS

CL-33679
3054
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESKPTSYSFDYWGQGTMVTVSS

CL-33680
3055
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTTYSFDYWGQGTMVTVSS

CL-33687
3056
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTSYSFDYWGQGTMVTVSS

CL-33688
3057
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTFKNQVVLTMTNMDPV

DTATYYCARIESIPTSYSFDYWGQGTMVTVSS

CL-33690
3058
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDETYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESDFTSYMFDYWGQGTMVTVSS

CL-33693
3059
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESNWWSYSFDYWGQGTMVTVSS

CL-33696
3060
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSFTTYSFDYWGQGTMVTVSS

CL-33698
3061
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESXGXSYSFDYWGQGTMVTVSS

CL-33705
3062
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESRLDTYSFDYWGQGTMVTVSS

CL-33707
3063
EVTLRESGPALVKPTQTLTLTCTFSGFSLDTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTSYSFDYWGQGTMVTVSS

CL-33709
3064
EVTLRESGPALVKPTQTLTLTCTFSGFSLATSGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIPWSYSFDYWGQGTMVTVSS

CL-33711
3065
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTGYSYSFDYWGQGTMVTVSS

CL-33712
3066
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRKPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTSYSFDYWGQGTMVTVSS

CL-33722
3067
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSFFSYSFDYWGQGTMVTVSS

CL-33725
3068
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDEYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGTSYSFDYWGQGTMVTVSS

CL-33734
3069
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLPGSYDFDYWGQGTMVTVSS

CL-33735
3070
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ELEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESNPLTYSFDYWGQGTMVTVSS

CL-33741
3071
EVTLRESGPALVKPTKTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGISYSFDYWGQGTMVTVSS

CL-33743
3072
EVTLRESGPALVKPTQTLTLTCTFSGFSLATYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLPTSYSFDYWGQGTMVTVSS

CL-33745
3073
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSPFAYSFDYWGQGTMVTVSS

CL-33746
3074
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWFTYAFDYWGQGTMVTVSS

CL-33747
3075
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIETIXPKYSFDYWGQGTMVTVSS

CL-33754
3076
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTTYAFDYWGQGTMVTVSS

CL-33755
3077
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSEWTYSFDYWGQGTMVTVSS

CL-33756
3078
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIQSSWTTYEFDYWGQGTMVTVSS

CL-33760
3079
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIETLGSSYSFDYWGQGTMVTVSS

CL-33766
3080
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRKPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSFTSYSFDYWGQGTMVTVSS

CL-33770
3081
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESGGISYSFDYWGQGTMVTVSS

CL-33773
3082
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLPTTYSFDYWGQGTMVTVSS

CL-33777
3083
EVTLRESGPALVKPTQTLTLTCTFSGFSLYTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESVGTSYSFDYWGQGTMVTVSS

CL-33781
3084
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWYSYNFDYWGQGTMVTVSS

CL-33782
3085
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWRSYCFDYWGQGTMVTVSS

CL-33784
3086
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSPMSYSFDYWGQGTMVTVSS

CL-33789
3087
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLPTSYCFDYWGQGTMVTVSS

CL-33791
3088
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWWTYSFDYWGQGTMVTVSS

CL-33794
3089
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESRPTSYCFDYWGQGTMVTVSS

CL-33795
3090
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESVPTSYSFDYWGQGTMVTVSS

CL-33798
3091
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIQSDGPMYSFDYWGQGTMVTVSS

CL-33802
3092
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESTGASYSFDYWGQGTMVTVSS

CL-33813
3093
EVTLRESGPALVKPTQTLTLTCTFSGFSLYTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLPTSYSFDYWGQGTMVTVSS

CL-33814
3094
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDTV

DTATYYCARIESTPWSYSFDYWGQGTMVTVSS

CL-33816
3095
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTSYAFDYWGQGTMVTVSS

CL-33823
3096
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ELEWLANIWWDDDKYYNPSLNNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSGPKYSFDYWGQGTMVTVSS

CL-33833
3097
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGWSYSFDYWGQGTMVTVSS

CL-33840
3098
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSAWTYSFDYWGQGTMVTVSS

CL-33842
3099
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESYGPKYSFDYWGQGTMVTVSS

CL-33844
3100
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKTRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIETSWWKYSFDYWGQGTMVTVSS

CL-33847
3101
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNLSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSPTSYSFDYWGQGTMVTVSS

CL-33849
3102
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIVSSYFTYSFDYWGQGTMVTVSS

CL-33858
3103
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDEEYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGISYSFDYWGQGTMVTVSS

CL-33861
3104
EVTLRESGPALVKPTQTLTLTCTFSGFSLYTSGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTTYSFDYWGQGTMVTVSS

CL-33862
3105
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIPTRYDFDYWGQGTMVTVSS

CL-41180
3106
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNRVVLTMTNMDPV

DTATYYCARIVSDWTTYSFDYWGQGTMVTVSS

CL-41185
3107
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTDMDPV

DTATYYCARIESSWTTYSFDYWGQGTMVTVSS

CL-41193
3108
RXHWRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIETFGPKYSFDYWGQGTMVTVSS

CL-41204
3109
RGNTEESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTTTYYCARIESLPTSYSFDYWGQGTMVTVSS

CL-41213
3110
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLXTNYSFDYWGQGTMVTVSS

CL-41224
3111
EVTLREGGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESHWWSYAFDYWGQGTMVTVSS

CL-41229
3112
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSFTSYSFDYWGQGTMVTEXC

CL-41232
3113
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESHWWSYAFDYWGQGTMVTVSS

CL-41233
3114
RXHXGESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTTYSFDYWGQGTMVTVSS

CL-41246
3115
EVTLRESGPALAKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESHWWSYAFDYWGQGTMVTVSS

CL-41252
3116
EVTLRESGPALVKPTQTLTLTCAFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTTYSFDYWGQGTMVTVSS

CL-41255
3117
EVTLRESGPALVEPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESNPWKYSFDYWGQGTMVTVSS

CL-41257
3118
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESNWRTYSFDYWGQGTMVTVSS

CL-41260
3119
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSFTSYSFDYWGQGTMVTVSS

CL-41261
3120
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESHWWSYAFDYWGQGTMVTVSI

CL-41262
3121
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIVSDWTTYSFDYWGQGTMVTVSS

CL-41268
3122
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGWSYSFDYWGQGTMVTVSS

CL-41269
3123
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLPTSYSFDYWGQGTMVTVSS

CL-41270
3124
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTTYSFDYWGQGTMVTVSS

CL-41272
3125
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESNPWKYSFDYWGQGTMVTVSS

CL-41273
3126
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIETFGPKYSFDYWGQGTMVTVSS

CL-41276
3127
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGIGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESMGPKYAFDYWGQGTMVTVSS

CL-41283
3128
EVTLRESGPALVKPTQTLTLTRTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIPTSYSFDYWGQGTMVTVSS

CL-41325
3129
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRKPPGK

ALEWLANIWWDGDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSGPKYSFDYWGQGTMVTVSS

CL-41342
3130
EVTLRESGPALVKPTQTLTLACTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESVWTKYYFDXGGQGTMVTVSS

CL-41348
3131
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYEMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTPKNQVVLTMTNMDPV

DTATYYCARIESVWTRYDFDYWGQGTMVKXVV

CL-41353
3132
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESLGTSYSFDYWGQGTMVTVSS

CL-41358
3133
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGPKYSFDYWGQGTMVTVSS

CL-41361
3134
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESVWTRYDFDYWGQGTMVTVSS

CL-41362
3135
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIETMGPKYSFDYWGQGTMVTVSS

CL-41365
3136
RGNTRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALKWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGPKYSFDYWGQGTMVTVSS

CL-41366
3137
EVTLRESGPAQVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIPTSYSFDYWGQGTMVTVSS

CL-41367
3138
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRKPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSGPKYSFDYWGQGTMVTVSS

CL-41368
3139
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGPKYSFDXGGQGTMVTVSS

CL-41369
3140
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIPTSYSFDYWGQGTMVTVSS

CL-41376
3141
EVKLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIQTIGTNYSFDYWGQGTMVTVSS

CL-41377
3142
EGQLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTSYSFDYWGQGTMVTVSS

CL-41381
3143
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTSYSFDYWGQSTMVTVSS

CL-41385
3144
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTSYSFDYWGQGTIVTVSS

CL-41399
3145
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKSRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTSYSFDYWGQGTMVTVSS

CL-41405
3146
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTAAYYCARIETIGPKYSFDYWGQGTMVTVSS

CL-41411
3147
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIQSGWTNYEFDYWGQGTMVTVVV

CL-41420
3148
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIQSMWTRYDFDYWGQGTMVTVSS

CL-41425
3149
RXHXRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSGPKYSFDYWGQGTMVTVSS

CL-41427
3150
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DAATYYCARIQSGWTNYEFDYWGQGTMVTVSS

CL-41436
3151
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTSYSFDYWSQGTMVTVSS

CL-41439
3152
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIETIGPKYSFDYWGQGTMVTVSS

CL-41443
3153
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSGPKYSFDYWGQGTMVTVSS

CL-41446
3154
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTSYSFDYWGQGTMVTVSS

CL-41447
3155
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQAVLTMTNMDPV

DTATYYCARIQSGWTNYEFDYWGQGTMVTVSS

CL-41448
3156
RGNTEKSGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSWTSYSFDYWGQGTMVTVSS

CL-41449
3157
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIQSGWTNYEFDYWGQGTMVTVSS

CL-41452
3158
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMEXVVR

CL-41459
3159
EVTLRESGPALVKPTQTLTLTCTFSGFILSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-41463
3160
EVTLRESGPALVKSTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

CL-41465
3161
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSS

Table 47 provides a list of amino acid sequences of VL regions of affinity matured humanized PDGF antibodies derived from hBDI-9E8.4. Amino acid residues of individual CDRs of each VL sequence are indicated in bold.

TABLE 47

List of Amino Acid Sequences Of Affinity

Matured hBDI-9E8.4 VL Variants

Clone
SEQ ID NO:
VL

CL-22656
3162
EIVLTQSXGTLSLSPGXRXTLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-22715
3163
EIVLXQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-22747
3164
EIVLTQSPGTLSLSPGERATLSCERSSGSIWYSYVSWYQQKPGQ

APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINKDLTFGGGTKVEIK

CL-22748
3165
EIVLTQSPGTLSLSPGERATLSCERSSGSIGYSYVSWYQQKPGQ

APRLVIYAADQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGIIIDITFGGGTKVEIK

CL-22749
3166
EIVLTQSPGTLSLSPGERATLSCERSSGSIEHAYVSWYQQKPGQ

APRLLIYGADHRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDFNNTITFGGGTKVEIK

CL-22750
3167
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHCYVSWYQQKPGQ

APRLVIYAADHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGKNIDGTFGGGTKVEIK

CL-22752
3168
EIVLTQSPGTLSLSPGERATLSCRASSGDIGDFCVSWYQQKPGQ

APRLLIYVDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGRRLDITFGGGTKVEIK

CL-22753
3169
EIVLTQSPGTLSLSPGERATLSCERSSGDIVLPYVSWYQQKPGQ

APRLVIYAADWRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDITIDTVFGGGTKVEIK

CL-22754
3170
EIVLTQSPGTLSLSPGERATLSCRASSGSIGYECVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDRQIVFGGGTKVEIK

CL-22755
3171
EIVLTQSPGTLSLSPGERATLSCRASSGSIVGSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGVHIDITFGGGTKVEIK

CL-22756
3172
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHSDVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIGQVFGGGTKVEIK

CL-22758
3173
EIVLTQSPGTLSLSPGERATLSCRASSGSIGHPYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGCHIYNVFGGGTKVEIK

CL-22759
3174
EIVLTQSPGTLSLSPGERATLSCERSSGSICDTYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIYIHIVFGGGTKVEIK

CL-22760
3175
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSCVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGIDIVIVFGGGTKVEIK

CL-22761
3176
EIVLTQSPGTLSLSPGERATLSCERSSGSIGYSDVSWYQQKPGQ

APRLLIYADDKRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDKYIVFGGGTKVEIK

CL-22763
3177
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHFYVSWYQQKPGQ

APRLVIYAADHRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGTNIEIVFGGGTKVEIK

CL-22764
3178
EIVLTQSPGTLSLSPGERATLSCERSSGDIGXADVSWYQQKPGQ

APRLVIYVDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGEYIDRTFGGGTKVEIK

CL-22765
3179
EIVLTQSPGTLSLSPGERATLSCRASSGSIGGSYVSWYQQKPGQ

APRLLIYADDHRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGINIGTVFGGGTKVEIK

CL-22766
3180
EIVLTQSPGTLSLSPGERATLSCERSSGDIECDFVSWYQQKPGQ

APRLVIYADDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGINNDITFGGGTKVEIK

CL-22767
3181
EIVLTQSPGTLSLSPGERATLSCERSSGDIGCSYVSWYQQKPGQ

APRLVIYGDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINKEITFGGGTKVEIK

CL-22768
3182
EIVLTQSPGTLSLSPGERATLSCERSSGSIGHSRVSWYQQKPGQ

APRLVIYVDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDNNIATVFGGGTKVEIK

CL-22769
3183
EIVLTQSPGTLSLSPGERATLSCERSSGSINHCHVSWYQQKPGQ

APRLVIYAADXRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIILDITFGGGTKVEIK

CL-22770
3184
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDHRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDFDIDITFGGGTKVEIK

CL-22771
3185
EIVLTQSPGTLSLSPGERATLSCRASSGSIRYTYVSWYQQKPGQ

APRLVIYAADEPPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINRNIVFGGGTKVEIK

CL-22772
3186
EIVLTQSPGTLSLSPGERATLSCERSSGDIGCTYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGISTVLVFGGGTKVEIK

CL-22773
3187
EIVLTQSPGTLSLSPGERATLSCERSSGDIRYCYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDVDIVFGGGTKVEIK

CL-22774
3188
EIVLTQSPGTLSLSPGERATLSCRASSGSISQSYVSWYQQKPGQ

APRLVIYADDLRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGINIDITFGGGTKVEIK

CL-22775
3189
EIVLTQSPGTLSLSPGERATLSCERSSGSIFYGCVSWYQQKPGQ

APRLLIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDINIVITFGGGTKVEIK

CL-22776
3190
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSYVSWYQQKPGQ

APRLVIYAADQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINKYAVFGGGTKVEIK

CL-22777
3191
EIVLTQSPGTLSLSPGERATLSCRASSGDISYSYVSWYQQKPGQ

APRLVIYVDDERASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDIYKDLTFGGGTKVEIK

CL-22778
3192
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDXRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDSNIDIVFGGGTKVEIK

CL-22779
3193
EIVLTQSPGTLSLSPGERATLSCERSSGSICYXYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDVNLEHTFGGGTKVEIK

CL-22780
3194
EIVLTQSPGTLSLSPGERATLSCRASSGDIRHCYVSWYQQKPGQ

APRLLIYPDDLRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-22781
3195
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYVDDHRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGTSLDNTFGGGTKVEIK

CL-22782
3196
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHSYVSWYQQKPGQ

APRLVIYAADHRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGVNIYITFGGGTKVEIK

CL-22783
3197
EIVLTQSPGTLSLSPGERATLSCRASSGSIRYSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDINKVIVFGGGTKVEIK

CL-22784
3198
EIVLTQSPGTLSLSPGERATLSCERSSGDIGKPTSPWYQQKPGQ

APRLVIYSADERPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGVNRDIVFGGGTKVEIK

CL-22785
3199
EIVLTQSPGTLSLSPGERATLSCERSSGSIGPCYVSWYQQKPGQ

APRLVIYADDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDINLVITFGGGTKVEIK

CL-22786
3200
EIVLTQSPGTLSLSPGERATLSCERSSGSIHYSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGISIDITFGGGTKVEIK

CL-22787
3201
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDPYVSWYQQKPGQ

APRLVIYAADPRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDISIYIVFGGGTKVEIK

CL-22788
3202
EIVLTQSPGTLSLSPGERATLSCERSSGDIKHCCVSWYQQKPGQ

APRLVIYLDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDISIDITFGGGTKVEIK

CL-22789
3203
EIVLTQSPGTLSLSPGERATLSCRASSGSIVQSYVSWYQQKPGQ

APRLLIYSDDPRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGLYRDITFGGGTKVEIK

CL-22790
3204
EIVLTQSPGTLSLSPGERATLSCRASSGSISYSYVSWYQQKPGQ

APRLLIYADDXRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQHYDIHINITFGGGTKVEIK

CL-22791
3205
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYAHVSWYQQKPGQ

APRLLIYGDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGKNSEITFGGGTKVEIK

CL-22792
3206
EIVLTQSPGTLSLSPGERATLSCRASSGSIGHSYVSWYQQKPGQ

APRLLIYDDDPRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGINVDIVFGGGTKVEIK

CL-22794
3207
EIVLTQSPGTLSLSPGERATLSCRASSGSIGHSCVSWYQQKPGQ

APRLVIYSADERASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDLNTLFVFGGGTKVEIK

CL-22795
3208
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHXYVSWYQQKPGQ

APRLVIYAADHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGISIAVVFGGGTKVEIK

CL-22796
3209
EIVLTQSPGTLSLSPGERATLSCERSSGSIGLSYVSWYQQKPGQ

APRLVIYAADQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDRHLDATFGGGTKVEIK

CL-22797
3210
EIVLTQSPGTLSLSPGERATLSCERSSGDIGCSYVSWYQQKPGQ

APRLLIYGADHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGIDIDITFGGGTKVEIK

CL-22798
3211
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDASVSWYQQKPGQ

APRLLIYAADQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDITIGVVFGGGTKVEIK

CL-22799
3212
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYCFVSWYQQKPGQ

APRLVIYAADLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIKIGITFGGGTKVEIK

CL-22800
3213
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYWDVSWYQQKPGQ

APRLLIYADDERASGIPDRFSGSGSGTDFTLTISRLEPEDFSVY

YCQSYGINKDFVFGGGTKVEIK

CL-22801
3214
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHTYVSWYQQKPGQ

APRLVIYTDDLRASGIPDRFSGSGSGTDFTLTISRLDPEDFAVY

YCQQYDLNIDIVFGGGTKVEIK

CL-22802
3215
EIVLTQSPGTLSLSPGERATLSCERSSGSIGXSHVSWYQQKPGQ

APRLLIYVDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIKKGXTFGGGTKVEIK

CL-22803
3216
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHSFVSWYQQKPGQ

APRLVIYADDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGVNIDITFGGGTKVEIK

CL-22804
3217
EIVLTQSPGTLSLSPGERATLSCRASSGSIFQSDVSWYQQKPGQ

APRLVIYADDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGKNIYIVFGGGTKVEIK

CL-22805
3218
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYSAVSWYQQKPGQ

APRLVXYVDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIKLDFVFGGGTKVEIK

CL-22806
3219
EIVLTQSPGTLSLSPGERATLSCRASSGSIVYSSVSWYQQKPGQ

APRLVIYVXDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDIHIDITFGGGTKVEIK

CL-22807
3220
EIVLTQSPGTLSLSPGERATLSCRASSGSIRDFYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGINLDNTFGGGTKVEIK

CL-22808
3221
EIVLTQSPGTLSLSPGERATLSCERSSGDISDSHVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDITFGGGTKVEIK

CL-22811
3222
EIVLTQSPGTLSLSPGERATLSCERSSGSIALSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINLDIVFGGGTKVEIK

CL-22812
3223
EIVLTQSPGTLSLSPGERATLSCERSSGDMRYSDVSWYQQKPGQ

APRMVIYAVDQRASGIPDRLSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDVGMVLTFGGGTKVEIK

CL-22813
3224
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHFYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGISIDLTFGGGTKVEIK

CL-22815
3225
EIVLTQSPGTLSLSPGERATLSCERSSGDIDHSYVSWYQQKPGQ

APRLVIYADDPRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGLNIDLTFGGGTKVEIK

CL-22816
3226
EIVLTQSPGTLSLSPGERATLSCERSSGSIRHSCVSWYQQKPGQ

APRLVIYADDHRASGIPDRFSDSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-22818
3227
EIVLTQSPGTLSLSPGERATLSCRASSGDIWHSYVSWYQQKPGQ

APRLVIYTDDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGCDKDITFGGGTKVEIK

CL-22819
3228
EIVLTQSPGTLSLSPGERATLSCRASSGSIGDFYVSWYQQKPGQ

APRLVIYADDQRPTGIPDRLSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGIHIEIVFGGGTKVEIK

CL-22820
3229
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHSAVSWYQQKPGQ

APRLLIYADDPRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGKNKELVFGGGTKVEIK

CL-22821
3230
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGINSYLVFGGGTKVEIK

CL-22822
3231
EIVLTQSPGTLSLSPGERATLSCRASSGDIGPSYVSWYQQKPGQ

APRLLIYPDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDINKELVFGGGTKVEIK

CL-22823
3232
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGKNVDIVFGGGTKVEIK

CL-22824
3233
EIVLTQSPGTLSLSPGERATLSCRASSGSILDTYVSWYQQKPGQ

APRLVIYADDSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDVNVDIVFGGGTKVEIK

CL-22825
3234
EIVLTQSPGTLSLSPGERATLSCRASSGSISQSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDXTIGIVFGGGTKVEIK

CL-22826
3235
EIVLTQSPGTLSLSPGERATLSCERSSGSIGFSYVSWYQQKPGQ

APRLVIYEDDPRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGANIEIVFGGGTKVEIK

CL-22827
3236
EIVLTQSPGTLSLSPGERATLSCRASSGYISHEYVSWYQQKPGQ

APRLVIYAADQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGIHIHVTFGGGTKVEIK

CL-22828
3237
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHSYVSWYQQKPGQ

APRLVIYEDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGGNIGIVFGGGTKVEIK

CL-22829
3238
EIVLTQSPGTLSLSPGERATLSCRASSGSIDASYVSWYQQKPGQ

APRLLIYTDDRRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGIILDIVFGGGTKVEIK

CL-22830
3239
EIVLTQSPGTLSLSPGERATLSCRASSGSIGYSYVSWYQQKPGQ

APRLLIYADDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGVIIYITFGGGTKVEIK

CL-22832
3240
EIVLTQSPGTLSLSPGERATLSCRASSGDIFYSYVSWYQQKPGQ

APRLVIYADDXRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-22833
3241
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYLYVSWYQQKPGQ

APXLVIYPDDXRASGIPDRFSGSGSGXDFTLTISRLEPEDXAVY

YCQQYDKTIDIVFGGGTKVEIK

CL-22834
3242
EIVLTQSPGTLSLSPGERATLSCRASSGDICESCVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINKDIVFGGGTKVEIK

CL-22835
3243
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSNVSWYQQKPGQ

APRLLIYEDDKRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGXLVPIVFGGGTKVEIK

CL-22836
3244
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYGIKVDSTFGGGTKVEIK

CL-22837
3245
EIVLTQSPGTLSLSPGERATLSCERSSGSIQSLHVSWYQQKPGQ

APRLLIYADDXRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGRHIGLVFGGGTKVEIK

CL-22838
3246
EIVLTQSPGTLSLSPGERATLSCERSSGSIGYCYVSWYQQKPGQ

APRLVIYADDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDLCIYITFGGGTKVEIK

CL-22839
3247
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSHVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIAITFGGGTKVEIK

CL-22840
3248
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYTYVSWYQQKPGQ

APRLLIYPDDKRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIRPTTFGGGTKVEIK

CL-22841
3249
EIVLTQSPGTLSLSPGERATLSCERSSGDIAHSYVSWYQQKPGQ

APRLVIYAADYRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDSHNNIVFGGGTKVEIK

CL-22842
3250
EIVLTQSPGTLSLSPGERATLSCRASSGSIRGLRVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGLNFDIVFGGGTKVEIK

CL-25631
3251
EIVLTQSPGTLSLSPGERATLSCRASSGSITYYYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINTDIVFGGGTKVEIK

CL-25634
3252
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-25648
3253
EIVLTQSPGTLSLSPGEXATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYVDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-25655
3254
EIVLTQSPGTLSLSPGERXTLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-25666
3255
EIVLTQXPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-25690
3256
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYSDDQRPGGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-25721
3257
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGYGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-25724
3258
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLLIYVDDWRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDVVFGGGTKVEIK

CL-25725
3259
EIVLTQSPGTLSLSPGERATLSCERSSGDIDYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDIVFGGGTKVEIK

CL-25726
3260
EIVLTQSPGTLSLSPGERATLSCRASSGSIGYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINTDVVFGGGTKVEIK

CL-25727
3261
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIYIDVTFGGGTKVEIK

CL-25728
3262
EIVLTQSPGTLSLSPGERATLSCERSSGSIGYSYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDIVFGGGTKVEIK

CL-25729
3263
EIVLTQSPGTLSLSPGERATLSCERSSGDIAGYYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDITFGGGTKVEIK

CL-25730
3264
EIVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQ

APRLVIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIVIDIXFGGGTKVEIK

CL-25731
3265
EIVLTQSPGTLSLSPGERATLSCRASSGSIVYSYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIYIDITFGGGTKVEIK

CL-25732
3266
EIVLTQSPGTLSLSPGERATLSCRASSGDIVYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDVTFGGGTKVEIK

CL-25733
3267
EIVLTQSPGTLSLSPGERATLSCRASSGDIWDAYVSWYQQKPGQ

APRLLIYADDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDITFGGGTKVEIK

CL-25734
3268
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYAYVSWYQQKPGQ

APRLVIYADDYRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDVDIVFGGGTKVEIK

CL-25735
3269
EIVLTQSPGTLSLSPGERATLSCRASSGDILDSYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDTIIDITFGGGTKVEIK

CL-25736
3270
EIVLTQSPGTLSLSPGERATLSCERSSGDIDDYYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIYIDVTFGGGTKVEIK

CL-25737
3271
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDFYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDVTIDVTFGGGTKVEIK

CL-25738
3272
EIVLTQSPGTLSLSPGERATLSCERSSGDIGLSYVSWYQQKPGQ

APRLVIYSDDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDVDIDVTFGGGTKVEIK

CL-25739
3273
EIVLTQSPGTLSLSPGERATLSCERSSGDIFYTYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDITFGGGTKVEIK

CL-25740
3274
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLLIYADDQRAIGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIYVDVVFGGGTKVEIK

CL-25741
3275
EIVLTQSPGTLSLSPGERATLSCRASSGDIEGSYVSWYQQKPGQ

APRLVIYSDDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-25742
3276
EIVLTQSPGTLSLSPGERATLSCRASSGDISCSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINTDIVFGGGTKVEIK

CL-25743
3277
EIVLTQSPGTLSLSPGERATLSCRASSGSIGSYYVSWYQQKPGQ

APRLVIYSDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIYIDVVFGGGTKVEIK

CL-25745
3278
EIVLTQSPGTLSLSPGERATLSCRASSGDIWYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIEIDVTFGGGTKVEIK

CL-25747
3279
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYSYVSWYQQKPGQ

APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIISDITFGGGTKVEIK

CL-25748
3280
EIVLTQSPGTLSLSPGERATLSCRASSGSIDYAYVSWYQQKPGQ

APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGITIDVVFGGGTKVEIK

CL-25749
3281
EIVLTQSPGTLSLSPGERATLSCRASSGSIYFAYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGITIDVVFGGGTKVEIK

CL-25751
3282
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINVDIVFGGGTKVEIK

CL-25752
3283
EIVLTQSPGTLSLSPGERATLSCRASSGDIAHSYVSWYQQKPGQ

APRLVIYTDDARASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIVDIVFGGGTKVEIK

CL-25754
3284
EIVLTQSPGTLSLSPGERATLSCERSSGDICQYYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLNIDVTFGGGTKVEIK

CL-25756
3285
EIVLTQSPGTLSLSPGERATLSCERSSGSIGDSYVSWYQQKPGQ

APRLLIYNDDDRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLTIDVTFGGGTKVEIK

CL-25758
3286
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ

APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-25759
3287
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDVDIVFGGGTKVEIK

CL-25760
3288
EIVLTQSPGTLSLSPGERATLSCERSSGSIWDMYVSWYQQKPGQ

APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIEIDITFGGGTKVEIK

CL-25761
3289
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYGDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDITFGGGTKVEIK

CL-25763
3290
EIVLTQSPGTLSLSPGERATLSCERSSGDIWESYVSWYQQKPGQ

APRLVIYADDERATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDIVFGGGTKVEIK

CL-25765
3291
EIVLTQSPGTLSLSPGERATLSCRASSGDIAYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-25767
3292
EIVLTQSPGTLSLSPGERATLSCRASSGSIFGAYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIITDIVFGGGTKVEIK

CL-25769
3293
EIVLTQSPGTLSLSPGERATLSCRASSGSIADSLVSWYQQKPGQ

APRLVIYTDDWRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-25770
3294
EIVLTQSPGTLSLSPGERATLSCERSSGSIGDSYVSWYQQKPGQ

APRLLIYTDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDITIDIVFGGGTKVEIK

CL-25771
3295
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDYYVSWYQQKPGQ

APRLVIYSDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDITFGGGTKVEIK

CL-25772
3296
EIVLTQSPGTLSLSPGERATLSCERSSGSIVHSYVSWYQQKPGQ

APRLVXYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIXVDIVFGGGTKVEIK

CL-25773
3297
EIVLTQSPGTLSLSPGERATLSCRASSGDIWYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGITVDIVFGGGTKVEIK

CL-25775
3298
EIVLTQSPGTLSLSPGERATLSCERSSGDIFYSYVSWYQQKPGQ

APRLVIYADDERASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIEIDIVFGGGTKVEIK

CL-25776
3299
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDVDIVFGGGTKVEIK

CL-25778
3300
EIVLTQSPGTLSLSPGERATLSCERSSGDIGLSYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLIIDIVFGGGTKVEIK

CL-25779
3301
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDIVFGGGTKVEIK

CL-25780
3302
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYSYVSWYQQKPGQ

APRLVIYADDERASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIEIDITFGGGTKVEIK

CL-25782
3303
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYSYVSWYQQKPGQ

APRLLIYFDDYRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIEIDIVFGGGTKVEIK

CL-25783
3304
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYYYVSWYQQKPGQ

APRLVIYADDERATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIYIDVVFGGGTKVEIK

CL-25784
3305
EIVLTQSPGTLSLSPGERATLSCRASSGDISDSYVSWYQQKPGQ

APRLVIYTDDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDIVFGGGTKVEIK

CL-25785
3306
EIVLTQSPGTLSLSPGERATLSCERSSGSIGDSYVSWYQQKPGQ

APRLVIYVDDWRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDVDIVFGGGTKVEIK

CL-25786
3307
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHSYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-25787
3308
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDIIDDIVFGGGTKVEIK

CL-25788
3309
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYSYVSWYQQKPGQ

APRLLIYADDFRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIITDITFGGGTKVEIK

CL-25789
3310
EIVLTQSPGTLSLSPGERATLSCERSSGDIYYSYVSWYQQKPGQ

APRLVIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDVTFGGGTKVEIK

CL-25790
3311
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGL

APRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGTYVDIVFGGGTKVEIK

CL-25791
3312
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVSWYQQKPGQ

APRLVIYADDQRASGIPDRXSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDXVFGGGTKVEIK

CL-25792
3313
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQYYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-25793
3314
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDWRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIYIDIVFGGGTKVEIK

CL-25794
3315
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDTIIDIVFGGGTKVEIK

CL-25795
3316
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDYYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVVFGGGTKVEIK

CL-25796
3317
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDTIIDIVFGGGTKVEIK

CL-25797
3318
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQYYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLNIDITFGGGTKVEIK

CL-25798
3319
EIVLTQSPGTLSLSPGERATLSCRASSGDIGESYVSWYQQKPGQ

APRLVIYSDDSRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-25799
3320
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYSYVSWYQQKPGQ

APRLVIYADDLRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIIDIVFGGGTKVEIK

CL-25800
3321
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDYYVSWYQQKPGQ

APRLVIYWDDYRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDVILDITFGGGTKVEIK

CL-25801
3322
EIVLTQSPGTLSLSPGERATLSCERSSGDISYTYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIITDIVFGGGTKVEIK

CL-25802
3323
EIVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQ

APRLVIYTDDWRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGSNIDVVFGGGTKVEIK

CL-25803
3324
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGILTDITFGGGTKVEIK

CL-25804
3325
EIVLTQSPGTLSLSPGERATLSCRASSGSIAHSYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIVDIVFGGGTKVEIK

CL-25805
3326
EIVLTQSPGTLSLSPGERATLSCRASSGSIVYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIITDIVFGGGTKVEIK

CL-25806
3327
EIVLTQSPGTLSLSPGERATLSCERSSGDISYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDITFGGGTKVEIK

CL-25807
3328
EIVLTQSPGTLSLSPGERATLSCRASSGSIGDTYVSWYQQKPGQ

APRLLIYADDWRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIEIDIVFGGGTKVEIK

CL-25808
3329
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDIVFGGGTKVEIK

CL-25809
3330
EIVLTQSPGTLSLSPGERATLSCERSSGSIGETYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGTIIDIVFGGGTKVEIK

CL-25810
3331
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-25812
3332
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-25813
3333
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLLIYADDYRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIVDITFGGGTKVEIK

CL-25814
3334
EIVLTQSPGTLSLSPGERATLSCERSSGDIGQSYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-25815
3335
EIVLTQSPGTLSLSPGERATLSCRESSGDILYTYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIEIDITFGGGTKVEIK

CL-25816
3336
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHSYVSWYQQKPGQ

APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIIDVTFGGGTKVEIK

CL-25818
3337
EIVLTQSPGTLSLSPGERATLSCRASSGDISDSYVSWYQQKPGQ

APRLLIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIIDIVFGGGTKVEIK

CL-25819
3338
EIVLTQSPGTLSLSPGERATLSCRASSGSIGHSYVSWYQQKPGQ

APRLVIYGDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDVDIDVVFGGGTKVEIK

CL-28175
3339
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYVDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-28178
3340
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVCGGGTKVEIK

CL-28195
3341
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPGRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-28212
3342
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDFYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-28215
3343
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDYYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTINRMEPEDFAVY

YCQSYDINMDIVFGGGTKVEIK

CL-28233
3344
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYGDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-29595
3345
EIVLTQSPGTLSLSPGERATLSCRASSGSISYSYVSWYQQKPGQ

APRLVIYADDLRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-29596
3346
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ

APRLLIYADDQRASGIPYRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINVDTVFGGGTKVEIK

CL-29597
3347
EIVLTQSPGTLSLSPGERATLSCERSSGSIGDAYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIVDVVFGGGTKVEIK

CL-29598
3348
EIVLTQSPGTLSLSPGERATLSCRASSGSIGDSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIAIDIVFGGGTKVEIK

CL-29599
3349
EIVLTQSPGTLSLSPGERATLSCRASSGSIEYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIVDIVFGGGTKVEIK

CL-29600
3350
EIVLTQSPGTLSLSPGERATLSCRASSGSIEGAYVSWYQQKPGQ

APRLVIYSDDERATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIITDIVFGGGTKVEIK

CL-29601
3351
EIVLTQSPGTLSLSPGERATLSCERSSGSIGGTYVSWYQQKPGQ

APRLVIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIEIDITFGGGTKVEIK

CL-29602
3352
EIVLTQSPGTLSLSPGERATLSCERSSGDIGSCYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVVFGGGTKVEIK

CL-29603
3353
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYTYVSWYQQKPGQ

APRLVIYADDVRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDVDIVFGGGTKVEIK

CL-29604
3354
EIVLTQSPGTLSLSPGERATLSCERSSGSIWGYYVSWYQQKPGQ

APRLVIYADDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDITFGGGTKVEIK

CL-29605
3355
EIVLTQSPGTLSLSPGERATLSCERSSGDIGEAYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDITFGGGTKVEIK

CL-29606
3356
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ

APRLLIYSDDNRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGTIIDITFGGGTKVEIK

CL-29607
3357
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDITIDIVFGGGTKVEIK

CL-29608
3358
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ

APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLIIDVVFGGGTKVEIK

CL-29609
3359
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDITFGGGTKVEIK

CL-29610
3360
EIVLTQSPGTLSLSPGERATLSCRASSGDIGDSYVSWYQQKPGQ

APRLVIYADDDRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDVDVTFGGGTKVEIK

CL-29611
3361
EIVLTQSPGTLSLSPGERATLSCRASSGDIAHSYVSWYQQKPGQ

APRLLIYVDDLRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDITIDIVFGGGTKVEIK

CL-29612
3362
EIVLTQSPGTLSLSPGERATLSCERSSGDIYSYYVSWYQQKPGQ

APRLLIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLNIDVVFGGGTKVEIK

CL-29613
3363
EIVLTQSPGTLSLSPGERATLSCRASSGDISESYVSWYQQKPGQ

APRLLIYTDDLRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDTDIVFGGGTKVEIK

CL-29614
3364
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSLVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGVIVDIVFGGGTKVEIK

CL-29615
3365
EIVLTQSPGTLSLSPGERATLSCRASSGDIYESYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDVTIDIVFGGGTKVEIK

CL-29617
3366
EIVLTQSPGTLSLSPGERATLSCERSSGDIGFAYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDIVFGGGTKVEIK

CL-29618
3367
EIVLTQSPGTLSLSPGERAPLSCERSSGSIWDSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDVDIDIVFGGGTKVEIK

CL-29620
3368
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDSYVSWYQQKPGQ

APRLVIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIIDITFGGGTKVEIK

CL-29621
3369
EIVLTQSPGTLSLSPGERATLSCRASSGSIGYSYVSWYQQKPGQ

APRLVIYADDRRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIRDIVFGGGTKVEIK

CL-29622
3370
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIVDIVFGGGTKVEIK

CL-29623
3371
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVTFGGGTKVEIK

CL-29624
3372
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDSYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIIDIVFGGGTKVEIK

CL-29625
3373
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYFYVSWYQQKPGQ

APRLVIYVDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-29626
3374
EIVLTQSPGTLSLSPGERATLSCRASSGSIGDTYVSWYQQKPGQ

APRLLIYSDDHRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-29627
3375
EIVLTQSPGTLSLSPGERATLSCRASSGDIWYSFVSWYQQKPGQ

APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIISDIVFGGGTKVEIK

CL-29628
3376
EIVLTQSPGTLSLSPGERATLSCERSSGSIGETYVSWYQQKPGQ

APRLVIYADDLRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIVDIVFGGGTKVEIK

CL-29629
3377
EIVLTQSPGTLSLSPGERATLSCRASSGDIGDCFVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-29630
3378
EIVLTQSPGTLSLSPGERATLSCRASSGDIRHSFVSWYQQKPGQ

APRLVIYWDDYRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVTFGGGTKVEIK

CL-29631
3379
EIVLTQSPGTLSLSPGERATLSCERSSGSIDECYVSWYQQKPGQ

APRLVIYADDDRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVVFGGGTKVEIK

CL-29632
3380
EIVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQ

APRLVIYTDDRRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGSNIDVVFGGGTKVEIK

CL-29634
3381
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQQYDIDTDIVFGGGTKVEIK

CL-29635
3382
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHSYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDITFGGGTKVEIK

CL-29636
3383
EIVLTQSPGTLSLSPGERATLSCRASSGDICHSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIVDIVFGGGTKVEIK

CL-29637
3384
EIVLTQSPGTLSLSPGERATLSCERSSGSINESYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDIVFGGGTKVEIK

CL-29638
3385
EIVLTQSPGTLSLSPGERATLSCERSSGSIWYSYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVTFGGGTKVEIK

CL-29639
3386
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ

APRLLIYADDERASRIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDVVFGGGTKVEIK

CL-29640
3387
EIVLTQSPGTLSLSPGERATLSCRASSGDIWYSYVSWYQQKPGQ

APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDITFGGGTKVEIK

CL-29641
3388
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQSYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIVIDITFGGGTKVEIK

CL-29642
3389
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ

APRLLIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-29643
3390
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDYYVSWYQQKPGQ

APRLVIYSDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLIIDITFGGGTKVEIK

CL-29644
3391
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYTYVSWYQQKPGQ

APRLVIYSDDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIVDIVFGGGTKVEIK

CL-29645
3392
EIVLTQSPGTLSLSPGERATLSCERSSGDISGAYVSWYQQKPGQ

APRLVIYGDDERASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDVTFGGGTKVEIK

CL-29646
3393
EIVLTQSPGTLSLSPGERATLSCRASSGDIGRSYVSWYQQKPGQ

APRLVIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDVNTDIVFGGGTKVEIK

CL-29647
3394
EIVLTQSPGTLSLSPGERATLSCERSSGSIWHTYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIIDITFGGGTKVEIK

CL-29648
3395
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYAYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIILDVTFGGGTKVEIK

CL-29649
3396
EIVLTQSPGTLSLSPGERATLSCRASSGDIEHSYVSWYQQKPGQ

APRLLIYVDDQRPTGIPDRFSGSGSGTDFTLTISRLXPEDFAVY

YCQSYGIREDIVFGGGTKVEIK

CL-29650
3397
EIVLTQSPGTLSLSPGERATLSCERSSGSIGFSYVSWYQQKPGQ

APRLVIYADDLRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGTYVDVVFGGGTKVEIK

CL-29651
3398
EIVLTQSPGTLSLSPGERATLSCRASSGDIWYSYVSWYQQKPGQ

APRLVIYSDDERPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGVDVDVVFGGGTKVEIK

CL-29652
3399
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-29653
3400
EIVLTQSPGTLSLSPGERATLSCRASSGDIEHSYVSWYQQKPGQ

APRLLIYADDYRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDPDITFGGGTKVEIK

CL-29654
3401
EIVLTQSPGTLSLSPGERATLSCRASSGDISHSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDITFGGGTKVEIK

CL-29655
3402
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDAYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIFIDIVFGGGTKVEIK

CL-29656
3403
EIVLTQSPGTLSLSPGERATLSCERSSGDIGEYYVSWYQQKPGQ

APRLVIYADDRRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVTFGGGTKVEIK

CL-29657
3404
EIVLTQSPGTLSLSPGERATLSCERSSGSIDYAYVSWYQQKPGQ

APRLVIYSDDYRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDITFGGGTKVEIK

CL-29658
3405
EIVLTQSPGTLSLSPGERATLSCRASSGDIWYSYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIVIDIVFGGGTKVEIK

CL-29659
3406
EIVLTQSPGTLSLSPGERATLSCERSSGSIGYSYVSWYQQKPGQ

APRLVMYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDVIIDVVFGGGTKVEIK

CL-29660
3407
EIVLTQSPGTLSLSPGERATLSCRASSGDIGYSYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDVTFGGGTKVEIK

CL-29661
3408
EIVLTQSPGTLSLSPGERATLSCRASSGSIWHSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCKSYGINIDVTFGGGTKVEIK

CL-29662
3409
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDVVFGGGTKVEIK

CL-29663
3410
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDITFGGGTKVEIK

CL-29664
3411
EIVLTQSPGTLSLSPGERATLSCRASSGDIRHSYVSWYQQKPGQ

APRLVIYADDDRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINTDIVFGGGTKVEIK

CL-29665
3412
EIVLTQSPGTLSLSPGERATLSCRASSGDIGGSYVSWYQQKPGQ

APRLVIYTDDWRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-29666
3413
EIVLTQSPGTLSLSPGERATLSCRASSGDISYSYVSWYQQKPGQ

APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIIDVVFGGGTKVEIK

CL-29667
3414
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDMYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-29668
3415
EIVLTQSPGTLSLSPGERATLSCERSSGDIDYTYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLTLDITFGGGTKVEIK

CL-29669
3416
EIVLTQSPGTLSLSPGERATLSCERSSSSIWHSYVSWYQQKPGQ

APRLVIYADDYRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVVFGGGTKVEIK

CL-29670
3417
EIVLTQSPGTLSLSPGERATLSCRASSGSIDYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIYIDVVFGGGTKVEIK

CL-29671
3418
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGQYIDVVFGGGTKVEIK

CL-29672
3419
EIVLTQSPGTLSLSPGERATLSCRASSGDIDESYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIIDIVFGGGTKVEIK

CL-29673
3420
EIVLTQSPGTLSLSPGERATLSCRASSGDIXYSYVSWYQQKPGQ

APRLVIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDSIIDVTFGGGTKVEIK

CL-29674
3421
EIVLTQSPGTLSLSPGERATLSCRASSGDIWYSYVSWYQQKPGQ

APRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINVDIVFGGGTKVEIK

CL-29675
3422
EIVLTQSPGTLSLSPGERATLSCERSSGSIMYAYVSWYQQKPGQ

APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLIIDVTFGGGTKVEIK

CL-29676
3423
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVSWYQQKPGQ

APRLVIYADDARATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDITFGGGTKVEIK

CL-29677
3424
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDISIDVTFGGGTKVEIK

CL-29678
3425
EIVLTQSPGTLSLSPGERATLSCERSSGSIGETYVSWYQQKPGQ

APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDIVFGGGTKVEIK

CL-29679
3426
EIVLTQSPGTLSLSPGERATLSCRASSGSIGDSYVSWYQQKPGQ

APRLLIYSDDDRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGISIDVTFGGGTKVEIK

CL-29681
3427
EIVLTQSPGTLSLSPGERATLSCRASSGDIGHSYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDITFGGGTKVEIK

CL-29682
3428
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIIDIVFGGGTKVEIK

CL-29683
3429
EIVLTQSPGTLSLSPGERATLSCERSSGDIYSYYVSWYQQKPGQ

APRLLIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVTFGGGTKVEIK

CL-29684
3430
EIVLTQSPGTLSLSPGERATLSCERSSGSIWHSYVSWYQQKPGQ

APRLVIYSDDQQASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-29685
3431
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIVIDIVFGGGTKVEIK

CL-29686
3432
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDTYVSWYQQKPGQ

APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLTIDIVFGGGTKVEIK

CL-29687
3433
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDICIDVTFGGGTKVEIK

CL-29688
3434
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLLIYSDDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIIDIVFGGGTKVEIK

CL-29689
3435
EIVLTQSPGTLSLSPGERATLSCERSSGSIGGYYVSWYQQKPGQ

APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIIDIVFGGGTKVEIK

CL-29690
3436
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ

APRLVIYGADLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDIVFGGGTKVEIK

CL-29722
3437
EIVLTQSPGTLSLSPGERATLSCERSXGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-29732
3438
EIVLTQSPGTLSLSPGERATLSCERSSVDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-29741
3439
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIHADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-29746
3440
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPVQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-29756
3441
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

ATRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-29759
3442
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYAYDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-29765
3443
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-29771
3444
EXXLTQSPGTLSLSPGERATXSCERSSGDXGDSYVSWYQQKPGQ

APRLVIYXDDQRPSGIPDRFSGSGSGTDFTLTISGLEPEDFAVY

YCQSXDINMDIVFGGGTKVEIK

CL-29780
3445
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGVGTKVEIK

CL-29781
3446
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFVVY

YCQSYDINIDIVFGGGTKVEIK

CL-33580
3447
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYXDDQRPSGIPDRFSGSGSGGDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-33673
3448
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLEVDIVFGGGTKVEIK

CL-33674
3449
EIVLTQSPGTLSLSPGERATLSCERSSGSIWDTYVSWYQQKPGQ

APRLVIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINVDIVFGGGTKVEIK

CL-33676
3450
EIVLTQSPGTLSLSPGERATLSCERSSGDIWGYYVSWYQQKPGQ

APRLLIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDVVFGGGTKVEIK

CL-33677
3451
EIVLTQSPGTLSLSPGERATLSCERSSGSIYYTYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDVDVVFGGGTKVEIK

CL-33678
3452
EIVLTQSPGTLSLSPGERATLSCERSSGDIWGYYVSWYQQKPGQ

APRLLIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDITFGGGTKVEIK

CL-33679
3453
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGLNVDVVFGGGTKVEIK

CL-33680
3454
EIVLTQSPGTLSLSPGERATLSCERSSGDIYETYVSWYQQKPGQ

APRLVIYSDDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVVFGGGTKVEIK

CL-33681
3455
EIVLTQSPGTLSLSPGERATLSCERSSGSIWYSYVSWYQQKPGQ

APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIITDVTFGGGTKVEIK

CL-33684
3456
EIVLTQSPGTLSLSPGERATLSCERSSGDIWGYYVSWYQQKPGQ

APRLLIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDVVFGGGTEVEIK

CL-33685
3457
EIVLTQSPGTLSLSPGERATLSCERSSGDIYYTYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-33687
3458
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDVVFGGGTKVEIK

CL-33688
3459
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-33690
3460
EIVLTQSPGTLSLSPGERATLSCKRSSGSIYDTYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDVDSDIVFGGGTKVEIK

CL-33691
3461
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDVTFGGGTKVEIK

CL-33692
3462
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDVTFGGGTKVEIK

CL-33693
3463
EIVLTQSPGTLSLSPGERATLSCERSSGSIYESYVSWYQQKPGQ

APRLLIYSDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDVVFGGGTKVEIK

CL-33694
3464
EIVLTQSPGTLSLSPGERATLSCERSSGSIYHTYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDVTFGGGTKVEIK

CL-33695
3465
EIVLTQSPGTLSLSPGERATLSCERSSGSIYDTYVSWYQQKPGQ

APRLVIYSDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDIVFGGGTKVEIK

CL-33697
3466
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDVDIVFGGGTKVEIK

CL-33698
3467
EIVLTQSPGTLSLSPGERATLSCERSSGDIWXYYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLFIDVTFGGGTKVEIK

CL-33700
3468
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHYYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLEIDVTFGGGTKVEIK

CL-33704
3469
EIVLTQSPGTLSLSPGERATLSCERSSGDIWSYYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLTVDVVFGGGTKVEIK

CL-33707
3470
EIVLTQSPGTLSLSPGERATLSCERSSGDIWSYYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDVTFGGGTKVEIK

CL-33708
3471
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVTFGGGTKVEIK

CL-33709
3472
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVTFGGGTKVEIK

CL-33710
3473
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDVVFGGGTKVEIK

CL-33712
3474
EIVLTQSPGTLSLSPGERATLSCRASSGSIYYSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVVFGGGTKVEIK

CL-33713
3475
EIVLTQSPGTLSLSPGERATLSCERYSGDIWYTYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDVDVVFGGGTKVEIK

CL-33716
3476
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLVIYADDLRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDVTFGGGTKVEIK

CL-33718
3477
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLNIDVVFGGGTKVEIK

CL-33719
3478
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLVIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDVTFGGGTKVEIK

CL-33720
3479
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLVIYTDDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIETDIVFGGGTKVEIK

CL-33721
3480
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDVDVTFGGGTKVEIK

CL-33722
3481
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIYIDVVFGGGTKVEIK

CL-33723
3482
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDVCIDVVFGGGTKVEIK

CL-33725
3483
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDVVFGGGTKVEIK

CL-33726
3484
EIVLTQSPGTLSLSPGERATLSCERSSGSIWYSYVSWYQQKPGQ

APRLVIYSDDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDVVFGGGTKVEIK

CL-33727
3485
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYWDDYRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDVDIVFGGGTKVEIK

CL-33729
3486
EIVLTQSPGTLSLSPGERATLSCERSSGDIWSYYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDITFGGGTKVEIK

CL-33730
3487
EIVLTQSPGTLSLSPGERATLSCERSSGDIWSYYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLNIDTVFGGGTKVEIK

CL-33732
3488
EIVLTQSPGTLSLSPGERATLSCERSSCDIWQYYVSWYQQKPGQ

APRLLIYADDQRATGIPDRFSGSGSGTDFTLIISRLEPEDFAVY

YCQSYDLDIDVVFGGGTKVEIK

CL-33733
3489
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIITDVVFGGGTKVEIK

CL-33734
3490
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHTYVSWYQQKPGQ

APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDVNIDVVFGGGTKVEIK

CL-33740
3491
EIVLTQSPGTLSLSPGERATLSCERSSGSIWSTYVSWYQQKPGQ

APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDVVIDIVFGGGTKVEIK

CL-33741
3492
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLLIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLIIDIVFGGGTKVEIK

CL-33742
3493
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHYYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDVTFGGGTKVEIK

CL-33743
3494
EIVLTQSPGTLSLSPGERATLSCERSSGSIWGYYVSWYQQKPGQ

APRLVIYADDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDETIDIVFGGGTKVEIK

CL-33745
3495
EIVLTQSPGTLSLSPGERATLSCERSSGDIYYTYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDITFGGGTKVEIK

CL-33746
3496
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQSYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDVDIVFGGGTKVEIK

CL-33747
3497
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-33755
3498
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGTNIDVVFGGGTKVEIK

CL-33756
3499
EIVLTQSPGTLSLSPGERATLSCERSSGDIWESYVSWYQQKPGQ

APRLVIYADDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIDDIVFGGGTKVEIK

CL-33757
3500
EIVLTQSPGTLSLSPGERATLSCERSSGDIWETYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVTFGGGTKVEIK

CL-33758
3501
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVVFGGGTKVEIK

CL-33760
3502
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGLNIDVVFGGGTKVEIK

CL-33761
3503
EIVLTQSPGTLSLSPGERATLSCERSSGDIWSYYVSWYQQKPGQ

APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDICIDVTFGGGTKVEIK

CL-33763
3504
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDIVFGGGTKVEIK

CL-33766
3505
EIVLTQSPGTLSLSPGERATLSCERSSGDIYDAYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDVDVVFGGGTKVEIK

CL-33768
3506
EIVLTQSPGTLSLSPGERATLSCERSSGSIWDTYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVVFGGGTKVEIK

CL-33771
3507
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQYYVSWYQQKPGQ

APRLLIYADDKRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDEDIDITFGGGTKVEIK

CL-33773
3508
EIVLTQSPGTLSLSPGERATLSCERSSGDIWSYYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLNIDVTFGGGTKVEIK

CL-33774
3509
EIVLTQSPGTLSLSPGERATLSCERSSGDIWSYYVSWYQQKPGQ

APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLYIDIVFGGGTKVEIK

CL-33775
3510
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ

APRLVIYADDMRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLNIDVTFGGGTKVEIK

CL-33776
3511
EIVLTQSPGTLSLSPGERATLSCERSSGDIGYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIIDIVFGGGTKVEIK

CL-33777
3512
EIVLTQSPGTLSLSPGERATLSCERSSGDIYETYVSWYQQKPGQ

APRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVVFGGGTKVEIK

CL-33778
3513
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGLITDVTFGGGTKVEIK

CL-33779
3514
EIVLTQSPGTLSLSPGERATLSCERSSGSIWETYVSWYQQKPGQ

APRLVIYADDRRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDVVFGGGTKVEIK

CL-33781
3515
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDTDIVFGGGTKVEIK

CL-33782
3516
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-33785
3517
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQTYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIVIDVVFGGGTKVEIK

CL-33787
3518
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQYYVSWYQQKPGQ

APRLVIYADDHRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDVTFGGGTKVEIK

CL-33790
3519
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHTYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDVDIDITFGGGTKVEIK

CL-33791
3520
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQAYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIEDITFGGGTKVEIK

CL-33792
3521
EIVLTQSPGTLSLSPGERATLSCERSSGDIYETYVSWYQQKPGQ

APRLVIYSDDHRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIITDIVFGGGTKVEIK

CL-33794
3522
EIVLTQSPGTLSLSPGERATLSCERSSGSIWDYYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLITDIVFGGGTKVEIK

CL-33795
3523
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-33796
3524
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLIRDIVFGGGTKVEIK

CL-33799
3525
EIVLTQSPGTLSLSPGERATLSCERSSGSIYETYVSWYQQKPGQ

APRLLIYADDWRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDITVDVVFGGGTKVEIK

CL-33801
3526
EIVLTQSPGTLSLSPGERATLSCERSSGDIWESYVSWYQQKPGQ

APRLVIYSDDQRPTGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIIDDIVFGGGTKVEIK

CL-33802
3527
EIVLTQSPGTLSLSPGERATLSCERSSGDIWEYYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDITFGGGTKVEIK

CL-33813
3528
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDVVFGGGTKVEIK

CL-33814
3529
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-33815
3530
EIVLTQSPGTLSLSPGERATLSCERSSGDIYETYVSWYQQKPGQ

APRLVIYSDDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDVDVVFGGGTKVEIK

CL-33816
3531
EIVLTQSPGTLSLSPGERATLSCERSSGDIYETYVSWYQQKPGQ

APRLVIYSDDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINVDVVFGGGTKVEIK

CL-33817
3532
EIVLTQSPGTLSLSPGERATLSCRASSGDISDKYVSWYQQKPGQ

APRLVIYADDYRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLCIDVTFGGGTKVEIK

CL-33819
3533
EIVLTQSPGTLSLSPGERATLSCRASSGDISDKYVSWYQQKPGQ

APRLLIYADDWRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDVDVVFGGGTKVEIK

CL-33825
3534
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQYYVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLDIDVTFGGGTKVEIK

CL-33826
3535
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLEIDVVFGGGTKVEIK

CL-33828
3536
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ

APRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDITVDVVFGGGTKVEIK

CL-33829
3537
EIVLTQSPGTLSLSPGERATLSCERSSGSIWYSYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVTFGGGTKVEIK

CL-33832
3538
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLIIDVTFGGGTKVEIK

CL-33833
3539
EIVLTQSPGTLSLSPGERATLSCERSSGDIWETYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDVDIVFGGGTKVEIK

CL-33834
3540
EIVLTQSPGTLSLSPGERATLSCERSSGSIWYSYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDSDIVFGGGTKVEIK

CL-33836
3541
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINVDIVFGGGTKVEIK

CL-33837
3542
EIVLTQSPGTLSLSPGERATLSCERSSGDIYQTYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDVVFGGGTKVEIK

CL-33839
3543
EIVLTQSPGTLSLSPGERATLSCERSSGSIWETYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGVDIDVVFGGGTKVEIK

CL-33840
3544
EIVLTQSPGTLSLSPGERATLSCERSSGDIYETYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVVFGGGTKVEIK

CL-33841
3545
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQYYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLFIDVTFGGGTKVEIK

CL-33844
3546
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ

APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIYVDIVFGGGTKVEIK

CL-33847
3547
EIVLTQSPGTLSLSPGERATLSCERSSGSIYYTYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIEIDITFGGGTKVEIK

CL-33848
3548
EIVLTQSPGTLSLSPGERATLSCERSSGDIYETYVSWYQQKPGQ

APRLVIYSDDHRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDTDIVFGGGTKVEIK

CL-33849
3549
EIVLTQSPGTLSLSPGERATLSCERSSGDIWYSYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-33854
3550
EIVLTQSPGTLSLSPGERATLSCERSSGDIWHTYVSWYQQKPGQ

APRLLIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINVDVVFGGGTKVEIK

CL-33857
3551
EIVLTQSPGTLSLSPGERATLSCERSSGDIWESYVSWYQQKPGQ

APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-33858
3552
EIVLTQSPGTLSLSPGERATLSCERSSGDIGHTYVSWYQQKPGQ

APRLVIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIISDVVFGGGTKVEIK

CL-33862
3553
EIVLTQSPGTLSLSPGERATLSCERSSGSIWGTYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVTFGGGTKVEIK

CL-41468
3554
EIVLTQSPGTLSLPPGERATLSCKRSSGSIYDTYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLTIDITFGGGTKVEIK

CL-41469
3555
EIVLTQSPGTLSLSPGERATLSCERSSGSIWHSYVSWYQQKPGQ

APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIYIDVVFGGGTRSKLS

CL-41472
3556
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ

APRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLTIDITFGGGTKVEIK

CL-41477
3557
EIVLTQSPGTLSLSPGERATPSCRASSGSIWYSFVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-41479
3558
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQPYDLFIDVTFGGGTKVEIK

CL-41480
3559
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQSYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAGY

YCQSYGINIDVVFGGGTKVEIK

CL-41486
3560
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDYYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLFIDVTFGGGTKVEIK

CL-41505
3561
EIVLTQSPGTLSLSPGERATLSCERSSGSIWHSYVSWYQQKPGQ

APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIETDIVFGGGTKVEIK

CL-41509
3562
EIVLTQSPGTWSLSPGERATLSCERSSGSNYDTYVSWYQQKPGQ

APRLLIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIETDIVFGGGTKVEIK

CL-41528
3563
EIVLTQSPGTLSLSPGERATLSCERSSGSIWHSYVSWYQQKPGQ

APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIYIDVVFGGDTKVEIK

CL-41529
3564
EIVLTQSPGTLSLSSGERATLSCERSSGSNYDTYVSWYQQKPGQ

APRLLIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIETDIVFGGGTKVEIK

CL-41532
3565
EIVLTQSPGTLSLSPGERATLSCRASSGSTWYSFVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-41535
3566
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLTIDITFGGGTKVEIK

CL-41536
3567
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLFIDXTFGGGTKVEIK

CL-41539
3568
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ

APRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEGFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-41543
3569
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ

ASRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-41547
3570
EIVLTQSPGTLSLSPGERATLSCERSSGSIWHSYVSWYQQKPGQ

APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIYIDVVFGGGTNVEIK

CL-41550
3571
EIVLTQSPGTLSLSPGERATLSCKRSSGSIYDTYVSWYQQKPGQ

APRLVIYSDDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLTIDITFGGGTKVEIK

CL-41554
3572
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQSYVSWYQQKPGQ

APRLVIYSDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-41556
3573
EIVLTQSPGTLSLSPGERATLSCERSSGSIWHSYVSWYQQKPGQ

APRLLIYSDDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIYIDVVFGGGTKVEIK

CL-41557
3574
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDTYVSWYQQKPGQ

APRLLIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIIIDIVFGGGTKVEIK

CL-41560
3575
EIFLTQSPGTLSLSPGKKATLSGKRSSGSIYNTYFSGYQQKPGQ

APKRVIYSDDRRPSGIPDRFSGSGXGTDFTLTISXLEPKDFAVY

YCQSYDLTINLXFGGGTKVXIX

CL-41561
3576
EIVLTQSPGTLSLSPGERATLSCERSSGSNYDTYVSWYQQKPGQ

APRLLIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIETDIVFGGGTKVEIK

CL-41562
3577
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

SPRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-41569
3578
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPRGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-41577
3579
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVVFGGGTKVEIS

CL-41581
3580
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSRYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-41591
3581
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGIDIDVVFGGGTKVEIK

CL-41599
3582
KSSLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-41600
3583
EIVLTQSLGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-41615
3584
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQMYVSWYQQKPGQ

APRLVIYGDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDITFGGGTKVEIK

CL-41616
3585
EIVLTQSPGTLSLPPGERATLSCERSSGDIWQTYVSWYQQKPGQ

APRLVIYGDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDITFGGGHKGRNX

CL-41639
3586
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDSAVY

YCQSYDLFIDVTFGGGTKVEIK

CL-41642
3587
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQRKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-41645
3588
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ

APRLVIYGDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDITFGGGTKVEIK

CL-41646
3589
EIVLTQSPGTLSLSPGERATLSCERSSGSIWQSYVSWYQQKPGQ

APRLVIYADDQRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDIDIDVVFGGGTKVEIK

CL-41649
3590
EIVLTQSPGTLSLSPGERATLSCERSSGDIWDYYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDLFIDVTFGGGTKVEIK

CL-41654
3591
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVH

YCQSYGINIDVVFGGGTKVEIK

CL-41655
3592
EIVLTQSPGTLSLSPGERATLSCERSSGDIWQTYVSWYQQKPGQ

APRLVIYGDDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-41668
3593
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVC

YCQSYGINIDVVFGGGTKVEIK

CL-41673
3594
EIVLTQSPGTLSLSPGERAPLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIX

CL-41685
3595
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTINRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-41705
3596
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ

APRLLIYADDQRASGIPDRLSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-41707
3597
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADGQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-41710
3598
EIVLTQSPSTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-41713
3599
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIN

CL-41714
3600
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVELS

CL-41720
3601
EIVLTQIPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-41725
3602
EIVLTQSPGTLSLSPGERATLSCERSSGSNYDTYVSWYQQKPGQ

APRLLIYADDLRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-41727
3603
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YRQSYGINIDVVFGGGTKVEIK

CL-41729
3604
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQ

APRLLIYADDQRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYGINIDVVFGGGTKVEIK

CL-41732
3605
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPIGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-41735
3606
EIVLTQSPGTLSLSPVERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-41737
3607
EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVY

YCQSYDINIDIVFGGGTKVEIK

CL-41738
3608
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQAP

RLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC

QQSWYDPLTFGQGTKLEIK

CL-41739
3609
EIVLTQSPATLSLSPGERAALSCRASQSVSTHMHWYQQKPGQAP

RLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC

QQSWYDPLTFGQGTKLEIK

CL-41740
3610
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQAP

RLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC

QQSRYDPLTFGQGTKLEIK

CL-41742
3611
EIVLTQSPGTLSLSPGERATLSCRASQSVSTHMHWYQQKPGQAP

RLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC

QQSWYDPLTFGQGTKLEIK

CL-41751
3612
AKLCXPVPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQAP

RLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC

QQSWYDPLTFGQGTKLEIK

CL-41752
3613
EIVLTQSPATLSLSPGERATLSCRASQSVSTHMHWYQQKPGQAP

RLLIYGASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC

QQSWYDPLTFGQGTKLRSN

TABLE 48

Amino Acid Residues Found In Each Position Of The Heavy

Chain Variable Region During The Affinity Maturation

Of Anti-PDGF-BB Antibody hBDI-9E8.4

hBDI-9E8.4-2I|CL-22843 Heavy Chain Variable Region

SEQ ID NO:
Sequence

3614
1 2 3 4 5 6

123456789012345678901234567890123456789012345678901234567890

EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWDDDKY

I Y SEVSIDL L DCYGEEH

R A R L C NNGTC

D A G HHVID

T C V AQN

M V E HVS

R Y I YNA

L R P NRF

C T A QYG

F E C SL

W S G LM

P C

7 8 9 10 11 12

12345678901234567890123456789012345678901234567890123456789012

YNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSS

SL NS LYQTGWPN E Y

T T NVASPWS D

LKYMFRK Y

MYWVCIR A

VLPLYFM C

RDLFAAA N

KGVNEME M

FAEDLYI W

CMKHVSV T

TRFYSLL Q

ESCTDGW G

RRDP I

Q KQ L

K V P

E N

P E

TABLE 49

Amino Acid Residues Found In Each Position Of The Light Chain

Variable Region During The Affinity Maturation

Of Anti-PDGF Antibody hBDI-9E8.4

hBDI-9E8.4-2I|CL-22843 Light Chain Variable Region

SEQ ID NO:
Sequence

3615
1 2 3 4 5 6

123456789012345678901234567890123456789012345678901234567890

EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGI

F RAY CSNWYTFFPR R MHGYGLQAIR

KE VYTYQYLS G SA RP T

S MSNMR WV H R

MHKH T W G

HGAN L Y

DECC V M

RSFA F K

EKLD N D

NFES P A

CRWT E E

ALD D N

LCP V

VAG S

FP F

T P

Q

K

7 8 9 10 11

12345678901234567890123456789012345678901234567890

PDRFSGSGSGTDFTLTISRLEFEDFAVYYCQSYDINIDIVFGGGTKVEIK

RKP GLFTNVT

Q VDSPL

H EEVAG

TTDYT

SIRGS

QYEHN

RCMEF

NVLVA

KSPLH

GRFQR

AANTQ

CLK

FG

H

K

TABLE 50

Variable Region Sequences of h9E8.4 Affinity

Matured Clones Converted to IgG

Protein
V Region

SEQ ID NO:
Clone
Region
123456789012345678901234567890

3616
CL-33578 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIQSGW

TNYEFDYWGQGTMVTVSS

3617
CL-33578
CDR-H1

GFSLSTYGMGVG

3618
CL-33578
CDR-H2

NIWWDDDKYYNPSLKN

3619
CL-33578
CDR-H3

IQSGWTNYEFDY

3620
CL-33578 VL

EIVLTQSPGTLSLSPGERATLSCERS

SGDIGDSYVSWYQQKPGQAPRLVIYA

DDQRPSGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYDINIDIVFGGG

TKVEIK

3621
CL-33578
CDR-L1

ERSSGDIGDSYVS

3622
CL-33578
CDR-L2

ADDQRPS

3623
CL-33578
CDR-L3

QSYDINIDIV

3624
CL-33587 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIQSMW

TRYDFDYWGQGTMVTVSS

3625
CL-33587
CDR-H1

GFSLSTYGMGVG

3626
CL-33587
CDR-H2

NIWWDDDKYYNPSLKN

3627
CL-33587
CDR-H3

IQSMWTRYDFDY

3628
CL-33587 VL

EIVLTQSPGTLSLSPGERATLSCERS

SGDIGDSYVSWYQQKPGQAPRLVIYA

DDQRPSGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYDINIDIVFGGG

TKVEIK

3629
CL-33587
CDR-L1

ERSSGDIGDSYVS

3630
CL-33587
CDR-L2

ADDQRPS

3631
CL-33587
CDR-L3

QSYDINIDIV

3632
CL-33675 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIESSG

PKYSFDYWGQGTMVTVSS

3633
CL-33675
CDR-H1

GFSLSTYGMGVG

3634
CL-33675
CDR-H2

NIWWDDDKYYNPSLKN

3635
CL-33675
CDR-H3

IESSGPKYSFDY

3636
CL-33675 VL

EIVLTQSPGTLSLSPGERATLSCRAS

SGSIWYSFVSWYQQKPGQAPRLLIYA

DDQRASGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYGINIDVVFGGG

TKVEIK

3637
CL-33675
CDR-L1

RASSGSIWYSFVS

3638
CL-33675
CDR-L2

ADDQRAS

3639
CL-33675
CDR-L3

QSYGINIDVV

3640
CL-33682 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTIKDTSKN

QVVLTMTNMDPVDTATYYCARIESSW

TSYSFDYWGQGTMVTVSS

3641
CL-33682
CDR-H1

GFSLSTYGMGVG

3642
CL-33682
CDR-H2

NIWWDDDKYYNPSLKN

3643
CL-33682
CDR-H3
IESSWTSYSFDY

3644
CL-33682 VL

EIVLTQSPGTLSLSPGERATLSCERS

SGSNYDTYVSWYQQKPGQAPRLLIYA

DDLRASGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYGINIDVVFGGG

TKVEIK

3645
CL-33682
CDR-L1

ERSSGSNYDTYVS

3646
CL-33682
CDR-L2

ADDLRAS

3647
CL-33682
CDR-L3

QSYGINIDVV

3648
CL-33683 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIETIG

PKYSFDYWGQGTMVTVSS

3649
CL-33683
CDR-H1

GFSLSTYGMGVG

3650
CL-33683
CDR-H2

NIWWDDDKYYNPSLKN

3651
CL-33683
CDR-H3

IETIGPKYSFDY

3652
CL-33683 VL

EIVLTQSPGTLSLSPGERATLSCRAS

SGSIWYSFVSWYQQKPGQAPRLLIYA

DDQRASGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYGINIDVVFGGG

TKVEIK

3653
CL-33683
CDR-L1

RASSGSIWYSFVS

3654
CL-33683
CDR-L2

ADDQRAS

3655
CL-33683
CDR-L3

QSYGINIDVV

3656
CL-33699 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGIGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIESMG

PKYAFDYWGQGTMVTVSS

3657
CL-33699
CDR-H1

GFSLSTYGMGIG

3658
CL-33699
CDR-H2

NIWWDDDKYYNPSLKN

3659
CL-33699
CDR-H3

IESMGPKYAFDY

3660
CL-33699 VL

EIVLTQSPGTLSLSPGERATLSCRAS

SGSIWYSFVSWYQQKPGQAPRLLIYA

DDQRASGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYGINIDVVFGGG

TKVEIK

3661
CL-33699
CDR-L1

RASSGSIWYSFVS

3662
CL-33699
CDR-L2

ADDQRAS

3663
CL-33699
CDR-L3

QSYGINIDVV

3664
CL-33701 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIESLG

TSYSFDYWGQGTMVTVSS

3665
CL-33701
CDR-H1

GFSLSTYGMGVG

3666
CL-33701
CDR-H2

NIWWDDDKYYNPSLKN

3667
CL-33701
CDR-H3
IESLGTSYSFDY

3668
CL-33701 VL

EIVLTQSPGTLSLSPGERATLSCERS

SGDIWDYYVSWYQQKPGQAPRLVIYA

DDQRPSGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYDLFIDVTFGGG

TKVEIK

3669
CL-33701
CDR-L1

ERSSGDIWDYYVS

3670
CL-33701
CDR-L2

ADDQRPS

3671
CL-33701
CDR-L3

QSYDLFIDVT

3672
CL-33706 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIETMG

PKYSFDYWGQGTMVTVSS

3673
CL-33706
CDR-H1

GFSLSTYGMGVG

3674
CL-33706
CDR-H2

NIWWDDDKYYNPSLKN

3675
CL-33706
CDR-H3

IETMGPKYSFDY

3676
CL-33706 VL

EIVLTQSPGTLSLSPGERATLSCRAS

SGSIWYSFVSWYQQKPGQAPRLLIYA

DDQRASGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYGINIDVVFGGG

TKVEIK

3677
CL-33706
CDR-L1

RASSGSIWYSFVS

3678
CL-33706
CDR-L2

ADDQRAS

3679
CL-33706
CDR-L3

QSYGINIDVV

3680
CL-33731 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIESIP

TSYSFDYWGQGTMVTVSS

3681
CL-33731
CDR-H1

GFSLSTYGMGVG

3682
CL-33731
CDR-H2

NIWWDDDKYYNPSLKN

3683
CL-33731
CDR-H3

IESIPTSYSFDY

3684
CL-33731 VL

EIVLTQSPGTLSLSPGERATLSCERS

SGSIWQSYVSWYQQKPGQAPRLVIYA

DDQRATGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYDIDIDVVFGGG

TKVEIK

3685
CL-33731
CDR-L1

ERSSGSIWQSYVS

3686
CL-33731
CDR-L2

ADDQRAT

3687
CL-33731
CDR-L3

QSYDIDIDVV

3688
CL-33737 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRKPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIESSG

PKYSFDYWGQGTMVTVSS

3689
CL-33737
CDR-H1

GFSLSTYGMGVG

3690
CL-33737
CDR-H2

NIWWDDDKYYNPSLKN

3691
CL-33737
CDR-H3
IESSGPKYSFDY

3692
CL-33737 VL

EIVLTQSPGTLSLSPGERATLSCRAS

SGSIWYSFVSWYQQKPGQAPRLLIYA

DDQRASGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYGINIDVVFGGG

TKVEIK

3693
CL-33737
CDR-L1

RASSGSIWYSFVS

3694
CL-33737
CDR-L2

ADDQRAS

3695
CL-33737
CDR-L3

QSYGINIDVV

3696
CL-33759 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIESVW

TRYDFDYWGQGTMVTVSS

3697
CL-33759
CDR-H1

GFSLSTYGMGVG

3698
CL-33759
CDR-H2

NIWWDDDKYYNPSLKN

3699
CL-33759
CDR-H3

IESVWTRYDFDY

3700
CL-33759 VL

EIVLTQSPGTLSLSPGERATLSCERS

SGDIWQTYVSWYQQKPGQAPRLVIYG

DDQRASGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYDIDIDITFGGG

TKVEIK

3701
CL-33759
CDR-L1

ERSSGDIWQTYVS

3702
CL-33759
CDR-L2

GDDQRAS

3703
CL-33759
CDR-L3

QSYDIDIDIT

3704
CL-33767 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIESIG

PKYSFDYWGQGTMVTVSS

3705
CL-33767
CDR-H1

GFSLSTYGMGVG

3706
CL-33767
CDR-H2

NIWWDDDKYYNPSLKN

3707
CL-33767
CDR-H3

IESIGPKYSFDY

3708
CL-33767 VL

EIVLTQSPGTLSLSPGERATLSCRAS

SGSIWYSFVSWYQQKPGQAPRLLIYA

DDQRASGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYGINIDVVFGGG

TKVEIK

3709
CL-33767
CDR-L1

RASSGSIWYSFVS

3710
CL-33767
CDR-L2

ADDQRAS

3711
CL-33767
CDR-L3

QSYGINIDVV

3712
CL-33769 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIESIG

PKYSFDYWGQGTMVTVSS

3713
CL-33769
CDR-H1

GFSLSTYGMGVG

3714
CL-33769
CDR-H2

NIWWDDDKYYNPSLKN

3715
CL-33769
CDR-H3

IESIGPKYSFDY

3716
CL-33769 VL

EIVLTQSPGTLSLSPGERATLSCRAS

SGSIWYSFVSWYQQKPGQAPRLLIYA

DDQRASGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYGINIDVVFGGG

TKVEIK

3717
CL-33769
CDR-L1

RASSGSIWYSFVS

3718
CL-33769
CDR-L2

ADDQRAS

3719
CL-33769
CDR-L3

QSYGINIDVV

3720
CL-33797 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIESLG

WSYSFDYWGQGTMVTVSS

3721
CL-33797
CDR-H1

GFSLSTYGMGVG

3722
CL-33797
CDR-H2

NIWWDDDKYYNPSLKN

3723
CL-33797
CDR-H3

IESLGWSYSFDY

3724
CL-33797 VL

EIVLTQSPGTLSLSPGERATLSCERS

SGDIWDYYVSWYQQKPGQAPRLVIYA

DDQRPSGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYDLFIDVTFGGG

TKVEIK

3725
CL-33797
CDR-L1

ERSSGDIWDYYVS

3726
CL-33797
CDR-L2

ADDQRPS

3727
CL-33797
CDR-L3

QSYDLFIDVT

3728
CL-33803 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIESLP

TSYSFDYWGQGTMVTVSS

3729
CL-33803
CDR-H1

GFSLSTYGMGVG

3730
CL-33803
CDR-H2

NIWWDDDKYYNPSLKN

3731
CL-33803
CDR-H3

IESLPTSYSFDY

3732
CL-33803 VL

EIVLTQSPGTLSLSPGERATLSCERS

SGDIWDTYVSWYQQKPGQAPRLLIYA

DDQRPSGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYDIIIDIVFGGG

TKVEIK

3733
CL-33803
CDR-L1

ERSSGDIWDTYVS

3734
CL-33803
CDR-L2

ADDQRPS

3735
CL-33803
CDR-L3

QSYDIIIDIV

3736
CL-33805 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIESHW

WSYAFDYWGQGTMVTVSS

3737
CL-33805
CDR-H1

GFSLSTYGMGVG

3738
CL-33805
CDR-H2

NIWWDDDKYYNPSLKN

3739
CL-33805
CDR-H3

IESHWWSYAFDY

3740
CL-33805 VL

EIVLTQSPGTLSLSPGERATLSCERS

SGSNYDTYVSWYQQKPGQAPRLLIYA

DDLRASGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYGIETDIVFGGG

TKVEIK

3741
CL-33805
CDR-L1

ERSSGSNYDTYVS

3742
CL-33805
CDR-L2

ADDLRAS

3743
CL-33805
CDR-L3

QSYGIETDIV

3744
CL-33811 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIESSW

TTYSFDYWGQGTMVTVSS

3745
CL-33811
CDR-H1

GFSLSTYGMGVG

3746
CL-33811
CDR-H2

NIWWDDDKYYNPSLKN

3747
CL-33811
CDR-H3

IESSWTTYSFDY

3748
CL-33811 VL

EIVLTQSPGTLSLSPGERATLSCERS

SGSIWHSYVSWYQQKPGQAPRLLIYS

DDQRATGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYGIYIDVVFGGG

TKVEIK

3749
CL-33811
CDR-L1

ERSSGSIWHSYVS

3750
CL-33811
CDR-L2

SDDQRAT

3751
CL-33811
CDR-L3

QSYGIYIDVV

3752
CL-33812 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIESNP

WKYSFDYWGQGTMVTVSS

3753
CL-33812
CDR-H1

GFSLSTYGMGVG

3754
CL-33812
CDR-H2

NIWWDDDKYYNPSLKN

3755
CL-33812
CDR-H3

IESNPWKYSFDY

3756
CL-33812 VL

EIVLTQSPGTLSLSPGERATLSCERS

SGDIWQSYVSWYQQKPGQAPRLVIYS

DDQRASGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYGINIDVVFGGG

TKVEIK

3757
CL-33812
CDR-L1

ERSSGDIWQSYVS

3758
CL-33812
CDR-L2

SDDQRAS

3759
CL-33812
CDR-L3

QSYGINIDVV

3760
CL-33820 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIESSF

TSYSFDYWGQGTMVTVSS

3761
CL-33820
CDR-H1

GFSLSTYGMGVG

3762
CL-33820
CDR-H2

NIWWDDDKYYNPSLKN

3763
CL-33820
CDR-H3

IESSFTSYSFDY

3764
CL-33820 VL

EIVLTQSPGTLSLSPGERATLSCKRS

SGSIYDTYVSWYQQKPGQAPRLVIYS

DDQRPSGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYDLTIDITFGGG

TKVEIK

3765
CL-33820
CDR-L1

KRSSGSIYDTYVS

3766
CL-33820
CDR-L2

SDDQRPS

3767
CL-33820
CDR-L3

QSYDLTIDIT

3768
CL-33845 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIVSDW

TTYSFDYWGQGTMVTVSS

3769
CL-33845
CDR-H1

GFSLSTYGMGVG

3770
CL-33845
CDR-H2

NIWWDDDKYYNPSLKN

3771
CL-33845
CDR-H3

IVSDWTTYSFDY

3772
CL-33845 VL

EIVLTQSPGTLSLSPGERATLSCRAS

SGSIWYSFVSWYQQKPGQAPRLLIYA

DDQRASGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYGINIDVVFGGG

TKVEIK

3773
CL-33845
CDR-L1

RASSGSIWYSFVS

3774
CL-33845
CDR-L2

ADDQRAS

3775
CL-33845
CDR-L3

QSYGINIDVV

3776
CL-33855 VH

EVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKN

QVVLTMTNMDPVDTATYYCARIETFG

PKYSFDYWGQGTMVTVSS

3777
CL-33855
CDR-H1

GFSLSTYGMGVG

3778
CL-33855
CDR-H2

NIWWDDDKYYNPSLKN

3779
CL-33855
CDR-H3

IETFGPKYSFDY

3780
CL-33855 VL

EIVLTQSPGTLSLSPGERATLSCRAS

SGSIWYSFVSWYQQKPGQAPRLLIYA

DDQRASGIPDRFSGSGSGTDFTLTIS

RLEPEDFAVYYCQSYGINIDVVFGGG

TKVEIK

3781
CL-33855
CDR-L1

RASSGSIWYSFVS

3782
CL-33855
CDR-L2

ADDQRAS

3783
CL-33855
CDR-L3

QSYGINIDVV

TABLE 51

Summary of Protein Expression And Purification Of

Affinity Matured Humanized Anti-Human PDGF-BB

Antibodies

Octet Titer
~Yield
SEC (%

Name
(mg/L)¹
(mg/L)²
monomer)³

CL-33578-IgG
176.5
98.9
91.3

CL-33587-IgG
155.7
109.1
94.2

CL-33675-IgG
275.2
57.7
96.9

CL-33682-IgG
203.6
80.7
94.6

CL-33683-IgG
136.7
24.5
48.1

CL-33701-IgG
114.9
79.2
97.9

CL-33706-IgG
169.8
25.8
100.0

CL-33731-IgG
137.0
73.6
95.8

CL-33803-IgG
98.0
50.5
96.7

CL-33805-IgG
227.5
66.5
97.9

CL-33811-IgG
190.2
31.7
99.0

CL-33812-IgG
171.0
76.4
96.7

CL-33820-IgG
135.3
75.0
95.7

CL-33855-IgG
50.9
13.8
94.3

CL-33699-IgG
ND
10.5
81.7

CL-33737-IgG
ND
5.0
88.0

CL-33759-IgG
ND
18.5
100.0

CL-33767-IgG
ND
16.5
50.9

CL-33845-IgG
ND
0.8
60.6

ND = Not Determined

¹Octet titer is the amount of IgG in the unpurified supernatant as determined by protein A binding compared to a standard curve using an Octet instrument.

²Yield is determined by the total amount of purified protein in mg divided by the total cell culture volume in liters.

³SEC % monomer is determined using HPLC size exclusion chromatography.

TABLE 52

Biacore Binding of Affinity-Matured Humanized

Anti-PDGF Antibodies

Antibody
k_on(M−1 s−1)
k_off(M−1)
K_D(M)

CL-33578
≧9.0E+07
2.70E−05
≦3.0E−13

CL-33587
≧9.0E+07
2.00E−05
≦2.2E−13

CL-33675
3.60E+07
2.20E−05
6.10E−13

CL-33682
≧9.0E+07
2.20E−05
≦2.4E−13

CL-33683
1.90E+07
8.20E−06
4.40E−13

CL-33701
7.30E+07
1.80E−05
2.40E−13

CL-33706
1.80E+07
1.20E−05
6.90E−13

CL-33731
8.10E+07
1.60E−05
2.00E−13

CL-33803
≧9.0E+07
1.40E−05
≦1.6E−13

CL-33805
6.80E+07
1.50E−05
2.10E−13

CL-33811
2.70E+07
1.20E−05
4.50E−13

CL-33812
6.30E+07
1.90E−05
3.00E−13

CL-33820
≧9.8E+07
1.60E−05
≦1.6E−13

CL-33855
2.00E+07
≦1.0E−06
≦5.0E−14

*Heterogeneous off-rate

Affinity matured humanized anti-PDGF-BB antibodies were characterized for PDGF-BB binding and potency. Human PDGF-BB binding affinity was determined by Biacore analysis (Example 1.1). Potency was evaluated in both cell-based and ELISA formats. The ability to block binding of hPDGF-BB to hPDGF-Rβ was tested in a competition ELISA format (Example 1.13) Inhibition of human and cynomolgus PDGF-BB-induced cell proliferation was assessed using NIH-3T3 cells (Examples 1.15 and 1.16). The data is summarized in Table 53 below.

TABLE 53

Summary of Characterization of Affinity Matured Humanized

Anti-Human PDGF-BB Antibodies

PDGF-BB IC₅₀Potency (nM)

hPDGF-BB
cynoPDGF-BB
hPDGF-BB/

Affinity Matured
NIH-3T3
NIH-3T3
hPDGFR□

Humanized IgG
Proliferation
Proliferation
Competition

CL-33578-Ig
0.033
0.023
0.049

CL-33587-Ig
0.046
0.029
<0.1

CL-33675-Ig
0.04
0.024
0.054

CL-33682-Ig
0.03
0.019
0.069

CL-33683-Ig
0.029
0.028
0.126

CL-33699-Ig
0.033
0.016
0.072

CL-33706-Ig
0.035
0.019
0.081

CL-33731Ig
0.036
0.023
0.068

CL-33759-Ig
0.293
0.18
1.267

CL-33811-Ig
0.032
0.012
0.1

CL-33812-Ig
0.033
0.028
0.043

CL-33820-Ig
0.017
0.013
0.066

CL-33855-Ig
0.037
0.019
0.162

CL-33701-Ig
0.056
0.012
0.059

CL-33737-Ig
0.03
0.024
0.092

CL-33803-Ig
0.024
0.018
0.044

C-L33767-Ig
0.09
0.042
0.114

CL-33845-Ig
0.171
0.073
0.409

CL-33805-Ig
0.039
0.018
0.063

Example 9
Methods of Selecting Preferred Humanized Antibodies as DVD-Ig Building Blocks
Example 9.1
A Technique for Assessing the Stability of Regions of the Parental Antibodies Intended for DVD-Ig Protein Incorporation

The technique of differential scanning calorimetry (DSC) can be used to determine the thermal stabilities of the different domains of an antibody (e.g. CH2, CH3, CH1-CL, and VH-VL). The temperature of the highest peak in a DSC thermogram (plotted as heat capacity versus temperature) of an antibody has been shown to correspond to the midpoint of the unfolding transition or process of that antibody's VH-VL region due to increasing temperature. This may be interpreted as a measure of VH-VL thermal stability. VH-VL regions with high thermal stability in the antibody format will also likely have high thermal stability when incorporated into the DVD-Ig format as one of the binding domains. Therefore, antibodies can be screened to determine those with VH-VL regions of high thermal stability. Those regions can then be incorporated into the DVD-Ig format to increase the probability of generating a more stable DVD-Ig molecule.

Example 9.2
Determination of the Thermal Stability of the VH-VL Regions of Anti-VEGF mAbs and Anti-PDGF mAbs by Differential Scanning Calorimetry

A total of 73 mAbs (45 anti-VEGF and 28 anti-PDGF) were selected and analyzed by DSC (Example 2.2) and the thermal stabilities of their VH-VL regions were quantitated by determining the temperature of the highest peak in the DSC thermograms as detailed in Example 9.1 (Table 54).

TABLE 54

Thermal Stability of Anti-VEGF and Anti-PDGF Antibodies

Temperature of highest peak in

Name
Target Antigen
DSC thermogram (° C.)

hBDB-4G8.1
VEGF
71.97

hBDB-4G8.2
VEGF
69.13

hBDB-4G8.3
VEGF
65.65

hBDB-4G8.4
VEGF
75.27

hBDB-4G8.5
VEGF
73.07

hBDB-4G8.6
VEGF
68.68

hBDB-4G8.7
VEGF
76.27

hBDB-4G8.8
VEGF
73.16

hBDB-4G8.9
VEGF
68.95

hBDB-4G8.10
VEGF
73.44

hBDB-4G8.11
VEGF
69.77

hBDB-4G8.12
VEGF
67.48

hBDB-4G8.13
VEGF
67.12

hBDB-4G8.14
VEGF
63.4

hBDB-4G8.15
VEGF
69.41

h4G8.3 EI
VEGF
68.31

h4G8 CL-32416
VEGF
68.95

h4G8 CL-34449
VEGF
72.7

h4G8 CL-34455
VEGF
70.69

h4G8 CL-34469
VEGF
70.23

h4G8 CL-34475
VEGF
70.69

h4G8 CL-34522
VEGF
67.49

h4G8 CL-34540
VEGF
69.87

h4G8 CL-34633
VEGF
69.22

h4G8 CL-34538
VEGF
71.15

h4G8 CL-34570
VEGF
66.84

h4G8 CL-34565
VEGF
71.15

hBEW-9A8.17
VEGF
64.56

hBEW-9A8.21
VEGF
54.25

hBEW-5C3.4
VEGF
66.94

hBEW-9E10.1
VEGF
71.88

hBEW-9E10.3
VEGF
71.24

hBEW-9E10.4
VEGF
71.77

hBEW-9E10.6
VEGF
71.24

hBEW-9A8.20
VEGF
61.85

hBEW-5C3.1
VEGF
63.15

hBEW-5C3.5
VEGF
64.83

hBEW-9E10.2
VEGF
71.37

hBEW-9E10.5
VEGF
71.24

hBEW-1B10.1
VEGF
87.95

hBEW-1B10.2
VEGF
86.38

hBEW-1E3.1
VEGF
62.74

hBEW-1E3.2
VEGF
66.29

hBEW-1E3.4
VEGF
66.11

hBEW-1E3.5
VEGF
68.83

hBDI-9E8.1
PDGF
77.6

hBDI-9E8.2
PDGF
76.28

hBDI-9E8.3
PDGF
87.4

hBDI-9E8.4
PDGF
84.2

hBDI-9E8.5
PDGF
77.69

hBDI-9E8.6
PDGF
75.91

hBDI-9E8.7
PDGF
87.4

hBDI-9E8.8
PDGF
84.29

hBDI-9E8.9
PDGF
82.09

hBDI-9E8.10
PDGF
83.37

hBDI-9E8.11
PDGF
80.9

hBDI-9E8.12
PDGF
82.64

hBDI-9E8.13
PDGF
85.39

CL-33578-IgG
PDGF
75.03

CL-33587-IgG
PDGF
76.37

CL-33675-IgG
PDGF
87.4

CL-33682-IgG
PDGF
78.52

CL-33683-IgG
PDGF
82.55

CL-33701-IgG
PDGF
73.62

CL-33706-IgG
PDGF
86.85

CL-33731-IgG
PDGF
77.33

CL-33803-IgG
PDGF
74.26

CL-33805-IgG
PDGF
80.35

CL-33811-IgG
PDGF
79.71

CL-33812-IgG
PDGF
78.15

CL-33820-IgG
PDGF
78.88

CL-33855-IgG
PDGF
82.18

hBFU-3E2.1
PDGF
68.31

Example 10
Generation of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules

The variable domain sequences from humanized anti-human VEGF-A and anti-human PDGF-BB mAbs were used to design the VH and VL domains of anti-human VEGF-A/anti-human PDGF-BB DVD-Ig molecules. In some cases, variable regions were synthesized using two-step PCR. Primers were designed with homologous flanking regions to the cloning vector and the linker region between each DVD variable pair. In some cases, variable regions were generated using gene synthesis. Bacterial transformations were performed to identify positive clones and constructs were harvested and purified for use in mammalian transfection using standard protocols known in the art.

The variable domains of the heavy and light chain were cloned in-frame into mutant human IgG1 (L234, 235A) heavy-chain or mutant human IgG1 (L234, 235A, H435A) heavy-chain, and kappa light-chain constant regions, respectively, into pHybE vectors to generate anti-human VEGF-A/anti-human PDGF-BB DVD-Ig molecules.

TABLE 55

Amino Acid Sequences of DVD-Ig Linkers

Seq ID

No
Name
Sequence

3784
HG-short
ASTKGP

3785
HG-long
ASTKGPSVFPLAP

3786
GS-H10
GGGGSGGGGS

3787
LK-short
RTVAAP

3788
LK-long
RTVAAPSVFIFPP

3789
GS-L10
RGGSGGGGSG

3790
GS-L10(dR)
GGSGGGGSGG

3791
GS-L11
RGGSGGGGSGG

3792

AKTTPKLEEGEFSEAR

3793

AKTTPKLEEGEFSEARV

3794

AKTTPKLGG

3795

SAKTTPKLGG

3796

SAKTTP

3797

RADAAP

3798

RADAAPTVS

3799

RADAAAAGGPGS

3800

RADAAAA(G₄S)₄

3801

SAKTTPKLEEGEFSEARV

3802

ADAAP

3803

ADAAPTVSIFPP

3804

TVAAP

3805

TVAAPSVFIFPP

3806

QPKAAP

3807

QPKAAPSVTLFPP

3808

AKTTPP

3809

AKTTPPSVTPLAP

3810

AKTTAP

3811

AKTTAPSVYPLAP

3812

ASTKGP

3813

ASTKGPSVFPLAP

3814

GGGGSGGGGSGGGGS

3815

GENKVEYAPALMALS

3816

GPAKELTPLKEAKVS

3817

GHEAAAVMQVQYPAS

3818

TVAAPSVFIFPPTVAAPSVFIFPP

3819

ASTKGPSVFPLAPASTKGPSVFPLAP

3820

GGGGSGGGGS

3821

GGSGGGGSG

G/S based sequences

(e.g., G4S (SEQ ID NO: 3822)

and G4S repeats (“G4S”

disclosed as SEQ ID NO: 3822))

TABLE 56

Heavy (H) and Light Chain (L) Composition of Anti-VEGF-A/Anti-PDGF-BB DVD-

Ig Molecules (first and second polypeptide chains are listed in alternating rows of the table)

SEQ ID NO

VD1-X1-

SEQ ID

DVD-Ig Variable Domain
Outer Variable

Inner Variable
VD2

NO
Corporate ID
Name
Domain Name
Linker
Domain Name
Formula

NA
AB014-GS-9E8.4^a
AB014 VH
GS-H10
hBDI-9E8.4 VH

AB014 VL
GS-L10
hBDI-9E8.4 VL

NA
9E8.4-GS-AB014^a
hBDI-9E8.4 VH
GS-H10
AB014 VH

hBDI-9E8.4 VL
GS-L10
AB014 VL

NA
AB014-SS-9E8.4^a
AB014 VH
HG-short
hBDI-9E8.4 VH

AB014 VL
LK-short
hBDI-9E8.4 VL

NA
9E8.4-SS-AB014^a
hBDI-9E8.4 VH
HG-short
AB014 VH

hBDI-9E8.4 VL
LK-short
AB014 VL

NA
AB014-SL-9E8.4^a
AB014 VH
HG-short
hBDI-9E8.4 VH

AB014 VL
LK-long
hBDI-9E8.4 VL

NA
9E8.4-SL-AB014^a
hBDI-9E8.4 VH
HG-short
AB014 VH

hBDI-9E8.4 VL
LK-long
AB014 VL

NA
AB014-LS-9E8.4^a
AB014 VH
HG-long
hBDI-9E8.4 VH

AB014 VL
LK-short
hBDI-9E8.4 VL

NA
9E8.4-LS-AB014^a
hBDI-9E8.4 VH
HG-long
AB014 VH

hBDI-9E8.4 VL
LK-short
AB014 VL

PR-1563988
9E8.4-GS-4G8.3^a
hBDI-9E8.4 VH
GS-H10
hBDB-4G8.3 VH

hBDI-9E8.4 VL
GS-L10
hBDB-4G8.3 VL

PR-1563990
9E8.4-SS-4G8.3^a
hBDI-9E8.4 VH
HG-short
hBDB-4G8.3 VH

hBDI-9E8.4 VL
LK-short
hBDB-4G8.3 VL

PR-1563998
9E8.4-SL-4G8.3^a
hBDI-9E8.4 VH
HG-short
hBDB-4G8.3 VH

hBDI-9E8.4 VL
LK-long
hBDB-4G8.3 VL

PR-1564009
9E8.4-LS-4G8.3^a
hBDI-9E8.4 VH
HG-long
hBDB-4G8.3 VH

hBDI-9E8.4 VL
LK-short
hBDB-4G8.3 VL

PR-1564010
4G8.3-GS-9E8.4^a
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4 VH

hBDB-4G8.3 VL
GS-H10
hBDI-9E8.4 VL

PR-1564011
4G8.3-SS-9E8.4^a
hBDB-4G8.3 VH
HG-short
hBDI-9E8.4 VH

hBDB-4G8.3 VL
LK-short
hBDI-9E8.4 VL

PR-1564012
4G8.3-SL-9E8.4^a
hBDB-4G8.3 VH
HG-short
hBDI-9E8.4 VH

hBDB-4G8.3 VL
LK-long
hBDI-9E8.4 VL

PR-1564013
4G8.3-LS-9E8.4^a
hBDB-4G8.3 VH
HG-long
hBDI-9E8.4 VH

hBDB-4G8.3 VL
LK-short
hBDI-9E8.4 VL

PR-1569574
9E8.4-GS-4G8.3
hBDI-9E8.4 VH
GS-H10
hBDB-4G8.3 VH

hBDI-9E8.4 VL
GS-L10
hBDB-4G8.3 VL

PR-1569579
9E8.4-SL-4G8.3
hBDI-9E8.4 VH
HG-short
hBDB-4G8.3 VH

hBDI-9E8.4 VL
LK-long
hBDB-4G8.3 VL

PR-1575573
9E8.4-LS-4G8.3
hBDI-9E8.4 VH
HG-long
hBDB-4G8.3 VH

hBDI-9E8.4 VL
LK-short
hBDB-4G8.3 VL

PR-1572102
4G8.3-GS-9E8.4 (g)
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4 VH

hBDB-4G8.3 VL
GS-L10
hBDI-9E8.4 VL

PR-1572103
4G8.3-GS(11)-9E8.4 (g)
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4 VH

hBDB-4G8.3 VL
GS-L11
hBDI-9E8.4 VL

PR-1572104
4G8.3-GS(noR)-9E8.4 (g)
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4 VH

hBDB-4G8.3 VL
GS-
hBDI-9E8.4 VL

L10 (dR)

PR-1572105
4G8.3-SL-9E8.4 (g)
hBDB-4G8.3 VH
HG-short
hBDI-9E8.4 VH

hBDB-4G8.3 VL
LK-long
hBDI-9E8.4 VL

PR-1572106
4G8.3-LS-9E8.4 (g)
hBDB-4G8.3 VH
HG-long
hBDI-9E8.4 VH

hBDB-4G8.3 VL
LK-short
hBDI-9E8.4 VL

PR-1575832
4G8.3-GS-9E8.4E
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4E VH

hBDB-4G8.3 VL
GS-L10
hBDI-9E8.4E VL

PR-1575834
4G8.3-SL-9E8.4E
hBDB-4G8.3 VH
HG-short
hBDI-9E8.4E VH

hBDB-4G8.3 VL
LK-long
hBDI-9E8.4E VL

PR-1575835
4G8.3-LS-9E8.4E
hBDB-4G8.3 VH
HG-long
hBDI-9E8.4E VH

hBDB-4G8.3 VL
LK-short
hBDI-9E8.4E VL

PR-1577165
9A8.12-GS-9E8.4E
hBEW-9A8.12
GS-H10
hBDI-9E8.4E VH

VH

hBEW-9A8.12 VL
GS-L10
hBDI-9E8.4E VL

PR-1577166
9A8.12-SL-9E8.4E
hBEW-9A8.12
HG-short
hBDI-9E8.4E VH

VH

hBEW-9A8.12 VL
LK-long
hBDI-9E8.4E VL

PR-1577547
9A8.12-LS-9E8.4E
hBEW-9A8.12
HG-long
hBDI-9E8.4E VH

VH

hBEW-9A8.12 VL
LK-short
hBDI-9E8.4E VL

PR-1578137
9E8.4E-GS-9A8.12
hBDI-9E8.4E VH
GS-H10
hBEW-9A8.12 VH

hBDI-9E8.4E VL
GS-L10
hBEW-9A8.12 VL

PR-1577548
9E8.4E-SL-9A8.12
hBDI-9E8.4E VH
HG-short
hBEW-9A8.12 VH

hBDI-9E8.4E VL
LK-long
hBEW-9A8.12 VL

PR-1577550
9E8.4E-LS-9A8.12
hBDI-9E8.4E VH
HG-long
hBEW-9A8.12 VH

hBDI-9E8.4E VL
LK-short
hBEW-9A8.12 VL

PR-1598261
4G8.2-GS-9E8.4
hBDB-4G8.2 VH
GS-H10
hBDI-9E8.4 VH

hBDB-4G8.2 VL
GS-L10
hBDI-9E8.4 VL

PR-1598262
4G8.4-GS-9E8.4
hBDB-4G8.4 VH
GS-H10
hBDI-9E8.4 VH

hBDB-4G8.4 VL
GS-L10
hBDI-9E8.4 VL

PR-1598263
4G8.5-GS-9E8.4
hBDB-4G8.5 VH
GS-H10
hBDI-9E8.4 VH

hBDB-4G8.5 VL
GS-L10
hBDI-9E8.4 VL

PR-1598264
4G8.12-GS-9E8.4
hBDB-4G8.12 VH
GS-H10
hBDI-9E8.4 VH

hBDB-4G8.12 VL
GS-L10
hBDI-9E8.4 VL

PR-1598265
4G8.13-GS-9E8.4
hBDB-4G8.13 VH
GS-H10
hBDI-9E8.4 VH

hBDB-4G8.13 VL
GS-L10
hBDI-9E8.4 VL

PR-1598266
4G8.14-GS-9E8.4
hBDB-4G8.14 VH
GS-H10
hBDI-9E8.4 VH

hBDB-4G8.14 VL
GS-L10
hBDI-9E8.4 VL

PR-1613183
CL-34565_GS_CL-33675
CL-34565 VH
GS-H10
CL-33675 VH

CL-34565 VL
GS-
CL-33675 VL

L10 (dR)

PR-1613184
CL-34565_GS_9E8.4
CL-34565 VH
GS-H10
hBDI-9E8.4 VH

CL-34565 VL
GS-
hBDI-9E8.4 VL

L10 (dR)

PR-1613185
CL-34565_GS_3E2.1
CL-34565 VH
GS-H10
hBFU-3E2.1 VH

CL-34565 VL
GS-
hBFU-3E2.1 VL

L10 (dR)

PR-1611291
4G8.5_GS_CL-33675
hBDB-4G8.5 VH
GS-H10
CL-33675 VH

hBDB-4G8.5 VL
GS-
CL-33675 VL

L10 (dR)

PR-1612489
4G8.5_GS_9E8.4
hBDB-4G8.5 VH
GS-H10
hBDI-9E8.4 VH

hBDB-4G8.5 VL
GS-
hBDI-9E8.4 VL

L10 (dR)

PR-1610560
4G8.5_GS_3E2.1
hBDB-4G8.5 VH
GS-H10
hBFU-3E2.1 VH

hBDB-4G8.5 VL
GS-
hBFU-3E2.1 VL

L10 (dR)

PR-1610561
9E10.1_GS_CL-33675
hBEW-9E10.1 VH
GS-H10
CL-33675 VH

hBEW-9E10.1 VL
GS-
CL-33675 VL

L10 (dR)

PR-1612491
9E10.1_GS_9E8.4
hBEW-9E10.1 VH
GS-H10
hBDI-9E8.4 VH

hBEW-9E10.1 VL
GS-
hBDI-9E8.4 VL

L10 (dR)

PR-1610562
9E10.1_GS_3E2.1
hBEW-9E10.1 VH
GS-H10
hBFU-3E2.1 VH

hBEW-9E10.1 VL
GS-
hBFU-3E2.1 VL

L10 (dR)

PR-1612492
9E10.6_GS_CL-33675
hBEW-9E10.6 VH
GS-H10
CL-33675 VH

hBEW-9E10.6 VL
GS-
CL-33675 VL

L10 (dR)

PR-1612493
9E10.6_GS_9E8.4
hBEW-9E10.6 VH
GS-H10
hBDI-9E8.4 VH

hBEW-9E10.6 VL
GS-
hBDI-9E8.4 VL

L10 (dR)

PR-1610563
9E10.6_GS_3E2.1
hBEW-9E10.6 VH
GS-H10
hBFU-3E2.1 VH

hBEW-9E10.6 VL
GS-
hBFU-3E2.1 VL

L10 (dR)

PR-1611292
1B10.1_GS_CL-33675
hBEW-1B10.1 VH
GS-H10
CL-33675 VH

hBEW-1B10.1 VL
GS-
CL-33675 VL

L10 (dR)

PR-1612494
1B10.1_GS_9E8.4
hBEW-1B10.1 VH
GS-H10
hBDI-9E8.4 VH

hBEW-1B10.1 VL
GS-
hBDI-9E8.4 VL

L10 (dR)

PR-1610564
1B10.1_GS_3E2.1
hBEW-1B10.1 VH
GS-H10
hBFU-3E2.1 VH

hBEW-1B10.1 VL
GS-
hBFU-3E2.1 VL

L10 (dR)

PR-1611293
1E3.4_GS_CL-33675
hBEW-1E3.4 VH
GS-H10
CL-33675 VH

hBEW-1E3.4 VL
GS-
CL-33675 VL

L10 (dR)

PR-1611294
1E3.4_GS_9E8.4
hBEW-1E3.4 VH
GS-H10
hBDI-9E8.4 VH

hBEW-1E3.4 VL
GS-
hBDI-9E8.4 VL

L10 (dR)

PR-1612495
1E3.4_GS_3E2.1
hBEW-1E3.4 VH
GS-H10
hBFU-3E2.1 VH

hBEW-1E3.4 VL
GS-
hBFU-3E2.1 VL

L10 (dR)

PR-1613186
CL-33675_GS_CL-34565
CL-33675 VH
GS-H10
CL-34565 VH

CL-33675 VL
GS-
CL-34565 VL

L10 (dR)

PR-1612496
CL-33675_GS_4G8.5
CL-33675 VH
GS-H10
hBDB-4G8.5 VH

CL-33675 VL
GS-
hBDB-4G8.5 VL

L10 (dR)

PR-1611295
CL-33675_GS_9E10.1
CL-33675 VH
GS-H10
hBEW-9E10.1 VH

CL-33675 VL
GS-
hBEW-9E10.1 VL

L10 (dR)

PR-1611296
CL-33675_GS_9E10.6
CL-33675 VH
GS-H10
hBEW-9E10.6 VH

CL-33675 VL
GS-
hBEW-9E10.6 VL

L10 (dR)

PR-1612498
CL-33675_GS_1B10.1
CL-33675 VH
GS-H10
hBEW-1B10.1 VH

CL-33675 VL
GS-
hBEW-1B10.1

L10 (dR)
VL

PR-1611297
CL-33675_GS_1E3.4
CL-33675 VH
GS-H10
hBEW-1E3.4

VH

CL-33675 VL
GS-
hBEW-1E3.4 VL

L10 (dR)

PR-1613187
9E8.4_GS_CL-34565
hBDI-9E8.4 VH
GS-H10
CL-34565 VH

hBDI-9E8.4 VL
GS-
CL-34565 VL

L10 (dR)

PR-1613188
9E8.4_GS_4G8.5
hBDI-9E8.4 VH
GS-H10
hBDB-4G8.5 VH

hBDI-9E8.4 VL
GS-
hBDB-4G8.5 VL

L10 (dR)

PR-1611298
9E8.4_GS_9E10.1
hBDI-9E8.4 VH
GS-H10
hBEW-9E10.1

VH

GS-
hBEW-9E10.1H

L10 (dR)
VL

PR-1611299
9E8.4_GS_9E10.6
hBDI-9E8.4 VH
GS-H10
hBEW-9E10.6

VH

hBDI-9E8.4 VL
GS-
hBEW-9E10.6

L10 (dR)
VL

PR-1611300
9E8.4_GS_1B10.1
hBDI-9E8.4 VH
GS-H10
hBEW-1B10.1 VH

hBDI-9E8.4 VL
GS-
hBEW-1B10.1

L10 (dR)
VL

PR-1611301
9E8.4_GS_1E3.4
hBDI-9E8.4 VH
GS-H10
hBEW-1E3.4

VH

hBDI-9E8.4 VL
GS-
hBEW-1E3.4 VL

L10 (dR)

PR-1613189
3E2.1_GS_CL-34565
hBFU-3E2.1 VH
GS-H10
CL-34565 VH

hBFU-3E2.1 VL
GS-
CL-34565 VL

L10 (dR)

PR-1612499
3E2.1_GS_4G8.5
hBFU-3E2.1 VH
GS-H10
hBDB-4G8.5 VH

hBFU-3E2.1 VL
GS-
hBDB-4G8.5 VL

L10 (dR)

PR-1612500
3E2.1_GS_9E10.1
hBFU-3E2.1 VH
GS-H10
hBEW-9E10.1

VH

hBFU-3E2.1 VL
GS-
hBEW-9E10.1

L10 (dR)
VL

PR-1612501
3E2.1_GS_9E10.6
hBFU-3E2.1 VH
GS-H10
hBEW-9E10.6

VH

hBFU-3E2.1 VL
GS-
hBEW-9E10.6

L10 (dR)
VL

PR-1612502
3E2.1_GS_1B10.1
hBFU-3E2.1 VH
GS-H10
hBEW-1B10.1 VH

hBFU-3E2.1 VL
GS-
hBEW-1B10.1

L10 (dR)
VL

PR-1613190
3E2.1_GS_1E3.4
hBFU-3E2.1 VH
GS-H10
hBEW-1E3.4

VH

hBFU-3E2.1 VL
GS-
hBEW-1E3.4 VL

L10 (dR)

PR-1629646
9E10.1_SL_CL-33675
hBEW-9E10.1 VH
HG-short
CL-33675 VH

hBEW-9E10.1 VL
LK-long
CL-33675 VL

PR-1629647
1B10.1_SL_CL-33675
hBEW-1B10.1 VH
HG-short
CL-33675 VH

hBEW-1B10.1 VL
LK-long
CL-33675 VL

PR-1629648
9E10.1_LS_CL-33675
hBEW-9E10.1 VH
HG-long
CL-33675 VH

hBEW-9E10.1 VL
LK-short
CL-33675 VL

PR-1629649
1B10.1_LS_CL-33675
hBEW-1B10.1 VH
HG-long
CL-33675 VH

hBEW-1B10.1 VL
LK-short
CL-33675 VL

PR-1564883
DVD3896^a
hBDI-5H1.9 VH
HG-short
hBDB-4G8.13

VH

hBDI-5H1.9 VL
LK-long
hBDB-4G8.13

VL

PR-1564893
DVD3897^a
hBDI-5H1.9 VH
HG-short
hBDB-4G8.14

VH

hBDI-5H1.9 VL
LK-long
hBDB-4G8.14

VL

PR-1564896
DVD3898^a
hBDI-5H1.9 VH
HG-short
hBDB-4G8.15

VH

hBDI-5H1.9 VL
LK-long
hBDB-4G8.15

VL

PR-1564898
DVD3899^a
hBDI-9E8.12 VH
HG-short
hBDB-4G8.14

VH

hBDI-9E8.12 VL
LK-long
hBDB-4G8.14

VL

PR-1564899
DVD3900^a
hBDI-9E8.12 VH
HG-short
hBDB-4G8.15

VH

hBDI-9E8.12 VL
LK-long
hBDB-4G8.15

VL

PR-1565023
DVD3901^a
hBDI-9E8.9 VH
HG-short
hBDB-4G8.13

VH

hBDI-9E8.9 VL
LK-long
hBDB-4G8.13

VL

PR-1565029
DVD3902^a
hBDI-9E8.9 VH
HG-short
hBDB-4G8.14

VH

hBDI-9E8.9 VL
LK-long
hBDB-4G8.14

VL

PR-1565030
DVD3903^a
hBDI-9E8.9 VH
HG-short
hBDB-4G8.15

VH

hBDI-9E8.9 VL
LK-long
hBDB-4G8.15

VL

PR-1565031
DVD3904^a
hBDI-5H1.13 VH
HG-short
hBDB-4G8.14

VH

hBDI-5H1.13 VL
LK-long
hBDB-4G8.14

VL

PR-1565032
DVD3905^a
hBDI-9E8.12 VH
HG-short
hBDB-4G8.15

VH

hBDI-9E8.12 VL
LK-long
hBDB-4G8.15

VL

PR-1565035
DVD3906^a
hBDI-5H1.13 VH
HG-short
hBDB-4G8.15

VH

hBDI-5H1.13 VL
LK-long
hBDB-4G8.15

VL

PR-1565033
DVD3907^a
hBDI-9E8.13 VH
HG-short
hBDB-4G8.15

VH

hBDI-9E8.13 VL
LK-long
hBDB-4G8.15

VL

^aThese DVDs were made with Ig gamma-1 constant region L234A, L235A, all other DVDs made with Ig gamma-1 constant region L234A, L235A, and H435A.

TABLE 57

Heavy (H) and Light Chain (L) Amino Acid Composition of

Some Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules

(Linker sequence in italics; CDR sequences in bold;

HC = heavy chain and LC = light chain)

Sequence
DVD-Ig Variable
Sequence

Identifier
Domain (Corporate ID)
12345678901234567890123456789012

SEQ ID NO: 3823
4G8.3-GS-9E8.4 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNY

(PR-1569574)

GMYWVRQAPGQGLEWMGWINTETGKPTYADDF

KGRFVFSLDTSVSTAYLQISSLKAEDTAVYYC

ARTNYYYRSYIFYFDYWGQGTMVTVSSGGGGS

GGGGSEVTLRESGPALVKPTQTLTLTCTFSGF

SLSTYGMGVGWIRQPPGKALEWLANIWWDDDK

YYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD

TATYYCARIESIGTTYSFDYWGQGTMVTVSSA

STKGPSVFPLAPSSKSTSGGTAALGCLVKDYF

PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL

SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK

VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPK

PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY

VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH

QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ

PREPQVYTLPPSREEMTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

YSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQ

KSLSLSPGK

SEQ ID NO: 3824
4G8.3-GS-9E8.4 LC
DTVLTQSPATLSLSPGERATLSCRASESVSTH

(PR-1569574)

MHWYQQKPGQAPRLLIYGASNLESGVPARFSG

SGSGTDFTLTISSLEPEDFAVYFCQQSWNDPF

TFGQGTKLEIKRGGSGGGGSGEFVLTQSPGTL

SLSPGERATLSCERSSGDIGDSYVSWYQQKPG

QAPRLVIYADDQRPSGIPDRFSGSGSGTDFTL

TISRLEPEDFAVYYCQSYDINIDIVFGGGTKV

EIKGTVAAPSVFIFPPSDEQLKSGTASVVCLL

NNFYPREAKVQWKVDNALQSGNSQESVTEQDS

KDSTYSLSSTLTLSKADYEKHKVYACEVTHQG

LSSPVTKSFNRGEC

SEQ ID NO: 3825
4G8.3-SL-9E8.4 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNY

(PR-1569579)

GMYWVRQAPGQGLEWMGWINTETGKPTYADDF

KGRFVFSLDTSVSTAYLQISSLKAEDTAVYYC

ARTNYYYRSYIFYFDYWGQGTMVTVSSASTKG

PEVTLRESGPALVKPTQTLTLTCTFSGFSLST

YGMGVGWIRQPPGKALEWLANIWWDDDKYYNP

SLKNRLTISKDTSKNQVVLTMTNMDPVDTATY

YCARIESIGTTYSFDYWGQGTMVTVSSASTKG

PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV

TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV

TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK

SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDT

LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV

EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL

NGKEYKCKVSNKALPAPIEKTISKAKGQPREP

QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA

VEWESNGQPENNYKTTPPVLDSDGSFFLYSKL

TVDKSRWQQGNVFSCSVMHEALHNAYTQKSLS

LSPGK

SEQ ID NO: 3826
4G8.3-SL-9E8.4 LC
DTVLTQSPATLSLSPGERATLSCRASESVSTH

(PR-1569579)

MHWYQQKPGQAPRLLIYGASNLESGVPARFSG

SGSGTDFTLTISSLEPEDFAVYFCQQSWNDPF

TFGQGTKLEIKRTVAAPSVFIFPPEFVLTQSP

GTLSLSPGERATLSCERSSGDIGDSYVSWYQQ

KPGQAPRLVIYADDQRPSGIPDRFSGSGSGTD

FTLTISRLEPEDFAVYYCQSYDINIDIVFGGG

TKVEIKGTVAAPSVFIFPPSDEQLKSGTASVV

CLLNNFYPREAKVQWKVDNALQSGNSQESVTE

QDSKDSTYSLSSTLTLSKADYEKHKVYACEVT

HQGLSSPVTKSFNRGEC

SEQ ID NO: 3827
4G8.3-LS-9E8.4 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNY

(PR-1575573)

GMYWVRQAPGQGLEWMGWINTETGKPTYADDF

KGRFVFSLDTSVSTAYLQISSLKAEDTAVYYC

ARTNYYYRSYIFYFDYWGQGTMVTVSSASTKG

PSVFPLAPEVTLRESGPALVKPTQTLTLTCTF

SGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMD

PVDTATYYCARIESIGTTYSFDYWGQGTMVTV

SSASTKGPSVFPLAPSSKSTSGGTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL

YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV

DKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLF

PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF

NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT

VLHQDWLNGKEYKCKVSNKALPAPIEKTISKA

KGQPREPQVYTLPPSREEMTKNQVSLTCLVKG

FYPSDIAVEWESNGQPENNYKTTPPVLDSDGS

FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNA

YTQKSLSLSPGK

SEQ ID NO: 3828
4G8.3-LS-9E8.4 LC
DTVLTQSPATLSLSPGERATLSCRASESVSTH

(PR-1575573)

MHWYQQKPGQAPRLLIYGASNLESGVPARFSG

SGSGTDFTLTISSLEPEDFAVYFCQQSWNDPF

TFGQGTKLEIKRTVAAPEFVLTQSPGTLSLSP

GERATLSCERSSGDIGDSYVSWYQQKPGQAPR

LVIYADDQRPSGIPDRFSGSGSGTDFTLTISR

LEPEDFAVYYCQSYDINIDIVFGGGTKVEIKG

TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY

PREAKVQWKVDNALQSGNSQESVTEQDSKDST

YSLSSTLTLSKADYEKHKVYACEVTHQGLSSP

VTKSFNRGEC

SEQ ID NO: 3829
4G8.3-GS-9E8.4 (g)
EVQLVQSGSELKKPGASVKVSCKASGYTFTNY

HC (PR-1572102)

GMYWVRQAPGQGLEWMGWINTETGKPTYADDF

KGRFVFSLDTSVSTAYLQISSLKAEDTAVYYC

ARTNYYYRSYIFYFDYWGQGTMVTVSSGGGGS

GGGGSEVTLRESGPALVKPTQTLTLTCTFSGF

SLSTYGMGVGWIRQPPGKALEWLANIWWDDDK

YYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD

TATYYCARIESIGTTYSFDYWGQGTMVTVSSA

STKGPSVFPLAPSSKSTSGGTAALGCLVKDYF

PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL

SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK

VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPK

PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY

VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH

QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ

PREPQVYTLPPSREEMTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

YSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQ

KSLSLSPGK

SEQ ID NO: 3830
4G8.3-GS-9E8.4 (g) LC
DTVLTQSPATLSLSPGERATLSCRASESVSTH

(PR-1572102)

MHWYQQKPGQAPRLLIYGASNLESGVPARFSG

SGSGTDFTLTISSLEPEDFAVYFCQQSWNDPF

TFGQGTKLEIKRGGSGGGGSGEFVLTQSPGTL

SLSPGERATLSCERSSGDIGDSYVSWYQQKPG

QAPRLVIYADDQRPSGIPDRFSGSGSGTDFTL

TISRLEPEDFAVYYCQSYDINIDIVFGGGTKV

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL

NNFYPREAKVQWKVDNALQSGNSQESVTEQDS

KDSTYSLSSTLTLSKADYEKHKVYACEVTHQG

LSSPVTKSFNRGEC

SEQ ID NO: 3831
4G8.3-SL-9E8.4 (g) HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNY

(PR-1572105)

GMYWVRQAPGQGLEWMGWINTETGKPTYADDF

KGRFVFSLDTSVSTAYLQISSLKAEDTAVYYC

ARTNYYYRSYIFYFDYWGQGTMVTVSSASTKG

PEVTLRESGPALVKPTQTLTLTCTFSGFSLST

YGMGVGWIRQPPGKALEWLANIWWDDDKYYNP

SLKNRLTISKDTSKNQVVLTMTNMDPVDTATY

YCARIESIGTTYSFDYWGQGTMVTVSSASTKG

PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV

TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV

TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK

SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDT

LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV

EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL

NGKEYKCKVSNKALPAPIEKTISKAKGQPREP

QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA

VEWESNGQPENNYKTTPPVLDSDGSFFLYSKL

TVDKSRWQQGNVFSCSVMHEALHNAYTQKSLS

LSPGK

SEQ ID NO: 3832
4G8.3-SL-9E8.4 (g) LC
DTVLTQSPATLSLSPGERATLSCRASESVSTH

(PR-1572105)

MHWYQQKPGQAPRLLIYGASNLESGVPARFSG

SGSGTDFTLTISSLEPEDFAVYFCQQSWNDPF

TFGQGTKLEIKRTVAAPSVFIFPPEFVLTQSP

GTLSLSPGERATLSCERSSGDIGDSYVSWYQQ

KPGQAPRLVIYADDQRPSGIPDRFSGSGSGTD

FTLTISRLEPEDFAVYYCQSYDINIDIVFGGG

TKVEIKrTVAAPSVFIFPPSDEQLKSGTASVV

CLLNNFYPREAKVQWKVDNALQSGNSQESVTE

QDSKDSTYSLSSTLTLSKADYEKHKVYACEVT

HQGLSSPVTKSFNRGEC

SEQ ID NO: 3833
9E10.1_GS_CL-33675
EIQLVQSGSELKKPGASVKVSCKASGYTFTNY

HC (PR-1610561)

GMYWVKQAPGQGLEYMGWIDTETGRPTYADDF

KGRFVFSLDTSVSTAYLQISSLKAEDTAVYFC

ARWSGDTTGIRGPWFAYWGQGTLVTVSSGGGG

SGGGGSEVTLRESGPALVKPTQTLTLTCTFSG

FSLSTYGMGVGWIRQPPGKALEWLANIWWDDD

KYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSGPKYSFDYWGQGTMVTVSS

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY

FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK

KVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPP

KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW

YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL

HQDWLNGKEYKCKVSNKALPAPIEKTISKAKG

QPREPQVYTLPPSREEMTKNQVSLTCLVKGFY

PSDIAVEWESNGQPENNYKTTPPVLDSDGSFF

LYSKLTVDKSRWQQGNVFSCSVMHEALHNAYT

QKSLSLSPGK

SEQ ID NO: 3834
9E10.1_GS_CL-33675
DIRMTQSPSSLSASVGDRVTIECLASEDIYSD

LC (PR-1610561)

LAWYQQKPGKSPKLLIYNANGLQNGVPSRFSG

SGSGTDYSLTISSLQPEDVATYFCQQYNYFPG

TFGQGTKLEIKGGSGGGGSGGEIVLTQSPGTL

SLSPGERATLSCRASSGSIWYSFVSWYQQKPG

QAPRLLIYADDQRASGIPDRFSGSGSGTDFTL

TISRLEPEDFAVYYCQSYGINIDVVFGGGTKV

EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL

NNFYPREAKVQWKVDNALQSGNSQESVTEQDS

KDSTYSLSSTLTLSKADYEKHKVYACEVTHQG

LSSPVTKSFNRGEC

SEQ ID NO: 3835
1B10.1_GS_CL-33675
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKY

HC (PR-1611292)

DMAWFRQAPGKGLEWVASITTSGVGTYYRDSV

KGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYC

ARGYGAMDAWGQGTTVTVSSGGGGSGGGGSEV

TLRESGPALVKPTQTLTLTCTFSGFSLSTYGM

GVGWIRQPPGKALEWLANIWWDDDKYYNPSLK

NRLTISKDTSKNQVVLTMTNMDPVDTATYYCA

RIESSGPKYSFDYWGQ

GTMVTVSSASTKGPSVFPLAPSSKSTSGGTAA

LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV

LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK

PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGG

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE

DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR

VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE

KTISKAKGQPREPQVY

TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEW

ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD

KSRWQQGNVFSCSVMHEALHNAYTQKSLSLSP

GK

SEQ ID NO: 3836
1B10.1_GS_CL-33675
DIQMTQSPSSLSASVGDRVTITCKASQDIDDY

LC (PR-1611292)

LSWYQQKPGKSPKLVIYAATRLADGVPSRFSG

SGSGTDYTLTISSLQPEDFATYYCLQSSSTPW

TFGGGTKVEIKGGSGGGGSGGEIVLTQSPGTL

SLSPGERATLSCRASSGSIWYSFVSWYQQKPG

QAPRLLIYADDQRASGIPDRFSGSGSGTDFTL

TISRLEPEDFAVYYCQSYGINIDVVFGGGTKV

EIKRTVAAPSVFIFPP

SDEQLKSGTASVVCLLNNFYPREAKVQWKVDN

ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA

DYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Example 11
Generation of CO-DVD-Ig Molecules

Cross-over DVD-Ig binding proteins are constructed as shown below. Each of VD1, VD2, VD3 and VD4 could be the VH or VL from a mAb. In cross-over DVD-Ig, VD1 and VD4 form one antigen binding domain. VD2 and VD3 form another binding domain.

embedded image

TABLE 58

Heavy Chain and Light Chain Amino Acid Sequences of Anti-Human

VEGF-A/Anti-Human PDGF-BB Cross-over DVD-Ig Molecules

(Linker sequence in italics; CDR sequences in bold)

Seq ID
Name (Corporate
Sequence

No
ID)
1234567890123456789012345678901234567890

3844
CODV001 HC
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA

(PR-1565040)
PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAY

LQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT

VSSGEVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTS

KNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWGQG

TTVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV

PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP

CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH

EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV

LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV

YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM

HEALHNHYTQKSLSLSPGK

3845
CODV001 LC
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQ

(PR-1565040)
KPGKAPKNVIYGNDQRPSGVPSRFSGSGSGNSATLTISSL

QPEDFATYFCQSYDSDIDIVFGQGTKVEIKGGGSGGGDIQ

MTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKA

PKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDF

ATYYCQQYSTVPWTFGQGTKVEIKGGGSGRTVAAPSVFIF

PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN

SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH

QGLSSPVTKSFNRGEC

3837
CODV002 HC
EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIR

(PR-1565042)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQA

VLTITNMDPVDTATYYCARISTGISSYYVMDAWGQGTTVT

VSSGEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNW

VRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSK

STAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQG

TLVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV

PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP

CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH

EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV

LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV

YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM

HEALHNHYTQKSLSLSPGK

3838
CODV002 LC
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKP

(PR-1565042)
GKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQP

EDFATYYCQQYSTVPWTFGQGTKVEIKGGGSGGGDFQLTQ

SPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAP

KNVIYGNDQRPSGVPSRFSGSGSGNSATLTISSLQPEDFA

TYFCQSYDSDIDIVFGQGTKVEIKGGGSGRTVAAPSVFIF

PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN

SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH

QGLSSPVTKSFNRGEC

213
CODV003 HC
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA

(PR-1565044)
PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAY

LQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT

VSSGEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTISKDTS

KNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWGQGT

MVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY

FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC

PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE

DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL

HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY

TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN

NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH

EALHNHYTQKSLSLSPGK

214
CODV003 LC
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQ

(PR-1565044)
KPGKAPKNVIYADDQRPSGVPSRFSGSGSGNSASLTISSL

QPEDFATYFCQSYDINIDIVFGQGTKVEIKGGGSGGGDIQ

MTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKA

PKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDF

ATYYCQQYSTVPWTFGQGTKVEIKGGGSGRTVAAPSVFIF

PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN

SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH

QGLSSPVTKSFNRGEC

215
CODV004 HC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR

(PR-1565051)
QPPGKGLEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQA

VLTITNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV

SSGEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWV

RQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKS

TAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGT

LVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY

FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC

PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE

DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL

HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY

TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN

NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH

EALHNHYTQKSLSLSPGK

216
CODV004 LC
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKP

(PR-1565051)
GKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQP

EDFATYYCQQYSTVPWTFGQGTKVEIKGGGSGGGDFQLTQ

SPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAP

KNVIYADDQRPSGVPSRFSGSGSGNSASLTISSLQPEDFA

TYFCQSYDINIDIVFGQGTKVEIKGGGSGRTVAAPSVFIF

PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN

SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH

QGLSSPVTKSFNRGEC

217
CODV005 HC
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQA

(PR-1565083)
PGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAY

LQMNSLRAEDTAVYFCARTNYYYRSYIFYFDYWGQGTLVT

VSSGEVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTS

KNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWGQG

TTVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV

PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP

CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH

EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV

LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV

YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM

HEALHNHYTQKSLSLSPGK

218
CODV005 LC
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQ

(PR-1565083)
KPGKAPKNVIYGNDQRPSGVPSRFSGSGSGNSATLTISSL

QPEDFATYFCQSYDSDIDIVFGQGTKVEIKGGGSGGGDTQ

LTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKA

PKLLIYGASNLESGVPSRFSGSGSGTDFTLTISSLQPEDF

ATYFCQQSWNDPFTFGQGTKVEIKGGGSGRTVAAPSVFIF

PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN

SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH

QGLSSPVTKSFNRGEC

219
CODV006 HC
EVTLKESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIR

(PR-1565084)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQA

VLTITNMDPVDTATYYCARISTGISSYYVMDAWGQGTTVT

VSSGEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYW

VKQAPGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSK

STAYLQMNSLRAEDTAVYFCARTNYYYRSYIFYFDYWGQG

TLVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV

PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP

CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH

EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV

LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV

YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM

HEALHNHYTQKSLSLSPGK

220
CODV006 LC
DTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKP

(PR-1565084)
GKAPKLLIYGASNLESGVPSRFSGSGSGTDFTLTISSLQP

EDFATYFCQQSWNDPFTFGQGTKVEIKGGGSGGGDFQLTQ

SPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAP

KNVIYGNDQRPSGVPSRFSGSGSGNSATLTISSLQPEDFA

TYFCQSYDSDIDIVFGQGTKVEIKGGGSGRTVAAPSVFIF

PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN

SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH

QGLSSPVTKSFNRGEC

221
CODV007 HC
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQA

(PR-1565085)
PGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAY

LQMNSLRAEDTAVYFCARTNYYYRSYIFYFDYWGQGTLVT

VSSGEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKGLEWLANIWWDDDKYYNPSLKNRLTISKDTS

KNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWGQGT

MVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY

FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC

PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE

DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL

HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY

TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN

NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH

EALHNHYTQKSLSLSPGK

222
CODV007 LC
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQ

(PR-1565085)
KPGKAPKNVIYADDQRPSGVPSRFSGSGSGNSASLTISSL

QPEDFATYFCQSYDINIDIVFGQGTKVEIKGGGSGGGDTQ

LTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKA

PKLLIYGASNLESGVPSRFSGSGSGTDFTLTISSLQPEDF

ATYFCQQSWNDPFTFGQGTKVEIKGGGSGRTVAAPSVFIF

PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN

SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH

QGLSSPVTKSFNRGEC

223
CODV008 HC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR

(PR-1565086)
QPPGKGLEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQA

VLTITNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV

SSGEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWV

KQAPGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKS

TAYLQMNSLRAEDTAVYFCARTNYYYRSYIFYFDYWGQGT

LVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY

FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC

PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE

DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL

HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY

TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN

NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH

EALHNHYTQKSLSLSPGK

224
CODV008 LC
DTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKP

(PR-1565086)
GKAPKLLIYGASNLESGVPSRFSGSGSGTDFTLTISSLQP

EDFATYFCQQSWNDPFTFGQGTKVEIKGGGSGGGDFQLTQ

SPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAP

KNVIYADDQRPSGVPSRFSGSGSGNSASLTISSLQPEDFA

TYFCQSYDINIDIVFGQGTKVEIKGGGSGRTVAAPSVFIF

PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN

SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH

QGLSSPVTKSFNRGEC

225
CODV009 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA

(PR-1571821)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY

LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSSGEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTS

KNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGT

MVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY

FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC

PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE

DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL

HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY

TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN

NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH

EALHNAYTQKSLSLSPGK

226
CODV009 LC
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQ

(PR-1571821)
KPGQAPRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRL

EPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGGSGGGDTV

LTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDF

AVYFCQQSWNDPFTFGQGTKLEIKGGGSGRTVAAPSVFIF

PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN

SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH

QGLSSPVTKSFNRGEC

227
CODV010 HC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR

(PR-1571823)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV

VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV

SSGEVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWV

RQAPGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVS

TAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGT

MVTVSSGGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY

FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC

PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE

DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL

HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY

TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN

NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH

EALHNAYTQKSLSLSPGK

228
CODV010 LC
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKP

(PR-1571823)
GQAPRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEP

EDFAVYFCQQSWNDPFTFGQGTKLEIKGGGSGGGEFVLTQ

SPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAP

RLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFA

VYYCQSYDINIDIVFGGGTKVEIKGGGSGRTVAAPSVFIF

PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN

SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH

QGLSSPVTKSFNRGEC

229
CODV011 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA

(PR-1575521)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY

LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSSGGGGSGGGGSEFVLTQSPGTLSLSPGERATLSCERSS

GDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGS

GSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKV

EIKGGGSGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY

FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC

PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE

DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL

HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY

TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN

NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH

EALHNAYTQKSLSLSPGK

230
CODV011 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR

(PR-1575521)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV

VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV

SSGGGGSGGGGSDTVLTQSPATLSLSPGERATLSCRASES

VSTHMHWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSG

TDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKG

GGSGRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE

AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK

ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

231
CODV012 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA

(PR-1571824)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY

LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSSGGGGSGGGEFVLTQSPGTLSLSPGERATLSCERSSGD

IGDSYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGS

GTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEI

KGGGSGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP

EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS

SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA

PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP

EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ

DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL

PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY

KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA

LHNAYTQKSLSLSPGK

232
CODV012 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR

(PR-1571824)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV

VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV

SSGGGGSGGGDTVLTQSPATLSLSPGERATLSCRASESVS

THMHWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSGTD

FTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGG

SGRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK

VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD

YEKHKVYACEVTHQGLSSPVTKSFNRGEC

233
CODV013 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA

(PR-1571825)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY

LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSSGGGGSGGGEFVLTQSPGTLSLSPGERATLSCERSSGD

IGDSYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGS

GTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEI

KGGSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP

VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL

GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE

AAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV

KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH

NAYTQKSLSLSPGK

234
CODV013 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR

(PR-1571825)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV

VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV

SSGGGGSGGGDTVLTQSPATLSLSPGERATLSCRASESVS

THMHWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSGTD

FTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGG

SGRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK

VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD

YEKHKVYACEVTHQGLSSPVTKSFNRGEC

235
CODV014 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA

(PR-1571826)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY

LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSSGGGGSEFVLTQSPGTLSLSPGERATLSCERSSGDIGD

SYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGSGTD

FTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGG

SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV

SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ

TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAG

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN

WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE

EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP

VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAY

TQKSLSLSPGK

236
CODV014 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR

(PR-1571826)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV

VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV

SSGGGGSGGGDTVLTQSPATLSLSPGERATLSCRASESVS

THMHWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSGTD

FTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGG

SGRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK

VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD

YEKHKVYACEVTHQGLSSPVTKSFNRGEC

237
CODV015 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA

(PR-1571827)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY

LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSSGGGGSGGGEFVLTQSPGTLSLSPGERATLSCERSSGD

IGDSYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGS

GTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEI

KGGGSGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP

EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS

SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA

PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP

EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ

DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL

PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY

KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA

LHNAYTQKSLSLSPGK

238
CODV015 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR

(PR-1571827)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV

VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV

SSGGGGSGGGDTVLTQSPATLSLSPGERATLSCRASESVS

THMHWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSGTD

FTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGS

RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ

WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE

KHKVYACEVTHQGLSSPVTKSFNRGEC

239
CODV016 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA

(PR-1571828)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY

LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSSGGGGSGGGEFVLTQSPGTLSLSPGERATLSCERSSGD

IGDSYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGS

GTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEI

KGGGSGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP

EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS

SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA

PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP

EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ

DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL

PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY

KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA

LHNAYTQKSLSLSPGK

240
CODV016 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR

(PR-1571828)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV

VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV

SSGGGGSDTVLTQSPATLSLSPGERATLSCRASESVSTHM

HWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFTL

TISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGSRTV

AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV

DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK

VYACEVTHQGLSSPVTKSFNRGEC

241
CODV017 HC
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKP

(PR-1571830)
GQAPRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEP

EDFAVYFCQQSWNDPFTFGQGTKLEIKGGGSGGGEFVLTQ

SPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAP

RLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPEDFA

VYYCQSYDINIDIVFGGGTKVEIKGGGSGASTKGPSVFPL

APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH

TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN

TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPK

DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK

TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL

PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL

VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS

KLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPGK

242
CODV017 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR

(PR-1571830)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV

VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV

SSGEVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWV

RQAPGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVS

TAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGT

MVTVSSGGRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF

YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL

TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

243
CODV018 HC
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQ

(PR-1571831)
KPGQAPRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRL

EPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGGSGGGDTV

LTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQA

PRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDF

AVYFCQQSWNDPFTFGQGTKLEIKGGGSGASTKGPSVFPL

APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH

TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN

TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPK

DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK

TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL

PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL

VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS

KLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPGK

244
CODV018 LC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA

(PR-1571831)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY

LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSSGEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTS

KNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGT

MVTVSSGGRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF

YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL

TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

245
CODV019 HC
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKP

(PR-1571832)
GQAPRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEP

EDFAVYFCQQSWNDPFTFGQGTKLEIKGGGSGGGGEVTLR

ESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMT

NMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSLGG

CGGGSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE

PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS

LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP

EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE

VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP

PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK

TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNAYTQKSLSLSPGK

246
CODV019 LC
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQ

(PR-1571832)
KPGQAPRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRL

EPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGGSGGGGEV

QLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPG

QGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQ

ISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVTVS

SLGGCGGGSRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN

FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST

LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

247
CODV020 HC
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQ

(PR-1571836)
KPGQAPRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRL

EPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGGSGGGGEV

QLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPG

QGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQ

ISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVTVS

SLGGCGGGSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV

PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP

CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH

EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV

LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV

YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM

HEALHNAYTQKSLSLSPGK

248
CODV020 LC
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKP

(PR-1571836)
GQAPRLLIYGASNLESGVPARFSGSGSGTDFTLTISSLEP

EDFAVYFCQQSWNDPFTFGQGTKLEIKGGGSGGGGEVTLR

ESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGK

ALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMT

NMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSLGG

CGGGSRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR

EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS

KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

249
CODV021 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA

(PR-1577053)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY

LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSSGGGGSGGGEFVLTQSPGTLSLSPGERATLSCERSSGD

IGESYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGS

GTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEI

KGGGSGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP

EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS

SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA

PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP

EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ

DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL

PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY

KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA

LHNAYTQKSLSLSPGK

250
CODV021 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR

(PR-1577053)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV

VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV

SSGGGGSGGGDTVLTQSPATLSLSPGERATLSCRASESVS

THMHWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSGTD

FTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGS

RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ

WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE

KHKVYACEVTHQGLSSPVTKSFNRGEC

251
CODV022 HC
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQA

(PR-1577056)
PGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAY

LQISSLKAEDTAVYYCARTNYYYRSYIFYFDYWGQGTMVT

VSSGGGGSGGGEFVLTQSPGTLSLSPGERATLSCERSSGD

IGESYVSWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGS

GTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEI

KGGGSGASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP

EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS

SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA

PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP

EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ

DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL

PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY

KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA

LHNAYTQKSLSLSPGK

252
CODV022 LC
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR

(PR-1577056)
QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQV

VLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTV

SSGGGGSDTVLTQSPATLSLSPGERATLSCRASESVSTHM

HWYQQKPGQAPRLLIYGASNLESGVPARFSGSGSGTDFTL

TISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGSRTV

AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV

DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK

VYACEVTHQGLSSPVTKSFNRGEC

Example 12
Generation of scFv-IgG Fusion Proteins

All Ig-scFv molecules used the same anti-VEGF-A mAb AB014 as the IgG molecule. A single chain Fv (scFv) anti-PDGF-BB antibody was fused to the C-terminus of AB014 heavy chain using various length of GS linker using standard molecular cloning techniques. Four different heavy chains and one common light chain were made, as shown in the table below. Each heavy chain and the common light chain were co-transfected into HEK293 cells and the resulting Ig-scFv fusion proteins were purified using rProtein-A chromatography.

TABLE 59

Heavy Chain and Light Chain Amino Acid Sequences of Anti-human

VEGF-A/anti-human PDGF-BB Ig-scFv Molecules

(Linker sequence in italics; CDR sequences in bold)

Seq ID
Name
Sequence

No
(Corporate ID)
1234567890123456789012345678901234567890

3839
AB014-GS6-9E8.4
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA

VH-VK HC
PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAY

(PR-1599234)
LQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT

VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV

TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG

TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA

AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK

FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL

NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS

REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT

PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN

AYTQKSLSLSPGKGGSGGGEVTLRESGPALVKPTQTLTLT

CTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWDDDKYY

NPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIE

SIGTTYSFDYWGQGTMVTVSSGGGGSGGGGSGGGGSEIVL

TQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQ

APRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRLEPED

FAVYYCQSYDINIDIVFGGGTKVEIK

3940
AB014-GS10-9E8.4
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA

VH-VK HC
PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAY

(PR-1599236)
LQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT

VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV

TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG

TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA

AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK

FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL

NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS

REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT

PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN

AYTQKSLSLSPGKGGSGGGGSGGEVTLRESGPALVKPTQT

LTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWDD

DKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYC

ARIESIGTTYSFDYWGQGTMVTVSSGGGGSGGGGSGGGGS

EIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQ

KPGQAPRLVIYADDQRPSGIPDRFSGSGSGTDFTLTISRL

EPEDFAVYYCQSYDINIDIVFGGGTKVEIK

3841
AB014-GS15-9E8.4
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA

VH-VK HC
PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAY

(PR-1599239)
LQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT

VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV

TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG

TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA

AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK

FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL

NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS

REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT

PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN

AYTQKSLSLSPGKGGSGGGGSGGGGSGGEVTLRESGPALV

KPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDT

ATYYCARIESIGTTYSFDYWGQGTMVTVSSGGGGSGGGGS

GGGGSEIVLTQSPGTLSLSPGERATLSCERSSGDIGDSYV

SWYQQKPGQAPRLVIYADDQRPSGIPDRFSGSGSGTDFTL

TISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIK

3842
AB014-GS10-9E8.4
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQA

VK-VH HC
PGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAY

(PR-1599240)
LQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT

VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV

TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG

TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA

AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK

FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL

NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS

REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT

PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN

AYTQKSLSLSPGKGGSGGGGSGGEIVLTQSPGTLSLSPGE

RATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP

SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINI

DIVFGGGTKVEIKGGGGSGGGGSGGGGSEVTLRESGPALV

KPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLAN

IWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDT

ATYYCARIESIGTTYSFDYWGQGTMVTVSS

3843
AB014 LC
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKP

GKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQP

EDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPP

SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ

ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG

LSSPVTKSFNRGEC

All HC use the exact same LC (last sequence in Table 59). The naming of the HC follows the following convention: VH name—Linker length (between Fc and scFv)—scFv name with orientation of scFv.

Example 13
In Vitro Characterization of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules and Other Bispecific Molecules
Example 13.1
Expression and Purification of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules and CO-DVD-Ig Molecules

All variants were transiently transfected into 200-500 mls of HEK 293 6e suspension cell cultures in a ratio of 60% to 40% light to heavy chain construct. 1 mg/ml PEI was used to transfect the cells. Alternatively variants were transiently transfected into 500 mls of Expi293 suspension cell cultures using the ExpiFectamine kit (LifeTechnologies A14524). Supernatants were harvested after six days in shaking flasks, spun down to pellet cells, and filtered through 0.22 μm filters to separate IgG from culture contaminates. All was purified via gravity flow using 1-2 ml of rProteinA sepharose fast flow beads (GE Healthcare, 17-1279-04) over poly prep chromatography columns (Bio Rad, 731-1550). Once supernatants had passed through the columns the beads were washed with 10 column volumes of binding buffer, and IgG was eluted with Immunopure IgG elution buffer (Pierce, 185 1520) and collected in 1 ml aliquots. Fractions containing DVD-Ig were pooled and dialyzed in PBS or 15 mM Histidine pH 6 overnight at 4° C.

TABLE 60

Expression Level and SEC Profile of Anti-VEGF-A/Anti-

PDGF-BB DVD-Ig, CO-DVD-Ig and IgG-scFv Fusion Proteins

Octet

Titer
Yield
SEC (%

Name
Corporate ID
(mg/L)
(mg/L)
monomer)

AB014-GS-9E8.4
NA
4.2
ND
ND

9E8.4-GS-AB014
NA
1.2
ND
ND

AB014-SS-9E8.4
NA
3.5
0.4
ND

9E8.4-SS-AB014
NA
3.5
0.6
ND

AB014-SL-9E8.4
NA
2.0
ND
ND

9E8.4-SL-AB014
NA
2.8
0.1
ND

AB014-LS-9E8.4
NA
3.3
ND
ND

9E8.4-LS-AB014
NA
3.6
ND
ND

9E8.4-GS-4G8.3
PR-1563988
6.5
2.8
94.5

9E8.4-SS-4G8.3
PR-1563990
5.9
4.5
92.1

9E8.4-SL-4G8.3
PR-1563998
3.4
2.0
94.0

9E8.4-LS-4G8.3
PR-1564009
10.7
8.0
93.3

4G8.3-GS-9E8.4
PR-1564010
3.6
2.1
98.4

4G8.3-SS-9E8.4
PR-1564011
5.7
3.1
99.4

4G8.3-SL-9E8.4
PR-1564012
2.6
0.7
99.4

4G8.3-LS-9E8.4
PR-1564013
6.7
3.1
99.2

DVD3896
PR-1564883
ND
2.8
100.0

DVD3897
PR-1564893
ND
2.7
79.1

DVD3898
PR-1564896
ND
22.0
93.0

DVD3899
PR-1564898
ND
14.7
87.4

DVD3900
PR-1564899
ND
12.1
72.4

DVD3901
PR-1565023
ND
1.3
99.1

DVD3902
PR-1565029
ND
3.2
98.3

DVD3903
PR-1565030
ND
2.9
98.0

DVD3904
PR-1565031
ND
13.8
97.8

DVD3905
PR-1565032
ND
15.1
92.5

DVD3906
PR-1565035
ND
28.2
85.5

DVD3907
PR-1565033
ND
0.5
ND

CODV001
PR-1565040
ND
88.4
87.6

CODV002
PR-1565042
ND
46.5
97.0

CODV003
PR-1565044
ND
37.3
77.3

CODV004
PR-1565051
ND
75.8
77.4

CODV005
PR-1565083
ND
104.5
86.9

CODV006
PR-1565084
ND
83.9
96.4

CODV007
PR-1565085
ND
43.9
77.4

CODV008
PR-1565086
ND
44.5
75.5

CODV009
PR-1571821
2.0
1.2
86.6

CODV010
PR-1571823
4.5
3.6
94.8

CODV011
PR-1575521
3.7
2.0
100.0

CODV012
PR-1571824
2.0
0.7
98.9

CODV013
PR-1571825
0.7
0.4
90.6

CODV014
PR-1571826
4.5
0.5
89.6

CODV015
PR-1571827
0.7
0.9
91.7

CODV016
PR-1571828
2.6
1.4
93.6

CODV017
PR-1571830
4.2
2.6
99.8

CODV018
PR-1571831
2.6
1.5
88.8

CODV019
PR-1571832
0.4
0.2
87.1

CODV020
PR-1571836
2.1
0.3
58.1

4G8.3-GS-9E8.4
PR-1569574
4.4
4.3
ND

4G8.3-SL-9E8.4
PR-1569579
0.7
0.5
ND

4G8.3-LS-9E8.4
PR-1575573
3.8
2.7
ND

4G8.3-GS-9E8.4 (g)
PR-1572102
2.5
0.4
98.8

4G8.3-GS(11)-9E8.4 (g)
PR-1572103
5.3
1.4
100.0

4G8.3-GS(noR)-9E8.4 (g)
PR-1572104
4.1
0.7
99.5

4G8.3-SL-9E8.4 (g)
PR-1572105
1.4
0.3
98.6

4G8.3-LS-9E8.4 (g)
PR-1572106
4.0
0.8
100.0

4G8.3-GS-9E8.4E
PR-1575832
9.8
8.1
99.2

4G8.3-SL-9E8.4E
PR-1575834
4.5
2.6
99.0

4G8.3-LS-9E8.4E
PR-1575835
16.0
9.7
99.6

CODV021
PR-1577053
2.6
0.3
92.8

CODV022
PR-1577056
2.0
0.2
93.2

9A8.12-GS-9E8.4E
PR-1577165
3.3
2.4
82.99

9A8.12-SL-9E8.4E
PR-1577166
1.1
0.2
51.54

9A8.12-LS-9E8.4E
PR-1577547
10.6
1.1
97.35

9E8.4E-GS-9A8.12
PR-1578137
12.0
3.8
97.3

9E8.4E-SL-9A8.12
PR-1577548
5.0
1.7
97.51

9E8.4E-LS-9A8.12
PR-1577550
2.5
2.5
96.96

AB014-GS6-9E8.4 VH-VK
PR-1599234
70.0
25.6
33.8

AB014-GS10-9E8.4 VH-
PR-1599236
70.0
24.3
34.7

VK

AB014-GS15-9E8.4 VH-
PR-1599239
70.0
29.3
39.3

VK

AB014-GS10-9E8.4 VK-
PR-1599240
47.0
21.4
33.2

VH

4G8.2-GS-9E8.4
PR-1598261
29.4
10.3
98.31

4G8.4-GS-9E8.4
PR-1598262
61.0
20.4
87.65

4G8.5-GS-9E8.4
PR-1598263
31.3
11.5
98.5

4G8.12-GS-9E8.4
PR-1598264
44.0
15.1
93.12

4G8.13-GS-9E8.4
PR-1598265
6.3
2.6
83.58

4G8.14-GS-9E8.4
PR-1598266
19.3
9.9
96.52

CL-34565_GS_CL-33675
PR-1613183
101.4
27.7
88.2

CL-34565_GS_9E8.4
PR-1613184
49.3
31.3
95.9

CL-34565_GS_3E2.1
PR-1613185
109.8
82.5
96.3

4G8.5_GS_CL-33675
PR-1611291
91.1
10.4
96.9

4G8.5_GS_9E8.4
PR-1612489
39.0
23.0
97.0

4G8.5_GS_3E2.1
PR-1610560
127.0
13.9
100.0

9E10.1_GS_CL-33675
PR-1610561
136.0
19.2
92.9

9E10.1_GS_9E8.4
PR-1612491
86.0
50.1
95.0

9E10.1_GS_3E2.1
PR-1610562
44.0
10.2
96.0

9E10.6_GS_CL-33675
PR-1612492
152.0
65.7
89.0

9E10.6_GS_9E8.4
PR-1612493
96.0
50.1
93.0

9E10.6_GS_3E2.1
PR-1610563
122.0
18.0
95.0

1B10.1_GS_CL-33675
PR-1611292
233.0
22.7
75.4

1B10.1_GS_9E8.4
PR-1612494
123.0
52.1
77.0

1B10.1_GS_3E2.1
PR-1610564
142.0
23.3
93.7

1E3.4_GS_CL-33675
PR-1611293
54.0
9.3
83.7

1E3.4_GS_9E8.4
PR-1611294
67.5
11.6
72.1

1E3.4_GS_3E2.1
PR-1612495
101.0
29.6
97.0

CL-33675_GS_CL-34565
PR-1613186
73.5
17.7
87.6

CL-33675_GS_4G8.5
PR-1612496
36.0
8.6
94.0

CL-33675_GS_9E10.1
PR-1611295
148.5
2.3
95.9

CL-33675_GS_9E10.6
PR-1611296
185.3
4.9
95.8

CL-33675_GS_1B10.1
PR-1612498
19.0
7.0
65.0

CL-33675_GS_1E3.4
PR-1611297
72.8
3.5
95.9

9E8.4_GS_CL-34565
PR-1613187
67.5
53.6
79.0

9E8.4_GS_4G8.5
PR-1613188
95.2
73.6
81.7

9E8.4_GS_9E10.1
PR-1611298
237.5
21.5
73.3

9E8.4_GS_9E10.6
PR-1611299
179.0
19.1
71.9

9E8.4_GS_1B10.1
PR-1611300
93.7
12.9
71.7

9E8.4_GS_1E3.4
PR-1611301
87.9
12.2
66.4

3E2.1_GS_CL-34565
PR-1613189
76.1
65.7
93.3

3E2.1_GS_4G8.5
PR-1612499
98.0
46.9
95.0

3E2.1_GS_9E10.1
PR-1612500
126.0
59.2
85.0

3E2.1_GS_9E10.6
PR-1612501
141.0
61.0
86.5

3E2.1_GS_1B10.1
PR-1612502
141.0
61.0
97.0

3E2.1_GS_1E3.4
PR-1613190
107.8
79.9
96.5

9E10.1_SL_CL-33675
PR-1629646
7.6
1.0
98.7

1B10.1_SL_CL-33675
PR-1629647
157.0
111.7
63.3

9E10.1_LS_CL-33675
PR-1629648
64.4
36.4
92.9

1B10.1_LS_CL-33675
PR-1629649
218.4
157.7
65.4

Example 13.2
Binding Affinity of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules and CO-DVD-Ig Molecules

The binding affinity of anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules and CO-DVD-Ig molecules to VEGF-A and PDGF-BB were measured by Biacore using the method described in Example 1.1 and the data is summarized in Tables 61 and 62 below.

TABLE 61

Biacore Binding of Anti-VEGF/anti-PDGF DVD-Ig Molecules

VEGF
PDGF

k_on
k_off
K_D
k_on
k_off
K_D

DVD Name
Corporate ID
(M−1 s−1)
(M−1)
(M)
(M−1 s−1)
(M−1)
(M)

9E8.4-GS-4G8.3
PR-1563988
2.2E+05
6.3E−05
2.9E−10
1.0E+07
2.0E−04
2.0E−11

9E8.4-SS-4G8.3
PR-1563990
1.6E+05
1.2E−04
7.8E−10
1.0E+07
2.0E−04
2.0E−11

9E8.4-SL-4G8.3
PR-1563998
7.0E+05
8.0E−05
1.2E−10
1.0E+07
1.9E−04
1.9E−11

9E8.4-LS-4G8.3
PR-1564009
2.7E+05
5.5E−05
2.0E−10
1.0E+07
2.0E−04
2.0E−11

4G8.3-GS-9E8.4
PR-1564010
3.3E+06
5.7E−05
1.7E−11
1.0E+07
1.4E−04
1.3E−11

4G8.3-SS-9E8.4
PR-1564011
3.1E+06
4.1E−05
1.3E−11
7.5E+06
1.5E−04
1.9E−11

4G8.3-SL-9E8.4
PR-1564012
3.1E+06
4.1E−05
1.3E−11
1.4E+07
1.4E−04
9.9E−12

4G8.3-LS-9E8.4
PR-1564013
3.1E+06
3.9E−05
1.2E−11
1.7E+07
1.4E−04
8.6E−12

DVD3904
PR-1565031
6.1E+05
1.1E−04
1.9E−10
1.0E+07
9.0E−04
9.0E−11

DVD3905
PR-1565032
1.1E+06
1.0E−04
9.4E−11
1.0E+07
1.8E−03
1.8E−10

DVD3906
PR-1565035
9.2E+05
9.3E−05
1.0E−10
1.0E+07
7.2E−03
7.2E−10

4G8.3-GS(9)-9E8.4 (g)
PR-1572102
6.0E+06
7.6E−05
1.3E−11
1.3E+07
1.7E−04
1.3E−11

4G8.3-GS(11)-9E8.4
PR-1572103
6.3E+06
7.5E−05
1.2E−11
1.4E+07
1.7E−04
1.3E−11

(g)

4G8.3-GS(noR)-9E8.4
PR-1572104
6.1E+06
6.9E−05
1.1E−11
1.5E+07
1.4E−04
8.9E−12

(g)

4G8.3-SL-9E8.4 (g)
PR-1572105
5.6E+06
6.1E−05
1.1E−11
1.3E+07
1.7E−04
1.3E−11

4G8.3-LS-9E8.4 (g)
PR-1572106
6.3E+06
5.1E−05
8.1E−12
1.8E+07
2.0E−04
1.1E−11

4G8.3-GS-9E8.4E
PR-1575832
6.1E+06
8.0E−05
1.3E−11
1.3E+07
2.7E−04
2.0E−11

4G8.3-SL-9E8.4E
PR-1575834
6.2E+06
6.3E−05
1.0E−11
1.7E+07
2.5E−04
1.5E−11

4G8.3-LS-9E8.4E
PR-1575835
5.8E+06
5.9E−05
1.0E−11
2.0E+07
2.8E−04
1.4E−11

9A8.12-GS-9E8.4E
PR-1577165
7.7E+05
1.4E−04
1.8E−10
3.3E+07
2.6E−04
8.1E−12

9A8.12-SL-9E8.4E
PR-1577166
2.5E+05
1.2E−04
4.7E−10
2.7E+07
2.3E−04
8.3E−12

9A8.12-LS-9E8.4E
PR-1577547
2.7E+05
9.3E−05
3.5E−10
3.6E+07
2.3E−04
6.5E−12

9E8.4E-SL-9A8.12
PR-1577548
2.2E+06
3.4E−04
1.6E−10
5.0E+07
3.2E−04
6.4E−12

9E8.4E-LS-9A8.12
PR-1577550
6.4E+05
1.5E−04
2.3E−10
5.0E+07
2.5E−04
5.0E−12

9E8.4E-GS-9A8.12
PR-1578137
4.7E+05
1.8E−04
3.8E−10
5.0E+07
4.4E−04
8.8E−12

CL-34565_GS_CL-
PR-1613183
1.2E+07
2.0E−05
1.7E−12
6.0E+07
1.1E−05
1.9E−13

33675

CL-34565_GS_9E8.4
PR-1613184
1.5E+07
1.6E−05
1.1E−12
3.5E+07
1.9E−04
5.4E−12

CL-34565_GS_3E2.1
PR-1613185
1.2E+07
1.7E−05
1.4E−12
4.5E+07
5.2E−04
1.2E−11

4G8.5_GS_CL-33675
PR-1611291
4.7E+06
3.1E−05
6.6E−12
1.6E+07
1.2E−05
7.4E−13

4G8.5_GS_9E8.4
PR-1612489
5.4E+06
4.6E−05
8.5E−12
5.8E+06
1.6E−04
2.8E−11

4G8.5_GS_3E2.1
PR-1610560
4.8E+06
4.2E−05
8.7E−12
4.1E+07
5.5E−04
1.3E−11

9E10.1_GS_CL-33675
PR-1610561
9.7E+06
1.7E−05
1.8E−12
2.0E+07
9.1E−06
4.5E−13

9E10.1_GS_9E8.4
PR-1612491
1.1E+07
2.5E−05
2.2E−12
6.8E+06
1.7E−04
2.5E−11

9E10.1_GS_3E2.1
PR-1610562
9.3E+06
2.3E−05
2.4E−12
4.1E+07
8.5E−04
2.1E−11

9E10.6_GS_CL-33675
PR-1612492
1.1E+07
2.2E−05
2.0E−12
2.4E+07
2.8E−05
1.2E−12

9E10.6_GS_3E2.1
PR-1610563
8.6E+06
2.5E−05
3.0E−12
5.8E+06
2.1E−04
3.6E−11

1B10.1_GS_CL-33675
PR-1611292
2.1E+06
1.3E−04
6.2E−11
2.2E+07
1.2E−05
5.4E−13

1E3.4_GS_3E2.1
PR-1612495
5.3E+06
5.2E−05
9.8E−12
4.5E+07
5.1E−04
1.2E−11

CL-33675_GS_4G8.5
PR-1612496
2.3E+05
4.0E−05
1.8E−10
3.8E+07
9.0E−06
2.3E−13

3E2.1_GS_4G8.5
PR-1612499
2.4E+05
3.9E−05
1.7E−10
≧9.0E+07
3.4E−04
≦3.8E−12

3E2.1_GS_9E10.1
PR-1612500
6.3E+05
1.2E−05
1.9E−11
≧9.0E+07
3.9E−04
≦4.3E−12

3E2.1_GS_9E10.6
PR-1612501
5.7E+05
2.3E−05
4.1E−11
≧9.0E+07
4.5E−04
≦5.3E−12

3E2.1_GS_1B10.1
PR-1612502
3.5E+05
1.2E−04
3.2E−10
8.4E+07
1.5E−04
1.8E−12

3E2.1_GS_1E3.4
PR-1613190
3.6E+05
9.2E−05
2.6E−10
≧9.0E+07
4.8E−04
≦5.3E−12

TABLE 62

Biacore Binding of Anti-VEGF/anti-PDGF CO-DVD-Ig Molecules

VEGF
PDGF

CO-DVD-Ig

k_on
k_off
K_D
k_on
k_off
K_D

Name
Corporate ID
(M−1 s−1)
(M−1)
(M)
(M−1 s−1)
(M−1)
(M)

CODV003
PR-1565044
no binding
2.3E+07
2.5E−04
1.1E−11

CODV004
PR-1565051
no binding
1.0E+07
8.7E−04
8.7E−11

CODV005
PR-1565083

3.5E−08
1.2E+07
1.3E−04
1.1E−11

CODV006
PR-1565084
no binding
2.2E+07
2.1E−04
9.7E−12

CODV007
PR-1565085

2.2E−08
2.9E+07
2.2E−04
7.3E−12

CODV008
PR-1565086
no binding
1.7E+07
1.3E−04
7.4E−12

CODV009
PR-1571821

2.6E−08
3.5E+07
2.0E−04
5.6E−12

CODV010
PR-1571823
5.7E+04
3.7E−04
6.6E−09
4.1E+07
1.6E−04
4.0E−12

CODV011
PR-1575521
1.1E+06
4.0E−05
3.8E−11
3.8E+07
6.9E−05
1.8E−12

CODV012
PR-1571824
2.7E+06
7.6E−05
2.8E−11
7.0E+07
1.0E−04
1.5E−12

CODV014
PR-1571826
2.2E+06
7.7E−05
3.6E−11
5.5E+07
1.3E−04
2.4E−12

CODV015
PR-1571827
2.7E+06
6.5E−05
2.4E−11
7.0E+07
9.1E−05
1.3E−12

CODV016
PR-1571828
2.9E+06
5.9E−05
2.0E−11
4.6E+07
1.1E−04
2.5E−12

CODV017
PR-1571830
—
—
5.7E−08
3.0E+07
2.0E−04
6.5E−12

CODV018
PR-1571831
—
—
3.1E−08
3.5E+07
1.9E−04
5.3E−12

CODV019
PR-1571832
2.9E+06
1.4E−04
5.0E−11
3.9E+07
1.7E−04
4.4E−12

CODV020
PR-1571836
3.1E+06
1.0E−04
3.3E−11
4.6E+07
1.6E−04
3.5E−12

CODV021
PR-1577053
3.8E+06
6.8E−05
1.8E−11
6.1E+07
1.2E−04
1.9E−12

CODV022
PR-1577056
4.5E+06
5.6E−05
1.3E−11
3.2E+07
1.3E−04
4.2E−12

Example 13.2.1
Binding of Anti-VEGF/anti-PDGF DVD-Ig Molecule (PR-1610561) to Various VEGF-A Isoforms and VEGF-A and PDGF-BB of Different Species

Binding of anti-VEGF/anti-PDGF DVD-Ig molecule (PR-1610561) and their parental monoclonal antibodies to various VEGF-A isoforms and VEGF-A and PDGF-BB of different species were measured by Biacore using the method described in Example 1.1 and the data is summarized in Table 63 below. Tables 63A-B summarize the high affinity for VEGF-A₁₆₅(65 pM), VEGF-A₁₂₁(230 pM), VEGF-A₁₁₁(290 pM), isoforms and the high affinity for soluble PDGF-BB (5 pM), observed for PR-1610561. The data shows that PR-1610561binds to both soluble and extracellular-matrix (ECM) bound forms of PDGF-BB.

TABLE 63

Binding of Anti-VEGF/Anti-PDGF DVD-Ig Molecule (PR-1610561) and Parental mAbs to VEGF-A Isoforms and PDGF

human VEGF 165
human PDGF-B

PR-1350437, 1925483
PR-1373790, 1926007

K_a
K_d
K_D
K_a
K_d
K_D

No

PR-
lot
(M⁻¹s⁻¹)
(s⁻¹)
(M)
(M⁻¹s⁻¹)
(s⁻¹)
(M)

1
9E10.1-GS-33675
PR-1610561
2213329
5.2E+05
3.4E−05
6.5E−11
≧1.0E+07
5.2E−05
≦5.2E−12

2
AB014 (Avastin)
PR-1545939
2129911
5.5E+05
4.1E−05
7.6E−11

3
AB642 (9E10.1)
PR-1594047
2169800
1.6E+07
2.8E−05
1.8E−12

4
CL-33675
PR-1593725
2178826

≧1.0E+07
5.8E−06
≦5.8E−13

human VEGF 121

PR-1515941, 2069355

K_a
K_d
K_D

No

PR-
lot
(M⁻¹s⁻¹)
(s⁻¹)
(M)

1
9E10.1-GS-33675
PR-1610561
2213329
1.8E+05
4.1E−05
2.3E−10

2
AB014 (Avastin)
PR-1545939
2129911
1.8E+05
5.1E−05
2.8E−10

3
AB642 (9E10.1)
PR-1594047
2169800
3.2E+06
6.8E−05
2.1E−11

4
CL-33675
PR-1593725
2178826

human VEGF 111

PR-1520687, 2074657

K_a
K_d
K_D

No

PR-
lot
(M⁻¹s⁻¹)
(s⁻¹)
(M)

1
9E10.1-GS-33675
PR-1610561
2213329
1.5E+05
4.3E−05
2.9E−10

2
AB014 (Avastin)
PR-1545939
2129911
1.4E+05
5.3E−05
3.8E−10

3
AB642 (9E10.1)
PR-1594047
2169800
1.8E+06
1.0E−04
5.8E−11

4
CL-33675
PR-1593725
2178826

cyno PDGF-B

PR-1575400, 2154322

cyno VEGF has similar
K_a
K_d
K_D

No

PR-
lot
sequence as human
(M⁻¹s⁻¹)
(s⁻¹)
(M)

1
9E10.1-GS-33675
PR-1610561
2213329

≧1.0E+07
8.1E−06
≦8.1E−13

2
AB014 (Avastin)
PR-1545939
2129911

3
AB642 (9E10.1)
PR-1594047
2169800

4
CL-33675
PR-1593725
2178826

≧1.0E+07
1.3E−05
≦1.3E−12

mouse VEGF
mouse PDGF-B

PR-1578904, 2150241
PR-1577160, 2147923

K_a
K_d
K_D
K_a
K_d
K_D

No

PR-
lot
(M⁻¹s⁻¹)
(s⁻¹)
(M)
(M⁻¹s⁻¹)
(s⁻¹)
(M)

1
9E10.1-GS-33675
PR-1610561
2213329

potentially
≧1.0E+07
5.2E−05
≦5.2E−12

very weak binding

2
AB014 (Avastin)
PR-1545939
2129911

no binding

3
AB642 (9E10.1)
PR-1594047
2169800

potentially

very weak binding

4
CL-33675
PR-1593725
2178826

≧1.0E+07
5.8E−06
≦5.8E−13

rat VEGF
rat PDGF-B

PR-1645045, 2235296
PR-1645048, 2235300

K_a
K_d
K_D
K_a
K_d
K_D

No

PR-
lot
(M⁻¹s⁻¹)
(s⁻¹)
(M)
(M⁻¹s⁻¹)
(s⁻¹)
(M)

1
9E10.1-GS-33675
PR-1610561
2213329

potentially
≧1.0E+07
5.2E−05
≦5.2E−12

very weak binding

2
AB014 (Avastin)
PR-1545939
2129911

no binding

3
AB642 (9E10.1)
PR-1594047
2169800

potentially

very weak binding

4
CL-33675
PR-1593725
2178826

≧1.0E+07
5.8E−06
≦5.8E−13

rabbit VEGF

PR-1563693, 2130027

K_a
K_d
K_D
rabbit PDGF-B has similar

No

PR-
lot
(M⁻¹s⁻¹)
(s⁻¹)
(M)
sequence as rat

1
9E10.1-GS-33675
PR-1610561
2213329
9.6E+05
4.0E−05
4.1E−11

2
AB014 (Avastin)
PR-1545939
2129911
9.4E+05
4.4E−05
4.7E−11

3
AB642 (9E10.1)
PR-1594047
2169800
1.6E+07
2.8E−05
1.8E−12

4
CL-33675
PR-1593725
2178826

TABLE 63A

Affinity of PR-1610561 to Various Isoforms of Human VEGF-A

Human VEGF-A

Isoforms

A₁₆₅
A₁₂₁
A₁₁₁

Affinity K_D(pM)
65
230
290

TABLE 63B

Affinity of PR-1610561 to Human PDGF-BB

Human PDGF-BB Forms
Soluble
ECM-associated

Affinity K_D(pM)
5
n/t

Cell Staining
n/t
+

Example 13.3
Neutralization Potencies of Anti-VEGF-A/anti-PDGF-BB DVD-Ig Molecules and CO-DVD-Ig Molecules

The DVD-Ig molecules and CO-DVD-Ig molecules were evaluated for their potencies to block VEGF₁₆₅/VEGFR2 interaction (Example 1.4) and neutralize VEGF₁₆₅activity in HMVEC-d or VEGFR2-3T3 proliferation assays (Examples 1.10 and 1.7). The molecules were also characterized for the ability to block PDGF-BB/PDGF-Rβ interaction (Example 1.13) and inhibition of PDGF-BB induced proliferation of NIH-3T3 cells (Example 1.15). The data is summarized in Table 64 below. PR-1610561 exhibited neutralization activity against human VEGF-A (IC₅₀of 145 pM) and human PDGF-BB (IC₅₀of 34 pM), as summarized in Table 64A.

TABLE 64

Human VEGF-A and Human PDGF-BB Neutralization Potency of

Anti-VEGF-A/anti-PDGF-BB DVD-Ig and CO-DVD-Ig Proteins

Potency IC50 (nM)

hVEGFR2
hPDGF β

VEGFR2-

Competition
Competition

HMVEC-d
3T3
NIH-3T3
ELISA
ELISA

DVD-Ig
Corporate ID
hVEGF₁₆₅
hVEGF₁₆₅
hPDGF-BB
IC₅₀nM
IC₅₀nM

9E8.4-GS-4G8.3
PR-1563988
2.643
>5
0.076
NT
NT

9E8.4-SS-4G8.3
PR-1563990
NT
>5
0.094
NT
NT

9E8.4-SL-4G8.3
PR-1563998
NT
>5
0.091
NT
NT

9E8.4-LS-4G8.3
PR-1564009
NT
>5
0.104
NT
NT

4G8.3-GS-9E8.4
PR-1564010
0.096
NT
NT
0.126
NT

4G8.3-GS-9E8.4E
PR-1575832
NT
2.953
>5
NT
NT

4G8.3-SS-9E8.4
PR-1564011
NT
0.747
5.511
NT
NT

4G8.3-SL-9E8.4
PR-1564012
NT
NT
0.365
0.086
NT

4G8.3-SL-9E8.4E
PR-1575834
NT
3.090
0.572
NT
NT

4G8.3-LS-9E8.4
PR-1564013
0.060
NT
0.152
0.092
NT

CODV009
PR-1571821
NT
>5
>5
NT
NT

CODV010
PR-1571823
NT
>5
2.139
NT
NT

CODV011
PR-1575521
NT
2.553
0.043
NT
NT

CODV012
PR-1571824
NT
1.424
0.182
NT
NT

CODV013
PR-1571825
NT
0.785
0.11
NT
NT

CODV014
PR-1571826
NT
3.768
0.469
NT
NT

CODV015
PR-1571827
0.104
0.407
0.075
NT
NT

CODV021
PR-1577053
NT
>5
0.056
NT
NT

CODV016
PR-1571828
0.115
0.503
0.096
NT
NT

CODV022
PR-1577056
NT
1.462
0.059
NT
NT

CODV017
PR-1571830
NT
>5
>5
NT
NT

CODV018
PR-1571831
NT
>5
>5
NT
NT

DVD3904
PR-1565031
NT
>5
>5
NT
NT

DVD3905
PR-1565032
NT
>5
>5
NT
NT

DVD3906
PR-1565035
NT
>5
>5
NT
NT

CODV003
PR-1565044
NT
>5
>5
NT
NT

CODV004
PR-1565051
NT
>5
>5
NT
NT

CODV005
PR-1565083
NT
>5
>5
NT
NT

CODV006
PR-1565084
NT
>5
>5
NT
NT

CODV007
PR-1565085
NT
>5
>5
NT
NT

CODV008
PR-1565086
NT
>5
>5
NT
NT

4G8.3-GS(9)-9E8.4 (g)
PR-1572102
0.417
0.986
.528
0.157
>5

4G8.3-GS(11)-9E8.4 (g)
PR-1572103
NT
0.318
0.298
NT
NT

4G8.3-GS(noR)-9E8.4 (g)
PR-1572104
NT
0.217
0.095
NT
NT

4G8.3-SL-9E8.4 (g)
PR-1572105
0.347
1.603
0.290
0.111
>5

4G8.3-LS-9E8.4 (g)
PR-1572106
NT
0.203
0.109
NT
NT

4G8.3-LS-9E8.4E
PR-1575835
NT
2.852
0.176
NT
NT

9A8.12-GS-9E8.4E
PR-1577165
NT
2.992
0.204
NT
NT

9A8.12-SL-9E8.4E
PR-1577166
NT
5.536
0.148
NT
NT

9A8.12-LS-9E8.4E
PR-1577547
NT
4.13
0.133
NT
NT

9E8.4E−SL-9A8.12
PR-1577548
NT
>5
0.147
NT
NT

9E8.4E−LS-9A8.12
PR-1577550
NT
>5
0.066
NT
NT

9E8.4E−GS-9A8.12
PR-1578137
NT
>5
0.327
NT
NT

hVEGF 4G8.3-GS-hPDGF
PR-1569574
0.341
1.02
0.630
0.137
>5

9E8.4 [hu IgG1/k]

mut(234, 235) H435A

hVEGF 4G8.3-SL-hPDGF
PR-1569579
0.36
1.178
0.427
0.133
>5

9E8.4 [hu IgG1/k]

mut(234, 235) H435A

hVEGF 4G8.3-LS-hPDGF
PR-1575573
NT
NT
NT
0.131
>5

9E8.4 [hu IgG1/k]

mut(234, 235) H435A

AB014-GS6-9E8.4
PR-1599234
0.124
NT
0.222
NT
NT

VH-VK

AB014-GS10-9E8.4
PR-1599236
0.095
NT
0.063
NT
NT

VH-VK

AB014-GS15-9E8.4
PR-1599239
0.13
NT
0.066
NT
NT

VH-VK

AB014-GS10-9E8.4
PR-1599240
0.086
NT
0.074
NT
NT

VK-VH

4G8.2-GS10-9E8.4
PR-1598261
0.221
NT
>5
NT
NT

4G8.4-GS10-9E8.4
PR-1598262
0.281
NT
1.327
NT
NT

4G8.5-GS10-9E8.4
PR-1598263
0.079
NT
>5
NT
NT

4G8.12-GS10-9E8.4
PR-1598264
0.079
NT
0.227
NT
NT

4G8.13-GS10-9E8.4
PR-1598265
0.907
NT
0.255
NT
NT

4G8.14-GS10-9E8.4
PR-1598266
0.113
NT
0.459
NT
NT

4G8.5_GS_CL-33675
PR-1611291
0.076
NT
0.05
NT
NT

4G8.5_GS_3E2.1
PR-1610562
0.072
NT
1.398
NT
NT

9E10.1_GS_CL-33675
PR-1610561
0.145
0.433
0.034
0.045
0.09

9E10.1_GS_3E2.1
PR-1610562
0.054
NT
5.724
NT
NT

9E10.6_GS_3E2.1
PR-1610563
0.06
NT
1.317
NT
NT

1B10.1_GS_CL-33675
PR-1611292
0.05
NT
0.037
NT
NT

1B10.1_GS_3E2.1
PR-1610564
0.084
NT
1.545
NT
NT

1E3.4_GS_CL-33675
PR-1611293
0.067
NT
0.037
NT
NT

1E3.4_GS_9E8.4
PR-1611294
0.092
NT
0.329
NT
NT

CL-33675_GS_9E10.1
PR-1611295
0.064
NT
0.031
NT
NT

CL-33675_GS_9E10.6
PR-1611296
0.082
NT
0.037
NT
NT

CL-33675_GS_1E3.4
PR-1611297
0.372
NT
0.039
NT
NT

9E8.4_GS_9E10.1
PR-1611298
0.073
NT
0.317
NT
NT

9E8.4_GS_9E10.6
PR-1611299
0.132
NT
0.213
NT
NT

9E8.4_GS_1B10.1
PR-1611300
0.391
NT
0.109
NT
NT

9E8.4_GS_1E3.4
PR-1611301
0.897
NT
0.131
NT
NT

4G8.5_GS_9E8.4
PR-1612489
0.069
NT
4.829
NT
NT

9E10.1_GS_9E8.4
PR-1612491
0.059
NT
1.913
NT
NT

9E10.6_GS_CL-33675
PR-1612492
0.05
NT
0.037
NT
NT

9E10.6_GS_9E8.4
PR-1612493
0.049
NT
1.14
NT
NT

1B10.1_GS_9E8.4
PR-1612494
0.127
NT
0.678
NT
NT

1E3.4_GS_3E2.1
PR-1612495
0.043
NT
6.253
NT
NT

CL-33675_GS_4G8.5
PR-1612496
0.219
NT
0.035
NT
NT

CL-33675_GS_1B10.1
PR-1612498
0.265
NT
0.11
NT
NT

3E2.1_GS_4G8.5
PR-1612499
0.743
NT
0.38
NT
NT

3E2.1_GS_9E10.1
PR-1612500
0.133
NT
0.394
NT
NT

3E2.1_GS_9E10.6
PR-1612501
0.188
NT
0.377
NT
NT

3E2.1_GS_1B10.1
PR-1612502
1.78
NT
0.187
NT
NT

CL-34565_GS_CL-33675
PR-1613183
0.059
NT
0.052
NT
NT

CL-34565_GS_9E8.4
PR-1613184
0.065
NT
0.323
NT
NT

CL-34565_GS_3E2.1
PR-1613185
0.053
NT
6.005
NT
NT

CL-33675_GS_CL-34565
PR-1613186
0.05
NT
0.043
NT
NT

9E8.4_GS_CL-34565
PR-1613187
0.058
NT
0.134
NT
NT

9E8.4_GS_4G8.5
PR-1613188
0.354
NT
0.108
NT
NT

3E2.1_GS_CL-34565
PR-1613189
0.063
NT
1.157
NT
NT

3E2.1_GS_1E3.4
PR-1613190
0.709
NT
0.896
NT
NT

NT—Not tested

TABLE 64A

Neutralization Activities in Cellular Assays

Protein
Human VEGF-A
Human PDGF-BB

Potency IC₅₀(pM)
145
34

Selected DVD-Ig molecules were further characterized for the ability to neutralize human VEGF₁₁₁and human VEGF₁₂₁, isoforms of human VEGF-A. The molecules were tested for inhibition of VEGF₁₁₁and human VEGF₁₂₁induced proliferation of VEGFR2-3T3 cells (Example 1.8). Neutralization of non-human VEGF-A species was also evaluated. Molecules were tested for inhibition of rabbit VEGF₁₆₅induced proliferation of VEGFR2-3T3 cells (Example 1.9). The data is summarized in Table 65 below. As noted, the amino acid sequence of cynomolgus monkey VEGF-A is identical to human VEGF-A. Parental antibodies had previously been examined for mouse VEGF₁₆₄cross-reactivity in a competition ELISA and no blocking was observed (Example 1.5).

TABLE 65

Neutralization of Different VEGF-A Isoforms by Anti-VEGF-A/

Anti-PDGF-BB DVD-Ig Molecules

Potency IC50 (nM)

human
human
rabbit

DVD-Ig and Controls
Corporate ID
VEGF₁₁₁
VEGF₁₂₁
VEGF₁₆₅

4G8.3-GS(9)-9E8.4
PR-1572102
0.771
0.182
0.869

(g)

4G8.3-SL-9E8.4 (g)
PR-1572105
0.654
0.139
1.194

4G8.3-LS-9E8.4 (g)
PR-1572106
0.431
0.148
0.601

4G8.3-LS-9E8.4E
PR-1575835
NT
NT
1.534

hVEGF 4G8.3-GS-
PR-1569574
0.674
0.124
0.841

hPDGF 9E8.4

[hu IgG1/k]

mut(234, 235) H435A

hVEGF 4G8.3-SL-
PR-1569579
0.576
0.154
1.213

hPDGF 9E8.4

[hu IgG1/k]

mut(234, 235) H435A

9E10.1_GS_CL-
PR-1610561
0.213
0.097
0.520

33675

NT—Not tested

Selected DVD-Ig molecules were further evaluated for their potencies to neutralize PDGF-BB of different species using the assay described in Examples 1.15-1.18. The data is summarized in Table 66 below. As noted, the amino acid sequence of rabbit PDGF-BB is identical to rat PDGF-BB.

TABLE 66

Neutralization of Different PDGF-BB Species by Anti-VEGF-

A/Anti-PDGF-BB DVD-Ig Molecules

Potency IC50 (nM)

DVD-Ig and
Corporate
cynoPDGF-
mPDGF-
ratPDGF-

Controls
ID
BB
BB
BB

4G8.3-GS-9E8.4
PR-1564010
NT
0.440
1.359

4G8.3-SL-9E8.4
PR-1564012
NT
0.290
0.650

4G8.3-SL-9E8.4E
PR-1575834
NT
0.772
NT

4G8.3-LS-9E8.4
PR-1564013
NT
0.110
0.210

4G8.3-GS(9)-9E8.4
PR-1572102
0.139
0.174
2.202

(g)

4G8.3-SL-9E8.4 (g)
PR-1572105
0.142
0.096
1.296

4G8.3-LS-9E8.4 (g)
PR-1572106
0.094
0.14
NT

hVEGF 4G8.3-GS-
PR-1569574
0.139
0.134
1.514

hPDGF 9E8.4

[hu IgG1/k]

mut(234, 235)

H435A

hVEGF 4G8.3-SL-
PR-1569579
0.144
0.150
0.994

hPDGF 9E8.4

[hu IgG1/k]

mut(234, 235)

H435A

9E10.1_GS_CL-
PR-1610561
0.035
0.032
0.038

33675

NT—Not tested

Selected DVD-Ig molecules were evaluated for their ability to neutralize in the presence of a second ligand. To evaluate hPDGF-BB potency, the DVD-Ig molecules were pre-incubated with an excess of human VEGF₁₆₅prior to testing in the NIH-3T3 proliferation assay (Example 1.21). To evaluate hVEGF₁₆₅potency, the DVD-Ig molecules were pre-incubated with an excess of human hPDGF-BB prior to testing in the VEGFR2-3T3 (KDR/Flk-1) phosphorylation assay (Example 1.20). The data is summarized in Table 67 below.

TABLE 67

Simultaneous binding to VEGF and PDGF

Co-incubation Potency

IC50 (nM)

DVD-Ig
Corporate ID
hPDGF-BB
hVEGF₁₆₅

9E8.4-GS-4G8.3
PR-1563988
NT
NT

9E8.4-SS-4G8.3
PR-1563990
NT
NT

9E8.4-SL-4G8.3
PR-1563998
NT
NT

9E8.4-LS-4G8.3
PR-1563009
NT
NT

4G8.3-GS-9E8.4
PR-1564010
NT
NT

4G8.3-SS-9E8.4
PR-1564011
NT
NT

4G8.3-SL-9E8.4
PR-1564012
NT
NT

4G8.3-LS-9E8.4
PR-1564013
NT
NT

4G8.3-GS(9)-9E8.4 (g)
PR-1572102
0.051
0.701

4G8.3-SL-9E8.4 (g)
PR-1572105
0.047
0.773

hVEGF 4G8.3-GS-
PR-1569574
0.032
0.594

hPDGF 9E8.4 [hu

IgG1/k] mut(234, 235)

H435A

hVEGF 4G8.3-SL-
PR-1569579
0.038
0.789

hPDGF 9E8.4 [hu

IgG1/k] mut(234, 235)

H435A

9E10.1_GS_CL-33675
PR-1610561
0.04
0.464

NT—Not tested

Selected DVD-Ig molecules were further evaluated for their ability to bind naturally derived human VEGF₁₆₅(Example 1.11) and naturally derived human PDGF-BB (Example 1.19). The data is summarized in Table 68 below.

TABLE 68

Binding of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to

hVEGF₁₆₅and hPDGF-BB by ELISA

Binding

Platelet derived
Y-79 derived

DVD-Ig
Corporate ID
hPDGF-BB
hVEGF₁₆₅

4G8.3-GS(9)-9E8.4 (g)
PR-1572102
Yes
NT

4G8.3-SL-9E8.4 (g)
PR-1572105
Yes
NT

hVEGF 4G8.3-GS-
PR-1569574
Yes
NT

hPDGF 9E8.4 [hu

IgG1/k] mut(234, 235)

H435A

hVEGF 4G8.3-SL-
PR-1569579
Yes
NT

hPDGF 9E8.4 [hu

IgG1/k] mut(234, 235)

H435A

9E10.1_GS_CL-33675
PR-1610561
Yes
Yes

NT—Not tested

Example 13.4
Species Cross-Reactivity of an Anti-VEGF/Anti-PDGF DVD-Ig Molecule (PR-1610561)

PR-1610561 was further evaluated for its ability to cross-react with cynomolgus monkey, mouse, rat, and rabbit using cell-based proliferation assays (Examples 1.6, 1.17, 1.18, and 1.25). The data is summarized in Table 69 below.

TABLE 69

Species Cross-Reactivity of Anti-VEGF/anti-

PDGF DVD-Ig Molecule (PR-1610561)

VEGF
PDGF

Protein
cyno
mo
rat
rab
cyno
mo
rat
rab

Affinity
65
—
—
41
0.8
0.3
3
3

K_D(pM)

Example 13.5
Reactivity of Anti-PDGF-BB Antibodies and Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to ECM-Associated PDGF-BB

As described in Example 1.27, first recombinant cell line HEK293 cells over-expressing PDGFBB-RM and then HUVEC naturally expressing ECM-associated PDGF-BB cells were used for staining:

HEK293 Cell Staining: PDGFB-RM transient transfected HEK 293 cells and parental HEK293 cells were re-suspended at 1E6 cells/mL in PBS and fixed in 4% paraformaldehyde at RT for 10 minutes, washed with PBS and 2E5 cells/tube were incubated in blocking buffer (10% goat serum in PBS) for one hour on ice. Cells were washed with PBS and incubated with primary antibody or DVD at 33 nM in antibody dilution buffer (5% goat serum in PBS) for one hour on ice. Cells were washed three times with PBS and incubated with Alexa Fluo 488 conjugated Goat anti-Human IgG (Jackson Immune, code: 109-546-098; lot: 108427) 1:400 dilution in antibody dilution buffer, incubate on ice for 45 minutes. Cells were washed three times with PBS and cytospin onto glass slides and mounted with mounting media with DAPI. Pictures were taken by fluorescent microscopy. Anti-PDGF-BB parental and affinity matured mAbs and three DVD-Ig molecules all showed positive staining on PDGFB-RM transient transfected 293 cells (FIG. 2A) and no staining on parental HEK 293 cells except for the slightly positive staining of affinity matured anti-PDGF-BB mAb. It is unclear if parental HEK 293 cells express low level of PDGF-BB endogenously

HUVEC Staining:

HUVEC cells secrete PDGF-BB, and low level of PDGF-BB may be captured on the cell surface as ECM-associated PDGF-BB. Affinity matured anti-PDGF-BB mAb and anti-VEGF/anti-PDGF DVD-Ig built with affinity-matured anti-PDGF-BB mAb was further assessed for its staining on naturally derived ECM-associated PDGF-BB on HUVEC cells. HUVECs (Lonza, cat#: C2519A lot: 181607) were trypsinized, resuspended at 2E4 cells/mL in culture media (Lonza, EGM2 MV Bulletkit: CC-3202). Cells were plated at 10,000 cells/500 μl/well in 8-chamber glass slide and incubated for 16 hours at 37° C., 5% CO₂. After incubation, cells were fixed with 200 μl 4% paraformaldehyde at RT for 10 minutes, washed with PBS and incubated in blocking buffer (10% goat serum in PBS) for one hour on ice. Cells were washed with PBS 3× and incubated with primary antibodies or DVD-Ig molecules at 33 nM in antibody dilution buffer (5% goat serum in PBS) for one hour on ice. Cells were washed three times with PBS and incubated with Alexa Fluo 488 conjugated Goat anti-Human IgG (JacksonImmune, code: 109-546-098; lot: 108427) 1:400 dilution in antibody dilution buffer, incubate on ice for 45 minutes. Cells were washed three times with PBS and mounted with mounting media with DAPI. Pictures were taken by fluorescent microscopy. As shown in FIG. 2B, affinity matured anti-PDGF-BB mAb showed positive staining on HUVEC cells while the staining of parental anti-PDGF-BB mAb on HUVEC cells is not evident (FIG. 2B). Anti-VEGF/anti-PDGF DVD-Ig (PR-1610561) built with affinity-matured anti-PDGF-BB mAb showed positive staining on HUVEC cells but control anti-tetanus toxoid DVD-Ig molecule also showed some weak staining which may be due to the background issue.

Example 13.6
Inhibition of Sprouting in HUVEC/MSC Co-culture Sprouting Assay by Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules

As described in Example 1.28, in early therapeutic treatment mode, Cytodex-3 beads (Sigma-Aldrich, cat# C3275) were coated with HUVEC cells (Lonza) overnight, and then embedded (100 beads/well) with human mesenchymal stem cells (Lonza, 20,000 cells/well) in fibrin gel in 24-well tissue culture plates. A 1:1 mixture of fresh EGM-2 complete media (Lonza) and fibroblast (Lonza) conditioned EGM-2 media were added on top of the fibrin gel along with 2 ng/mL of recombinant human HGF. Medium was replaced every 2-3 days till the end of the experiment. After EC sprouts and pericyte coverings were formed, usually on day 4, anti-VEGF-A (4G8.4), anti-PDGFBB (9E8.) or anti-PDGFBB/VEGF-A DVD-Ig were added to the culture medium at 10 nM. 10 days later cells were fixed in 4% PFA overnight at 4° C. Endothelial cells were stained with anti-PECAM (Abcam, ab32457), followed by fluorescence-conjugated secondary antibody, and pericytes were labeled with anti-aSMA-Cy3 (Sigma, C6198). Cells were then viewed by an inverted fluorescence microscope and 5× images were captured (FIG. 3). As seen in the pictures, DVD-Ig molecules as well as the combination of anti-VEGF and anti-PDGF mAbs are able to prevent sprouting formation greater than that of anti-VEGF mAb alone. Neither anti-PDGF mAb or anti-PDGF aptamer alone appear to have any significant inhibition of sprouting formation (FIG. 3). Similar experiments were also conducted in prophylactic and later therapeutic treatment modes and the results clearly demonstrated that anti-VEGF/anti-PDGF DVD-Ig (PR-1610561) strongly inhibited sprouting formation in this 3D co-culture assay.

Example 13.7
Characterization of FcRn and FcγRs Binding

Anti-VEGF/anti-PDGF DVD-Ig molecules, including 4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, 4G8.3-GS-9E8.4(g), 4G8.3-SL-9E8.4(g), 9E10.1GS_CL-33675, are human IgG1/κ isotype with L234A, L235A mutations to attenuate FcγRs binding and H435A mutation to eliminate FcRn binding. The binding of DVD-Ig molecules to FcRn from various species and the binding of DVD-Ig molecules to various FcγRs were characterized by Biacore using the method described in Example 1.2. The data is summarized in Tables 70 and 71 below.

TABLE 70

Binding of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules

to FcRn from Different Species, Measured by Biacore

Steady State
1:1 Binding fit

huFcRn
cynoFcRn
rabbitFcRn
ratFcRn
muFcRn

K_D
K_D
K_D
ka
kd
K_D
ka
kd
K_D

Immobilized
(M)
(M)
(M)
(1/Ms)
(1/s)
(M)
(1/Ms)
(1/s)
(M)

4G8.3-GS-9E8.4(g)
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB

PR-1572102

4G8.3-SL-9E8.4(g)
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB

PR-1572105

9E10.1_GS_C
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB

L-33675 PR-1610561

4G8.3-GS-9E8.4
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB

PR-1569574

4G8.3-SL-9E8.4
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB

PR-1569579

* NSB = No significant binding at the concentration tested;

n/a = not available

TABLE 71

Binding of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to Various Human FcγRs, Measured by Biacore

huFcRIIa
huFcRIIa
huFcRIIIa
huFcRIIIa

huFcRIIb
131H
131R
158F
158V

K_D
K_D
K_D
K_D
ka
kd
K_D

Sample
(M)
(M)
(M)
(M)
(1/Ms)
(1/s)
(M)
Fit

4G8.3-GS-9E8.4(g)
NSB
NSB
NSB
NSB
n/a
n/a
7.40E−06
steady state

PR-1572102

4G8.3-SL-9E8.4(g)
NSB
NSB
NSB
NSB
n/a
n/a
6.20E−06
steady state

PR-1572105

9E10.1_GS_CL-33675
NSB
NSB
NSB
NSB
n/a
n/a
1.1E−05*
steady state

PR-1610561

4G8.3-GS-9E8.4
NSB
NSB
NSB
NSB
n/a
n/a
1.6E−05*
steady state

PR-1569574

4G8.3-SL-9E8.4
NSB
NSB
NSB
NSB
n/a
n/a
1.2E−05*
steady state

PR-1569579

*NSB = No significant binding at the concentration tested;

n/a = not available

Example 14
Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules
Example 14.1
Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules

Twenty one DVD-Ig molecules were selected for a screen of their solubility and stability profiles. Samples were prepped and evaluated according to Example 2.4. The DVD-Ig proteins were prepared in a formulation buffer and stored at 40° C. and 5° C. for up to 21 days. Samples were pulled and analyzed by SEC to determine changes in aggregation (Table 72). The molecules were evaluated at the listed concentrations. SEC was used to quantitate the aggregation percentage.

TABLE 72

Aggregation and Solubility Screening Of Selected DVD-Ig

Molecules Stored At 40° C. and 5° C. for 21 Days

in a Formulation Buffer

% Aggregation

Concentration
Change from T0

DVD-Ig Molecule
(mg/ml)
T21 d 5° C.
T21 d 40° C.

4G8.3-GS-9E8.4
100
0.24
*

4G8.3-SL-9E8.4
100
0.27
*

CL-34565_GS_CL-33675
48.7
0.20
0.25

CL-34565_GS_9E8.4
4.3
−0.30
0.05

CL-34565_GS_3E2.1
10.9
−1.12
−0.89

4G8.5_GS_CL-33675
50
−0.09
*

4G8.5_GS_9E8.4
50
−0.09
12.50

4G8.5_GS_3E2.1
50
0.53
14.63

9E10.1_GS_CL-33675
50
−2.08
−3.09

9E10.1_GS_9E8.4
50.7
2.95
−0.39

9E10.1_GS_3E2.1
43.2
−6.16
−9.05

9E10.6_GS_CL-33675
50
3.17
1.87

9E10.6_GS_3E2.1
34.9
−0.63
−0.65

1B10.1_GS_CL-33675
50
0.72
1.10

1E3.4_GS_3E2.1
50
0.17
*

CL-33675_GS_4G8.5
38.7
0.15
2.34

3E2.1_GS_4G8.5
50
16.15
*

3E2.1_GS_9E10.1
30.4
*
*

3E2.1_GS_9E10.6
50
0.17
5.55

3E2.1_GS_1B10.1
38.6
−6.33
*

3E2.1_GS_1E3.4
50
10.12
*

* Samples were too degraded or compromised to evaluate with SEC (e.g. gelled, precipitated).

Example 14.2
Further Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules (Stability During Storage at 40° C., 25° C., and 5° C.)

Based on the physicochemical screen discussed above (Example 14.1), three anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules (4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, and 9E10.1-GS-33675) were selected for further characterization. Sample prep and analysis was performed according to Example 2.4.

Briefly, the molecules were prepared in a formulation buffer at 100±10 mg/ml and stored at 40° C., 25° C., and 5° C. for 84 days. Samples were periodically pulled for characterization (Tables 73-75 below).

As mentioned in Example 2.4, both 25° C. (room temperature) and 5° C. (storage temperature) are typical temperatures at which the samples would be subjected either during preparation and storage for manufacture or as part of the final drug product presentation. Also, storage at 40° C. is considered an accelerated stability condition which provides an indication of long-term stability prospects.

TABLE 73

Stability of 4G8.3-GS-9E8.4 During Storage. Aggregate, Monomer,

And Fragment Percentages Were Quantitated By SEC

Area Under SEC

%
%
%
Chromatogram Signal

Aggregate
Monomer
Fragment
Relative to T0

T0
1.8
97.3
0.9
1.00

T7 d 40° C.
*
*
*
*

T7 d 25° C.
2.2
97.0
0.9
0.91

T7 d 5° C.
1.9
97.2
0.9
0.92

T21 d 40° C.
*
*
*
*

T21 d 25° C.
3.0
96.4
0.6
0.84

T21 d 5° C.
1.8
97.8
0.5
0.90

T42 d 40° C.
*
*
*
*

T42 d 25° C.
3.4
95.6
1.0
0.88

T42 d 5° C.
2.0
97.3
0.7
1.00

T63 d 40° C.
*
*
*
*

T63 d 25° C.
4.2
94.7
1.0
0.85

T63 d 5° C.
2.1
97.4
0.5
0.92

T84 d 40° C.
*
*
*
*

T84 d 25° C.
5.0
93.7
1.3
0.79

T84 d 5° C.
2.2
97.3
0.6
0.85

* Samples were too degraded or compromised to evaluate with SEC (e.g. gelled, precipitated).

TABLE 74

Stability of 4G8.3-SL-9E8.4 During Storage. Aggregate, Monomer,

And Fragment Percentages Were Quantitated by SEC

Area Under SEC

%
%
%
Chromatogram Signal

Aggregate
Monomer
Fragment
Relative to T0

T0
4.2
94.7
1.1
1.00

T7 d 40° C.
*
*
*
*

T7 d 25° C.
6.6
92.2
1.3
0.86

T7 d 5° C.
4.3
94.7
1.0
0.82

T21 d 40° C.
*
*
*
*

T21 d 25° C.
8.5
90.5
1.1
0.77

T21 d 5° C.
3.9
95.3
0.8
0.87

T42 d 40° C.
*
*
*
*

T42 d 25° C.
13.2
85.6
1.3
0.80

T42 d 5° C.
4.5
94.4
1.1
0.97

T63 d 40° C.
*
*
*
*

T63 d 25° C.
13.2
85.3
1.5
0.73

T63 d 5° C.
4.3
95.0
0.7
0.87

T84 d 40° C.
*
*
*
*

T84 d 25° C.
10.3
88.1
1.6
0.62

T84 d 5° C.
4.5
94.7
0.7
0.80

* Samples were too degraded or compromised to evaluate with SEC (e.g. gelled, precipitated).

TABLE 75

Stability of 9E10.1-GS-33675 During Storage. Aggregate, Monomer,

And Fragment Percentages Were Quantitated by SEC.

Area Under SEC

%
%
%
Chromatogram Signal

Aggregate
Monomer
Fragment
Relative to T0

T0
0.8
98.4
0.7
1.00

T7 d 40° C.
5.3
93.8
0.8
0.84

T7 d 25° C.
4.8
94.6
0.6
0.89

T7 d 5° C.
3.7
95.5
0.8
0.92

T21 d 40° C.
6.1
92.5
1.4
0.77

T21 d 25° C.
4.4
95.0
0.6
0.82

T21 d 5° C.
6.7
92.8
0.5
0.89

T42 d 40° C.
13.8
83.9
2.3
0.76

T42 d 25° C.
4.7
94.6
0.8
0.85

T42 d 5° C.
7.7
91.7
0.5
0.92

T63 d 40° C.
19.8
77.0
3.2
0.77

T63 d 25° C.
4.8
94.4
0.8
0.84

T63 d 5° C.
8.4
91.2
0.4
0.94

T84 d 40° C.
22.8
73.2
4.0
0.68

T84 d 25° C.
5.3
93.7
1.0
0.80

T84 d 5° C.
8.1
91.5
0.4
0.88

Both 4G8.3-GS-9E8.4 and 4G8.3-SL-9E8.4 formed a white precipitate when stored at 40° C. after 7 days and thus could not be analyzed by SEC. The samples are assumed to be completely aggregated. At 25° C., there was an observable increase in aggregation for both molecules. The aggregation was less rapid for 4G8.3-GS-9E8.4 than for 4G8.3-SL-9E8.4. Aggregation of the former increased from 1.8% to 5.0% after 84 days while that of the latter started at 4.2% and reached as high as 13.2% over the course of 84 days. At 5° C., there is no noticeable aggregate increase for the two molecules.

For 9E10.1-GS-33675, aggregation at 5° C. increased from 0.8% to 6.7% by 21 days and levelled off at ˜8% from 42 to 84 days. At 25° C., aggregation increased from 0.8% to 4.7% by 7 days and levelled off at that value up to 84 days. Finally, aggregation at 40° C. increased from 0.8% to 22.8% in an apparently linear fashion over the course of 84 days. The aggregation at 40° C. for 9E10.1-GS-33675 is much less that that observed for the other two DVD-Ig molecules. This may be the result of the universal formulation buffer used.

There was no apparent change in fragmentation for all three DVD-Ig molecules at 25° C. or 5° C. At 40° C., an apparent and expected increase in fragmentation was observed for 9E10.1-GS-33675 after 21 days.

Example 14.3
Further Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules (Stability to Freeze-Thaw Stress)

Based on the earlier physicochemical screen (Example 14.1), three anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules (4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, and 9E10.1-GS-33675) were selected for further characterization. Sample prep, stress, and analysis were performed according to Example 2.5. Briefly, the molecules were prepared in a formulation buffer at concentrations of 100±10 mg/ml or 1 mg/ml and subjected to four cycles of freezing (˜80° C.) and thawing (30° C.). Samples were characterized after the second and fourth thaw (Tables 76-81 below).

As mentioned in Example 2.5, protein samples are typically frozen at −80° C. for long term storage as well as shipping to remote manufacturing sites. The samples are then thawed in order to complete the drug product manufacturing process.

TABLE 76

Stability of 4G8.3-GS-9E8.4 at 100 ± 10 mg/ml When Subjected

To Freeze-Thaw Stress (−80° C./30° C.). Aggregate,

Monomer, And Fragment Percentages Were Quantitated by SEC.

Area Under SEC

%
%
%
Chromatogram Signal

Aggregate
Monomer
Fragment
Relative to T0

F/T 0
1.8
97.3
0.9
1.00

F/T 2
1.8
97.4
0.8
0.90

F/T 4
2.2
96.9
0.9
0.92

TABLE 77

Stability of 4G8.3-SL-9E8.4 at 100 ± 10 mg/ml

When Subjected To Freeze-Thaw stress (−80°

C./30° C.). Aggregate, Monomer, And Fragment

Percentages Were Quantitated by SEC

Area Under SEC

%
%
%
Chromatogram Signal

Aggregate
Monomer
Fragment
Relative to T0

F/T 0
4.2
94.7
1.1
1.00

F/T 2
4.1
95.2
0.7
0.83

F/T 4
4.3
94.4
1.3
0.82

TABLE 78

Stability of 9E10.1-GS-33675 at 100 ± 10 mg/ml

when Subjected To Freeze-Thaw Stress (−80°

C./30° C.). Aggregate, Monomer, And Fragment

Percentages Were Quantitated by SEC.

Area Under SEC

%
%
%
Chromatogram Signal

Aggregate
Monomer
Fragment
Relative to T0

F/T 0
0.8
98.4
0.7
1.00

F/T 2
1.1
98.5
0.4
0.91

F/T 4
1.8
97.6
0.6
0.88

TABLE 79

Stability of 4G8.3-GS-9E8.4 at 1 mg/ml When

Subjected To Freeze-Thaw Stress (−80°

C./30° C.). Aggregate, Monomer, And Fragment

Percentages Were Quantitated by SEC.

Area Under SEC

%
%
%
Chromatogram Signal

Aggregate
Monomer
Fragment
Relative to T0

F/T 0
1.8
97.3
0.9
1.00

F/T 2
1.9
97.5
0.6
0.95

F/T 4
2.0
97.1
0.9
0.96

TABLE 80

Stability of 4G8.3-SL-9E8.4 at 1 mg/When Subjected To

Freeze-Thaw Stress (−80° C./30° C.). Aggregate,

Monomer, And Fragment Percentages Were Quantitated by SEC.

Area Under SEC

%
%
%
Chromatogram Signal

Aggregate
Monomer
Fragment
Relative to T0

F/T 0
4.2
94.7
1.1
1.00

F/T 2
3.9
95.4
0.7
0.94

F/T 4
4.1
94.9
1.0
0.94

TABLE 81

Stability of 9E10.1-GS-33675 at 1 mg/ml When Subjected

To Freeze-Thaw Stress (−80° C./30° C.). Aggregate,

Monomer, And Fragment Percentages Were Quantitated by SEC.

Area Under SEC

%
%
%
Chromatogram Signal

Aggregate
Monomer
Fragment
Relative to T0

F/T 0
0.8
98.4
0.7
1.00

F/T 2
1.0
98.6
0.5
0.98

F/T 4
1.2
98.2
0.6
0.98

For all three DVD-Igs, at either 100±10 mg/ml or 1 mg/ml, no apparent increase in aggregation was observed due to freeze-thaw stress after two cycles.

Example 14.4
Further Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules (Viscosity Determination)

Based on the earlier physicochemical screen (Example 14.1), three anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules (4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, and 9E10.1-GS-33675) were selected for further characterization. The molecules were prepared in a formulation buffer at 100±10 mg/ml and the viscosities were measured at room temperature (Example 2.6). The viscosities were 5.1, 7.2, and 7.2 centipoise, respectively. The values are within the range that enables ease of administration via a small diameter needle attached to a syringe.

Example 14.5
Further Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules (Thermal Stability Assessment)

Based on the earlier physicochemical screen (Example 14.1), three anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules (4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, and 9E10.1-GS-33675) were selected for further characterization. The molecules were prepared in a formulation buffer at 1 mg/ml according to Example 2.3 and the thermal stabilities were determined according to Example 2.2. The midpoint temperatures of the first transition of unfolding are 52° C., 51° C., and 62° C., respectively. The temperatures at which the first transitions began to appear are 44° C., 42° C., and 62° C., respectively. The data indicate that 9E10.1-GS-33675 has a significantly greater thermal stability than the other two DVD-Ig molecules.

Example 14.6
Physicochemical Properties of an Anti-VEGF/anti-PDGF DVD-Ig Molecule (PR-1610561)

Testing of PR-1610561 revealed high thermostability (T_onset=62° C.), solubility at least at 76 mg/ml, and a viscosity at 100 mg/ml at room temperature of 7.2 centipoise, which is within the range that enables ease of administration via a small diameter needle attached to a syringe. PR-1610561 has appropriate storage stability in a universal buffer and freeze-thaw stability.

Example 14.76
Intact and Reduced Molecular Weight Determination

Q-TOF LC-MS can detect mass differences between proteins that can result from mis-sense mutations, post-translational modifications, truncations, and other covalent changes that affect protein molecular weight. Table 82 shows the intact molecular weight and deglycosylated intact molecular weight of all three DVD-Ig molecules. Table 83 shows the molecular weights of light chain, heavy chain and deglycosylated heavy chain. The observed molecular weights of the three DVD-Ig molecules match well with the theoretical values with difference of less than 3 Dalton, which is well within the expected range of the error for the instrument.

TABLE 82

Intact molecular weight

Intact MW
Deglycosylated Intact MW

Theoretical
Observed
Theoretical
Observed

PR-1572102
203220
203219
200330
200330

PR-1572105
204350
204348
201460
201460

PR-1610561
202452
202450
199562
199562

TABLE 83

Reduced molecular weight

Light Chain
Heavy Chain
Deglycosylated

MW
MW
HC MW

Theo-
Ob-
Theo-
Ob-
Theo-
Ob-

retical
served
retical
served
retical
served

PR-1572102
36080
36080
65533
65533
64088
64091

PR-1572105
36735
36734
65444
65444
63999
64002

PR-1610561
36006
36005
65224
65224
63779
63780

Example 14.8
Oligosaccharide Profiles by Fc Molecular Weight

DVD-Ig molecules contain N-linked oligosaccharides in the Fc region of the heavy chain Fc molecular weight measurement can provide a semi-quantitative analysis of the oligosaccharide profiles. Table 84 shows the results of oligosaccharide profiles by Fc molecular weight. The oligosaccharide profiles of all three DVD-Ig molecules were similar to what is normally observed for mAbs, with 70-73% Gal 0F and 21-24% Gal 1F. The level of high mannose species was very low in all three samples. No significant level of aglycosylated species was detected.

TABLE 84

Oligosaccharide Profiles By Fc Molecular Weight

Species
PR-1572102
PR-1572105
PR-1610561

Man 5
1.0
1.1
0.4

Gal 0F-GlcNAc
0.5
0.4
0.0

Gal 0
0.5
0.2
0.7

Gal 0F
73.4
73.4
70.8

Lys-1
0.8
0.3
0.8

Gal 1F
21.0
21.2
23.8

Gal 2F
2.8
3.3
3.6

Example 14.9
Charge Heterogeneity by Weak Cation Exchange Chromatography and Imaged Isoelectric Focusing

Weak cation exchange (WCX) chromatography separates molecules on the basis of the differences in their net surface charge. Variation in the extent of C terminal processing and certain post-translational modifications can lead to different species of an antibody with different charge distributions. Molecules that vary in their charge properties will exhibit different degrees of interaction with ion exchange resins, thus different elution profiles. Each chromatogram is characterized by a predominant peak (“main”) and species eluting before (“acidic”) or after (“basic”). The relative abundances of these species types are shown in Table 85.

TABLE 85

Results of Weak Cation Exchange Chromatography Analysis

Acidic (%)
Main (%)
Basic (%)

PR-1572102
9.2
63.9
26.9

PR-1572105
14.9
52.4
32.7

PR-1610561
17.7
56.5
25.8

Imaged capillary isoelectric focusing (icIEF) is a technique that separates proteins on the basis of their isoelectric points or pI values. Different proteins have different pI and peak profiles, which makes icIEF an ideal identity assay. In icIEF, proteins with different pI values focus into distinctive bands in a linear pH gradient formed by ampholytes after applying high voltage. Table 86 shows the theoretical pI (calculated based on amino acid sequence) and the observed pI values measured by imaged icIEF. Also shown in Table 86 are the relative abundances of different charge species detected by imaged icIEF.

TABLE 86

Results of Imaged Isoelectric Focusing

pI by

Thoe. pI
icIEF
Acidic (%)
Main (%)
Basic (%)

PR- 1572102
6.13
6.78
14.3
71.6
14.1

PR-1572105
6.13
6.74
25.3
60.2
14.4

PR-1610561
6.67
7.27
27.2
63.2
9.6

Example 15
Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules
Example 15.1
Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Intravenously Administered in huFcRN Transgenic Mice

Studies were conducted in accordance with the AbbVie IACUC guidelines. Anti-VEGF/anti-PDGF DVD-Ig molecules PR-1572102 (lot 2211502), PR-1572105 (lot 2211597), or PR-1610561 (lot 2213329) were administered to huFcRn B6.Cg transgenic mice (5/group) at 5 mg/kg by slow intravenous bolus dose injection. Blood samples were collected from each mouse at 1, 24 and 96 hours and 7, 10, 14 and 21 days post dose. All samples were stored at −80° C. until analysis. DVD-Ig serum concentrations were measured using a Meso Scale Discovery (MSD) electrochemiluminescence (ECL) Ligand Binding Assay. Biotinylated VEGF ligand was coated onto streptavidin MSD plates for capture of anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules from blood samples, and detection was achieved with a sulfo-tag goat anti-human IgG antibody. Concentrations were calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).

All three anti-VEGF/PDGF DVD-Ig molecules carrying the H435A substitution had serum concentrations rapidly clear, with measurable concentrations only to 24 hours. These results are in agreement with the rapid clearance observed with other H435A modified antibody and DVD-Ig molecules in human FcRn transgenic mice.

Example 15.2
Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Intravitreously Administered in Rabbit

Studies were conducted in accordance with the Abbott IACUC guidelines. Female New Zealand White rabbits were used for the ocular pharmacokinetic characterization of Anti-VEGF-A/anti-PDGF-BB DVD-Igs: PR-1572102, PR-1572105 and PR-1610561. Animals (4 animals) were split into two cohorts of two for determination of ocular pharmacokinetics. Samples of aqueous humour were taken at 4, 24, 48, 72, 120, 168, 336 and 504 hours post dosing. With cohort 1 providing samples at 4, 48, 120 and 168 hours, and cohort 2 providing samples at 24, 72, 336 and 504 hours, post dosing. Drug levels in the eye were determined from concentrations in aqueous humour as a surrogate for the vitreous concentrations. Vitreous was harvested from each animal as a terminal sample after their last aqueous humour sample. The proportion of aqueous to vitreous concentration was determined from these terminal time points. Blood samples for the harvest of serum used to estimate systemic exposure after vitreous dosing were also collected at 4, 24, 48, 72, 120, and 168 hours post dosing from all animals, and at 336 and 504 hours from the animals in cohort 2. Test articles were dosed into the vitreous compartment at a range of 0.25 to 0.50 mg per eye with a dose volume of no more than 0.050 mL. Only the right eye of each animal was dosed. Prior to dosing, animals were anesthetized with xylazine/ketamine. The eye was prepared by first applying topical analgesic drops (procaine HCl Ophthalmic solution, 0.5%), then the injections site was swabbed with a saturated povidone-iodine swabstick (10% solution equivalent to 1% available iodine) prior to injection. The intravitreal dose was administered with a 26 gauge needle. The point of entry for the injection was 1-2 mm from the limbus through the sclera. After injection, a sterile cotton eye spear was placed on the injection site and held for 30 seconds to prevent leakage Animals were anesthetized for aqueous fluid collection. At the selected time points after dosing, the aqueous fluid was collected using a 30 gauge needle inserted through the cornea. The needle was advanced just past the bevel and fluid was collected. The samples provided approximately 0.05-0.1 mL of aqueous humour per sampling period. At the selected time points after dosing, blood samples were obtained from an ear vein or artery. Hemostasis following collection was achieved by the application of manual pressure and topical clotting factor or tissue glue as needed. The samples were from 0.5-1 ml in volume, and were allowed to clot for harvest of serum. Aqueous, vitreous and serum samples were stored at −80° C., and submitted for drug level determinations.

All DVD-Ig serum concentrations were measured using a GYROS method employing biotinylated VEGF ligand for capture, and Alexa Flour 647 goat anti-human IgG detection. Concentrations were calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).

TABLE 87

Ocular Half Lives in Rabbit from Analysis of Aqueous Humor

Experiment
Test Article
Corporate ID
Half life (hours)

#1
9E10.1_GS_CL-33675
PR-1610561
111

#2
9E10.1_GS_CL-33675
PR-1610561
Pending

Example 15.3
Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Intravenously Administered in Cynomolgus Monkey

Studies are conducted in accordance with the AbbVie IACUC guidelines. Female cynomolgus are used for the systemic pharmacokinetic characterization of Anti-VEGF-A/anti-PDGF-BB DVD-Igs, including PR-1572102, PR-1572105 and PR-1610561 after intravenous dosing. Monkeys are dosed intravenously at 5 mg/kg by slow bolus into the saphenous vein over approximately 2 minutes with a volume of 0.5 mL/kg. Samples are taken for determination of the pharmacokinetics of the test compounds at 0, 0.08, 4, 8, 24, 72, 168, 240, 336, 504 and 672 hours post dosing. At the selected time points after dosing, blood samples are obtained from a femoral vein. Hemostasis following collection is achieved by the application of manual pressure and topical clotting factor or tissue glue as needed. The samples may be approximately 1 ml in volume, and are allowed to clot for harvest of serum. Serum samples are stored at −80° C., and submitted for drug level determinations.

DVD-Ig serum concentrations are measured using either a GYROS or a MSD method. GYROS employs biotinylated VEGF ligand for capture, and Alexa Flour 647 goat anti-human IgG detection. MSD employs biotinylated VEGF ligand for capture, and Sulfo-tag goat anti-human IgG or sulfo-tag VEGF for detection. Concentrations are calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters are calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).

Example 15.4
Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Intravitreously Administered in Cynomolgus Monkey

Studies are conducted in accordance with the AbbVie IACUC guidelines. Female cynomolgus are used for the ocular pharmacokinetic characterization of Anti-VEGF-A/anti-PDGF-BB DVD-Igs, including PR-1572102, PR-1572105 and PR-1610561. Animals (4 animals) are split into two cohorts of two for determination of ocular pharmacokinetics. Samples of aqueous humour are taken at 4, 24, 48, 72, 120, 168, 336 and 504 hours post dosing. With cohort 1 providing samples at 4, 48, 120 and 168 hours, and cohort 2 providing samples at 24, 72, 336 and 504 hours, post dosing. Drug levels in the eye are determined from concentrations in aqueous humour as a surrogate for the vitreous concentrations. Blood samples for the harvest of serum used to estimate systemic exposure after vitreous dosing are also collected at 4, 24, 48, 72, 120, and 168 hours post dosing from all animals, and at 336 and 504 hours from the animals in cohort 2. Test articles are dosed into the vitreous compartment at a range of 0.25 to 0.50 mg per eye with a dose volume of no more than 0.050 mL. Only the right eye of each animal is dosed. Prior to dosing, animals are anesthetized with xylazine/ketamine. The eye is prepared by first applying topical analgesic drops (procaine HCl Ophthalmic solution, 0.5%), then the injections site is swabbed with a saturated povidone-iodine swabstick (10% solution equivalent to 1% available iodine) prior to injection. The intravitreal dose is administered with a 26 gauge needle. The point of entry for the injection is 1-2 mm from the limbus through the sclera. After injection, a sterile cotton eye spear is placed on the injection site and held for 30 seconds to prevent leakage. Animals are anesthetized for aqueous fluid collection. At the selected time points after dosing, the aqueous fluid is collected using a 30 gauge needle inserted through the cornea. The needle is advanced just past the bevel and fluid was collected. The samples provide approximately 0.05-0.1 mL of aqueous humour per sampling period. At the selected time points after dosing, blood samples are obtained from an ear vein or artery. Hemostasis following collection is achieved by the application of manual pressure and topical clotting factor or tissue glue as needed. The samples are approximately 1 ml in volume, and are allowed to clot for harvest of serum. Aqueous, vitreous and serum samples are stored at −80° C., and submitted for drug level determinations.

Example 16
Efficacy of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Human VEGF Transgenic Mice
Example 16.1
Efficacy of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to Inhibit Subretinal Neovascularization in Rho/huVEGF Transgenic Mice

Transgenic mice in which the rhodopsin promoter drives expression of human VEGF₁₆₅in photoreceptors (Rho-VEGF mice) have onset of VEGF expression at P7 and starting at P10, develop sprouts of NV from the deep capillary bed of the retina that grow through the photoreceptor layer and form an extensive network of new vessels in the subretinal space. Since the new vessels originate from retinal capillaries and not choroidal vessels, it is technically a model of retinal angiomatous proliferation (RAP) which occurs in roughly 30% of patients with neovascular AMD, but in general it mimics critical features of wet AMD. At P14, hemizygous Rho-VEGF mice were given an intraocular injection of test reagents. At P21, the mice were euthanized, and eyes were fixed in 10% phosphate-buffered formalin for 2 hours. Retinas were dissected, blocked with 5% normal swine serum in PBS for 1 hour, stained with FITC-conjugated GSA, a vascular stain, for 2 hours to stain vascular cells, flat mounted with the photoreceptor side up, and examined by fluorescence microscopy. The area of subretinal NV was measured with image analysis by an investigator blinded with respect to treatment group. The other eye will provide information regarding systemic effect of an intraocular injection.

In the study below, nine treatment groups were evaluated: DVD-Ig Control (DVD 889), Eylea, Anti VEGF mAb, Anti PDGF mAb, Anti VEGF+Anti PDGF (combination Ab treatment), Anti-VEGF/anti-PDGF DVD-Ig. Only eye measurements in the experimental eye were analyzed and reported here using one way ANOVA analysis. Posthoc comparison of treatment vs the DVD control groups was analysed by Dunnett's test. Results are shown in See FIG. 4 and in Table 88 below. Further, differences in PDGF neutralization potencies and the molecular size of the DVD-Ig versus IgG did not have an effect in this model.

An overall ANOVA F-test for significance was used and the data was shown to be significant (p<0.0001). Comparison of the test groups to the DVD-Ig control group shows that the difference from all the groups was significant (Dunnet test p<0.0001). PR-1610561 was significantly more effective at inhibiting subretinal neovascularization in Rho/huVEGF transgenic mice than Eylea (Tukey HSD test pvalue=0.0031). PR-1610561 was more effective, but not significantly different from, the anti-VEGF and anti-PDGF (potency matched mAbs) combination group.

TABLE 88

Inhibition Efficacy of Anti-VEGF-A, Anti-PDGF-

BB, Anti-VEGF-A + Anti-PDGF-BB, and Anti-

VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to Subretinal

Neovascularization in Rho/huVEGF Transgenic Mice

Cor-
N (# of

porate
ani-

Std
Std
CV

Groups
ID#
mals)
Mean
Dev
Err
(%)

DVD negative
PR-
8
0.0892
0.0665
0.0235
74

control
1250499

Eylea
—
19
0.0198
0.0224
0.0051
113

Anti VEGF
—
7
0.0164
0.0088
0.0033
54

Anti PDGF
—
16
0.0297
0.0265
0.0066
89

Anti VEGF +
—
10
0.0119
0.0182
0.0058
153

Anti PDGF

Anti-VEGF/
PR-
9
0.0033
0.0038
0.0013
115

anti-PDGF
1610561

DVD-Ig

Example 16.2
Efficacy of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules in Tet-Opsin-Human VEGF₁₆₅Double-Transgenic Mice

When given injections of doxycycline, Tet-opsin-VEGF double-transgenic mice with Dox-inducible expression of VEGF express 10-fold higher levels of human VEGF₁₆₅than Rho-VEGF-transgenic mice and develop severe NV and exudative retinal detachments within 3 to 5 days. Tet-opsin-VEGF mice provide a severe model where mice develop exudative retinal detachments and only the most effective agents have a significant impact. Double-hemizygous Tet-opsin-VEGF mice were given intraocular injections of test reagent in the right eyes. For the next 3 days, the mice were also administered a daily subcutaneous injection of 50 mg/kg doxycycline. At the 4th day, mice were euthanized and fundus photographs taken with Micron III retinal imaging microscope (Phoenix Research Laboratories, Pleasanton, Calif.). Also, OCT images were taken by Bioptigen Image-guided OCT (Envisu R4110, Bioptigen Inc. Morrisville, N.C.). Then eyes were frozen in optimal cutting temperature embedding solution. Ten-micron ocular serial sections were cut through the entire eye, stained with H&E stain and examined by light microscopy. After that mean length of the retinal detachment per section was measured with image analysis by an investigator blinded with respect to treatment group. The percentage of the detached retina was computed. Retinal detachment was graded as no detachment (0); partial retinal detachment (1); or total retinal detachment (2).

Anti-VEGF-A, anti-PDGF-BB, and the combination of anti-VEGF-A and anti-PDGF-BB were tested for their ability to suppress retinal detachment (RD) in tet-opsin-VEGF double transgenic mice. Results showed differences among the 3 test groups (P=0.01, Kruskal-Wallis test). Based on the RD number, the combination of anti-VEGF-A and anti-PDGF-BB (7 NRD, 1 PRD, 0 TRD), and the anti-VEGF-A alone (5 NRD, 0 PRD, 0 TRD) groups were more effective than anti-PDGF-BB alone (2 NRD, 2 PRD, 2 TRD) in preventing RD in Tet-opsin-VEGF double transgenic mice.

The differences in efficacy between PR-1610561, Eylea, and control IgG were compared next in tet-opsin-VEGF mice. Differences were also found among the 3 groups (P=0.01, Kruskal-Wallis test). PR-1610561 (10 NRD, 0 PRD, 1 TRD) and Eylea (4 NRD, 3 PRD, 1 TRD) were more effective than IgG control (2 NRD, 2 PRD, 2 TRD) in preventing RD in Tet-opsin-VEGF double transgenic mice. The data is summarized in Table 89 below.

TABLE 89

The efficacy of test articles in tet-

opsin-VEGF double transgenic mice

Anti-
Anti-
Anti-

IgG
VEGF
PDGF
VEGF +
PR-

Grade
control
mAb
mAb
Anti-PDGF
1610561
Eylea

0
2
5
2
7
10
4

(NRD)

1
1
0
2
1
0
3

(PRD)

2
6
0
3
0
1
1

(TRD)

Total
9
5
7
8
11
8

eyes

The effects of PR-1610561 in a tet/opsin/huVEGF double transgenic mouse retinal detachment model were also analyzed by another grading system (Table 89A). 1 μl of reagent was injected into one eye, followed by subcutaneous injection of doxycycline at 500 mg/kg once a day for three days, and then fundus images and OCTs were done at day 4. Retinal detachment was graded as no detachment (0); no retinal detachment but at least one sign selected from dilated retinal vessels, retinal edema, or hemorrhage (1); one or less than one quadrant of retinal detachment (2); two or three quandrants of retinal detachment or shallow pan retinal detachment (3); or severe bullous retinal detachment (4).

TABLE 89A

Efficacy of Anti-VEGF, Anti-PDGF, Anti-VEGF + Anti-PDGF, and Anti-

VEGF/Anti-PDGF DVD-Ig Molecules in Tet/Opsin/huVEGF Double Transgenic Mice

Grade
DVD889
Anti-VEGF
Anti-PDGF
Combo
PR-1610561
Aflibercept

0
1
4
1
4
3
1

1
1
1
1
2
7
3

2
1
0
2
0
0
1

3
0
0
0
1
1
1

4
6
0
3
0
0
1

Total eyes
9
5
7
8
11
7

evaluated

The results in the tables above show that PR-1610561 has similar efficacy to a combination of anti-VEGF-A and anti-PDGF-BB, and is superior to Aflibercept alone in suppressing subretinal neovascularization in Rho/huVEGF transgenic mice. PR-1610561 is also superior to the combination of Aflibercept and anti-PDGF-BB in the prevention of vascular leakage in Rho/huVEGF transgenic mice.

Example 16.3
Effects of Anti-VEGF/Anti-PDGF on Ocular Neovascularization and Vascular Permeability/Perfusion

This study compared the effects of intraocular injections of anti-VEGF/anti-PDGF DVD-Ig molecules, anti-VEGF mAb alone, anti-PDGF alone, and a combination of antibodies.

DVD-Ig molecules and DVD-Ig Fab fragments were selected for evaluation, first in Rho/VEGF mice and then in Tet/opsin/VEGF double transgenic mice.

Studies used rho/VEGF and Tet/opsin/VEGF mouse models as described in Example 16.1. The compounds evaluated are shown in Table 90 below. About 20 mice were included per experiment, where one eye was injected with agent and the other eye was not injected.

TABLE 90

Study Agents

4G8.3-GS-9E8.4 (PR-1572102; DVD-Ig-1)

4G8.3-LS-9E8.4 (PR-PR-1575573; DVD-Ig-2)

4G8.3-SL-9E8.4 (PR-1572105; DVD-Ig-3)

DVD 889(IgG control)

Anti-VEGF IgG 4G83

Anti-PDGF-BB IgG 9E8.4

Anti-VEGF IgG 24 μg + Anti-PDGF-BB IgG

Avastin 24 μg

Anti-PDGF-BB aptamer E10030.1

Avastin 24 μg + Anti-PDGF-BB aptamer

Transgenic mice in which the rhodopsin promoter drives expression of VEGF in photoreceptors (rho/VEGF mice) develop retinal angiomatous proliferation (RAP) which originates from the deep capillary bed of the retina and grows through the photoreceptor layer to reach the subretinal spaces. The transgenic mice were utilized to determine the effects of DVD-Ig molecules on subretinal neovascularization. The rho/VEGF mice have an onset of VEGF expression at P7 and, starting at P10, develop sprouts of NV from the deep capillary bed of the retina that grow through the photoreceptor layer and form an extensive network of new vessels in the subretinal space. At P14, hemizygous Rho-VEGF mice were given an intraocular injection of test reagents. At P21, the mice were euthanized, and eyes were fixed in 10% phosphate-buffered formalin for 2 hours. Retinas were dissected, blocked with 5% normal swine serum in PBS for 1 hour, stained with FITC-conjugated GSA for 2 hours to stain vascular cells, flat mounted with the photoreceptor side up, and examined by fluorescence microscopy. The area of subretinal NV was measured with image analysis by an investigator blinded with respect to treatment group.

Compared with the control DVD-Ig molecule, DVD-Ig-1 and DVD-Ig-3 significantly decreased choroidal neovascularization (CNV) (p=0.02, 0.04), whereas DVD-Ig-2 did not show much effect. Compared with the IgG control, the combined administration of anti-VEGF IgG and anti-PDGF-BB IgG significantly decreased CNV (p=0.045), while administration of anti-VEGF IgG or anti-PDGF IgG alone did not significantly reduce subretinal NV. No other difference was observed in eyes injected with Avastin, anti-PDGF-BB aptamer, or a mixture of Avastin and anti-PDGF-BB aptamer. Significantly decreased subretinal NV was found after administration of DVD-Ig-1 and DVD-Ig-3, when compared to the mixture of Avastin and the anti-PDGF-BB aptamer. No other difference was found between DVD-Ig reagents and the combined administration of anti-VEGF-IgG and anti-PDGF IgG. FIG. 5.

No difference was found in the untreated eyes of mice injected with anti-VEGF/anti-PDGF DVD-Ig molecules, control DVD-Ig, anti-VEGF mAb alone, anti-PDGF alone, and a combination of antibodies (ANOVA, P>0.05), indicating there was no clear systemic effect of intraocular injection. FIG. 6.

Tet/opsin/VEGF mice express higher levels of VEGF in photoreceptors than rho/VEGF mice, resulting in severe NV and vascular leakage with exudative retinal detachment. The efficacy of intraocular injections of anti-VEGF/anti-PDGF DVD-Ig molecules in this transgenic mouse was also evaluated. Mice were given intraocular injections of test reagent in the right eye. For the next 3 days, the mice were also administered a daily subcutaneous injection of 50 mg/kg doxycycline. At the 4th days, mice were euthanized and fundus photographs were taken with Micron III retinal imaging microscope (Phoenix Research Laboratories, Pleasanton, Calif.). OCT images were taken by Bioptigen Image-guided OCT (Envisu R4110, Bioptigen Inc. Morrisville, N.C.). Then eyes were frozen in optimal cutting temperature embedding solution. Ten-micron ocular serial sections were cut through the entire eye, stained with H&E stain and examined by light microscopy. Mean length of the retinal detachment per section was measured with image analysis by an investigator blinded with respect to treatment group. The percentage of the retina that was detached was computed.

Five mice in each test group were injected with DVD-Ig reagents separately. In DVD-Ig-1 injected eyes, two were not detached and three were partially detached, while three eyes were totally detached and two partially detached in the uninjected eye. In DVD-Ig-3 injected eyes, one was not detached, two were partially detached, and two were totally detached, while all the uninjected eyes were totally detached. In the DVD-Ig-2 injected eyes, one was not detached and four were totally detached, while one eye was partially detached and four eyes were totally detached in the uninjected eye. In the IgG control group, one injected eye was not detached, one eye was partially detached, and three eyes were totally detached, while all eyes were totally detached in the uninjected eye. FIG. 7.

Thus, DVD-Ig-1 and DVD-Ig-3 appeared to perform at least as well as a combination of anti-VEGF mAb and anti-PDGF mAb for the measured parameters, while requiring the administration of only one compound.

Example 17
Generation and Identification of Various Molecular Formats Optimal for Applications in Ocular Diseases

Several attributes were considered in the design of a therapeutic biologic for the treatment of wet AMD:

PK, Efficacy and Frequency of Administration:

Longer ocular duration may support less frequent intravitreous injection. The size of the administered molecule may play a role in determining ocular half-life. This is supported by consistently longer ocular half-life for the current anti-VEGF agents with larger molecular size in humans and in experimental animals. Bevacizumab, which has a larger molecular size (150 kDa) than ranibizumab (49 kDa), also seems to have more robust duration of efficacy in both Rho/huVEGF and tet/huVEGF transgenic mice, the two models used for preclinical efficacy.

FcRn and FcγR Binding and Safety:

Fc neonatal receptor (FcRn), which plays a role for long circulating half-life of IgG molecules in serum, may or may not play an important role in determining ocular half-life. The molecules with wild type FcRn binding, however, will have long systemic half-life and may increase safety risk due to unnecessary systemic exposure of intravitreously injected molecules. FcRn is also perceived to play a role in active efflux of IgGs across blood-retina barrier. This may lead to shortened ocular retention time for the intravitreously inject molecules. Effector functions are not needed for the efficacy of anti-wet AMD agents. But both VEGF-A and PDGF-BB may be associated with extracellular matrix when they are initially synthesized and secreted. The ECM-associated VEGF-A and PDGF-BB therefore may potentially mediate effector functions.

Affinity, Valency and Potency:

Both VEGF-A and PDGF-BB are homodimeric molecules. If a monovalent molecular format similar to that of ranibizumab (Fab) is used for bispecific molecules targeting VEGF and PDGF for the treatment of wet AMD, high affinity may be needed to maintain binding and potent neutralization of both VEGF-A and PDGF-BB.

Manufacturability:

Any viable format needs to have acceptable expression, purification, formulation properties to accommodate DS and DP manufacturing.

Various binding protein formats disclosed herein may satisfy these characteristics:

(1) Full length DVD-Ig [L234A, L235A] (200 kDa, lacks binding to FcgRs)

(2) Full length DVD-Ig [L234A, L235A, H435A] (200 kDa, lacks binding to FcgRs and FcRn)

(3) Half DVD-Ig (100 kDa, lacks binding to FcgRs and FcRn)

(4) DVD-Fab (75 kDa, no Fc)

Example 17.1
Generation of Various Molecular Formats Including DVD-Ig [L234A, L235A], DVD-Ig [L234A, L235A and H435A], DVD-Ig [L234A, L235A and H435R], Half DVD-Ig and DVD-Fab

This example evaluates the impact of Fc mutations on the PK properties of DVD-Ig binding proteins. DVD-038 was used a tool molecule to study various DVD-Ig formats, including a half-DVD-Ig (DVD038 [L234A, L235A] Half-DVD), full DVD-Ig binding proteins having three constant domain mutations (DVD038 [L234A, L235A and H435A] and DVD038 [L234A, L235A and H435R]), and a full DVD-Ig binding protein having two constant domain mutations (DVD038 [L234A, L235A]). The data below was used to evaluate options for producing a VEGF/PDGF binding protein structure with good drug-like properties and exhibiting high ocular duration but low systemic circulation. DVD038 is a dual variable domain binding protein that binds HER2 and VEGF.

To prepare mutants of DVD038, overlapping PCR was used with primers designed to include the desired mutations. PCR products were digested and ligated into the cloning vector. Bacterial transformation was performed to identify positive clones and constructs were harvested and purified for use in mammalian transfection using standard protocols known in the art.

All variants were transiently transfected into 10 L of HEK 293 6E suspension cell cultures in a Wave-bag with a ratio of 60% to 40% light to heavy chain construct. 0.5 mg/mL PEI was used to transfect the cells. Supernatants were harvested after 11 days by centrifugation at 16000 g for 20 minutes followed by filtration using Pall Serum Capsule and Pall AcroPak 1000. All except DVD-Fab were purified on MabSelectSuRe resin (GE Healthcare, 17-5438-04). Following equilibration with PBS pH 7.4, the supernatant was loaded on the resin and washed with PBS pH 7.4. DVD-Ig protein was eluted with 50 mM Glycine, 50 mM NaCl pH 3.5. DVD-Fab was purified using Protein G Sepharose 4 FF resin (GE Healthcare, 17-0618-04). Elution was performed with Immunopure IgG elution buffer (Pierce, 185 1520). Fractions containing DVD-Ig were pooled and dialyzed in 30 mM Histidine pH 6, 8% sucrose overnight at 4° C.

Example 17.2
Binding of Various Formats to FcRns from Different Species

As described in Example 1.2, all variants of DVD038, except for DVD038 Fab which does not have an Fc region, were analyzed for their binding to FcRns from different species. The data is summarized in Table 91 below.

TABLE 91

Binding of Various Formats to FcRns from Different Species

Hu
Cyno
Rabbit

Corporate
FcRn
FcRn
FcRn
Rat FcRn

Test Articles
ID
KD (M)
KD (M)
KD (M)
ka (1/Ms)
kd (1/s)
KD (M)

DVD038 (L234A,
PR-1578399
6.26E−06
3.13E−06
6.76E−07
3.06E+04
2.57E−02
8.40E−07

L235A) Half DVD-Ig

DVD038 (L234A,
PR-1564681
7.96E−06
2.57E−06
3.98E−07
5.15E+04
5.53E−02
1.07E−06

L235A, H435R)

DVD038 (L234A,
PR-1565009
4.90E−06
1.74E−06
2.75E−07
3.66E+04
1.94E−02
5.31E−07

L235A)

DVD038 (L234A,
PR-1565689
NSB
NSB
NSB
NSB

L235A, H435A)

HERCEPTIN
—
4.53E−06
2.62E−06
4.69E−07
3.27E+04
1.81E−02
5.55E−07

* NSB = no significant binding

Example 17.3
Pharmacokinetic Properties of Different Formats in huFcRn Transgenic Mice Administered Intravenously

Studies were conducted in accordance with the Abbott IACUC guidelines. DVD038 (L234A, L235A) (PR-1565009), DVD038 (L234A, L235A, H435R) (PR-1564681), and DVD038 (L234A, L235A, H435A) (PR-1565689) were administered to huFcRn transgenic mice (5/group) at 6.7 mg/kg by slow intravenous bolus dose injection. Blood samples were collected from each mouse at 1, 24 and 96 hours and 7, 10, 14 and 21 days post dose. All samples were stored at −80° C. until analysis. DVD-Ig serum concentrations were measured using a Meso Scale Discovery (MSD) electrochemiluminescence (ECL) Ligand Binding Assay. Biotinylated VEGF ligand was coated onto streptavidin MSD plates for capture of anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules from blood samples, and detection was achieved with a sulfo-tag goat anti-human IgG antibody. Concentrations were calculated by four-parameter logistic fit using XLfit4.

Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).

TABLE 92

PK in huFcRn Transgenic Mice

CL

Test Articles
Corporate ID
T½ (d)
(mL/h/kg)

DVD038 (L234A, L235A)
PR-1565009
2.8
0.81

DVD038 (L234A, L235A, H435R)
PR-1564681
1.8
1.25

DVD038 (L234A, L235A, H435A)
PR-1565689
0.6
1.58

The results demonstrate a trend for increased clearance and shorter half-life for DVD constructs with reduced or lack of Fc binding in huFcRn transgenic mice.

Example 17.4
Pharmacokinetic Properties of Different Formats in CD-1 Mice Administered Intravenously

Studies were conducted in accordance with the Abbott IACUC guidelines. DVD038 (L234A, L235A) (PR-1565009), DVD038 (L234A, L235A, H435R) (PR-1564681), DVD038 (L234A, L235A, H435A) (PR-1565689), DVD038 half DVD-Ig (L234A, L235A) (PR-1578399) and DVD-Fab (PR-1574215) were administered to CD-1 mice (5/group) at 6.7 mg/kg by slow intravenous bolus dose injection. Blood samples were collected from each mouse at 1, 24 and 96 hours and 7, 10, 14 and 21 days post dose. All samples were stored at −80° C. until analysis. DVD-Ig serum concentrations were measured using a Meso Scale Discovery (MSD) electrochemiluminescence (ECL) Ligand Binding Assay. Biotinylated VEGF ligand was coated onto streptavidin MSD plates for capture of anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules from blood samples, and detection was achieved with a sulfo-tag goat anti-human IgG antibody. Concentrations were calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).

TABLE 93

PK in CD-1 Mice

CL

Test Articles
Corporate ID
T½ (d)
(mL/h/kg)

DVD038 (L234A, L235A)
PR-1565009
7.6
0.46

DVD038 (L234A, L235A, H435R)
PR-1564681
6.4
0.29

DVD038 (L234A, L235A, H435A)
PR-1565689
2.7
0.73

DVD038 Half DVD-Ig (L234A,
PR-1578399
0.4
8.86

L235A)

DVD038 DVD-Fab
PR-1574215
0.2
20.76

Results demonstrate a trend for increased clearance and shorter half-life for DVD constructs with reduced or lack of Fc binding in CD-1 mice. Molecules composed of a fragment of immunoglobulin structure are cleared fastest.

Example 17.5
Pharmacokinetic Properties of Different Formats in Rabbits Administered Intravitreously

Studies were conducted in accordance with the AbbVie IACUC guidelines. Female New Zealand White rabbits were used for the ocular pharmacokinetic characterization of formats DVD038 (PR-1565009, lot 2131983), DVD038 H435A (PR-1565689, lot 2131481), DVD038 Dhab (PR-1578399, lot 2149586) and DVDFab (PR-1574215, lot 2143755). Animals (4 animals) were split into two cohorts of two for determination of ocular pharmacokinetics. Samples of aqueous humour were taken at 48, 168, 336 and 504 hours post dosing. With cohort 1 providing samples at 48 and 168 hours, and cohort 2 providing samples at 336 and 504 hours, post dosing. Drug levels in the eye were determined from concentrations in aqueous humour. Blood samples for the harvest of serum used to estimate systemic exposure after vitreous dosing were also collected at 4, 24, 48, 72, 120, 168 hours post dosing from all animals, and at 336 and 504 hours from the animals in cohort 2. Test articles were dosed into the vitreous compartment at 0.50 mg per eye with a volume of no more than 0.050 mL. Only the right eye of each animal was dosed. Prior to dosing, animals were anesthetized with xylazine/ketamine. The eye was prepared by first applying topical analgesic drops (procaine HCl Ophthalmic solution, 0.5%), then the injections site was swabbed with a saturated povidone-iodine swab stick (10% solution equivalent to 1% available iodine) prior to injection. The intravitreal dose was administered with a 26 gauge needle. The point of entry for the injection was 1-2 mm from the limbus through the sclera. After injection, a sterile cotton eye spear was placed on the injection site and held for 30 seconds to prevent leakage. Animals were anesthetized for aqueous fluid collection. At the selected time points after dosing, the aqueous fluid was collected using a 30 gauge needle inserted through the cornea. The needle was advanced just past the bevel and fluid was collected. The samples provided approximately 0.05-0.1 mL of aqueous humour per sampling period. At the selected time points after dosing, blood samples were obtained from an ear vein or artery. Hemostasis following collection was achieved by the application of manual pressure and topical clotting factor or tissue glue as needed. The samples were from 0.5-1 ml in volume, and were allowed to clot for harvest of serum. Aqueous, vitreous and serum samples were stored at −80° C., and submitted for drug level determinations.

The serum, and aqueous humour concentrations for these molecules were measured using either a GYROS or a MSD method. GYROS employs a biotinylated VEGF ligand for capture, and Alexa Flour 647 goat anti-human IgG detection. MSD employs biotinylated VEGF ligand for capture, and Sulfo-tag goat anti-human IgG or sulfo-tag VEGF for detection. Results were comparable between the two methods. Concentrations were calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie). Results from the experiment are shown in Table 94.

TABLE 94

Ocular Half Lives in Rabbit from Analysis of Aqueous Humor

Test Articles
Corporate ID
Half life

DVD038 (L234A, L235A)
PR-1565009
151

DVD038 (L234A, L235A, H435A)
PR-1565689
157

DVD038 Half DVD-Ig (L234A, L235A)
PR-1578399
90

DVD038 DVD-Fab
PR-1574215
110

Population analysis of the pooled data sets was performed on the composite profile from multiple animals at each dose level. The analysis provided parameter estimates with reasonable variability (CV<30%). The larger molecular weight constructs show a weak trend towards a longer ocular half-life.

TABLE 95

Exemplary DVD-Ig Binding Proteins And Component Subunits

SEQ

ID NO
DVD-Ig
Outer VD name
Linker
Inner VD name

45
PR-1563988H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBDB-4G8.3 VH (VEGF)

(SEQ ID NO: 1)

(SEQ ID NO: 17)

46
PR-1563988L
hBDI-9E8.4 VL (PDGF)
GS-L10
hBDB-4G8.3 VL (VEGF)

(SEQ ID NO: 2)

(SEQ ID NO: 18)

47
PR-1563990H
hBDI-9E8.4 VH (PDGF)
HG-short
hBDB-4G8.3 VH (VEGF)

(SEQ ID NO: 1)

(SEQ ID NO: 17)

48
PR-1563990L
hBDI-9E8.4 VL (PDGF)
LK-short
hBDB-4G8.3 VL (VEGF)

(SEQ ID NO: 2)

(SEQ ID NO: 18)

49
PR-1563998H
hBDI-9E8.4 VH (PDGF)
HG-short
hBDB-4G8.3 VH (VEGF)

(SEQ ID NO: 1)

(SEQ ID NO: 17)

50
PR-1563998L
hBDI-9E8.4 VL (PDGF)
LK-long
hBDB-4G8.3 VL (VEGF)

(SEQ ID NO: 2)

(SEQ ID NO: 18)

51
PR-1564009H
hBDI-9E8.4 VH (PDGF)
HG-long
hBDB-4G8.3 VH (VEGF)

(SEQ ID NO: 1)

(SEQ ID NO: 17)

51
PR-1564009L
hBDI-9E8.4 VL (PDGF)
LK-short
hBDB-4G8.3 VL (VEGF)

(SEQ ID NO: 2)

(SEQ ID NO: 18)

53
PR-1564010H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 17)

(SEQ ID NO: 1)

54
PR-1564010L
hBDB-4G8.3 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 18)

(SEQ ID NO: 2)

55
PR-1564011H
hBDB-4G8.3 VH (VEGF)
HG-short
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 17)

(SEQ ID NO: 1)

56
PR-1564011L
hBDB-4G8.3 VL (VEGF)
LK-short
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 18)

(SEQ ID NO: 2)

57
PR-1564012H
hBDB-4G8.3 VH (VEGF)
HG-short
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 17)

(SEQ ID NO: 1)

58
PR-1564012L
hBDB-4G8.3 VL (VEGF)
LK-long
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 18)

(SEQ ID NO: 2)

59
PR-1564013H
hBDB-4G8.3 VH (VEGF)
HG-long
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 17)

(SEQ ID NO: 1)

60
PR-1564013L
hBDB-4G8.3 VL (VEGF)
LK-short
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 18)

(SEQ ID NO: 2)

61
PR-1564883H
hBDI-5H1.9 VH (PDGF)
HG-short
hBDB-4G8.13 VH (VEGF)

(DVD3896H)a
(SEQ ID NO: 3)

(SEQ ID NO: 19)

62
PR-1564883L
hBDI-5H1.9 VL (PDGF)
LK-long
hBDB-4G8.13 VL (VEGF)

(DVD3896L)a
(SEQ ID NO: 4)

(SEQ ID NO: 20)

63
PR-1564893H
hBDI-5H1.9 VH (PDGF)
HG-short
hBDB-4G8.14 VH (VEGF)

(DVD3897H)a
(SEQ ID NO: 3)

(SEQ ID NO: 21)

64
PR-1564893L
hBDI-5H1.9 VL (PDGF)
LK-long
hBDB-4G8.14 VL (VEGF)

(DVD3897L)a
(SEQ ID NO: 4)

(SEQ ID NO: 22)

209
PR-1564896H
hBDI-5H1.9 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)

(DVD3898H)a
(SEQ ID NO: 3)

(SEQ ID NO: 23)

65
PR-1564896L
hBDI-5H1.9 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)

(DVD3898L)a
(SEQ ID NO: 4)

(SEQ ID NO: 24)

66
PR-1564898H
hBDI-5H1.12 VH (PDGF)
HG-short
hBDB-4G8.14 VH (VEGF)

(DVD3899H)a
(SEQ ID NO: 211)

(SEQ ID NO: 21)

67
PR-1564898L
hBDI-5H1.12 VL (PDGF)
LK-long
hBDB-4G8.14 VL (VEGF)

(DVD3899L)a
(SEQ ID NO: 212)

(SEQ ID NO: 22)

68
PR-1564899H
hBDI-5H1.12 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)

(DVD3900H)a
(SEQ ID NO: 211)

(SEQ ID NO: 23)

69
PR-1564899L
hBDI-5H1.12 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)

(DVD3900L)a
(SEQ ID NO: 212)

(SEQ ID NO: 24)

70
PR-1565023H
hBDI-9E8.9 VH (PDGF)
HG-short
hBDB-4G8.13 VH (VEGF)

(DVD3901H)a
(SEQ ID NO: 7)

(SEQ ID NO: 19)

71
PR-1565023L
hBDI-9E8.9 VL (PDGF)
LK-long
hBDB-4G8.13 VL (VEGF)

(DVD3901L)a
(SEQ ID NO: 8)

(SEQ ID NO: 20)

72
PR-1565029H
hBDI-9E8.9 VH (PDGF)
HG-short
hBDB-4G8.14 VH (VEGF)

(DVD3902H)a
(SEQ ID NO: 7)

(SEQ ID NO: 21)

73
PR-1565029L
hBDI-9E8.9 VL (PDGF)
LK-long
hBDB-4G8.14 VL (VEGF)

(DVD3902L)a
(SEQ ID NO: 8)

(SEQ ID NO: 22)

74
PR-1565030H
hBDI-9E8.9 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)

(DVD3903H)a
(SEQ ID NO: 7)

(SEQ ID NO: 23)

75
PR-1565030L
hBDI-9E8.9 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)

(DVD3903L)a
(SEQ ID NO: 8)

(SEQ ID NO: 24)

76
PR-1565031H
hBDI-9E8.12 VH (PDGF)
HG-short
hBDB-4G8.14 VH (VEGF)

(DVD3904H)a
(SEQ ID NO: 9)

(SEQ ID NO: 21)

77
PR-1565031L
hBDI-9E8.12 VL (PDGF)
LK-long
hBDB-4G8.14 VL (VEGF)

(DVD3904L)a
(SEQ ID NO: 10)

(SEQ ID NO: 22)

78
PR-1565032H
hBDI-9E8.12 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)

(DVD3905H)a
(SEQ ID NO: 5)

(SEQ ID NO: 23)

79
PR-1565032L
hBDI-9E8.12 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)

(DVD3905L)a
(SEQ ID NO: 6)

(SEQ ID NO: 24)

80
PR-1565035H
hBDI-5H1.10 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)

(DVD3906H)a
(SEQ ID NO: 9)

(SEQ ID NO: 23)

81
PR-1565035L
hBDI-5H1.10 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)

(DVD3906L)a
(SEQ ID NO: 10)

(SEQ ID NO: 24)

82
PR-1565033H
hBDI-9E8.10 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)

(DVD3907H)a
(SEQ ID NO: 9)

(SEQ ID NO: 23)

83
PR-1565033L
hBDI-9E8.10 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)

(DVD3907L)a
(SEQ ID NO: 10)

(SEQ ID NO: 24)

84
PR-1569574H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBDB-4G8.3 VH (VEGF)

(SEQ ID NO: 1)

(SEQ ID NO: 17)

85
PR-1569574L
hBDI-9E8.4 VL (PDGF)
GS-L10
hBDB-4G8.3 VL (VEGF)

(SEQ ID NO: 2)

(SEQ ID NO: 18)

86
PR-1569579H
hBDI-9E8.4 VH (PDGF)
HG-short
hBDB-4G8.3 VH (VEGF)

(SEQ ID NO: 1)

(SEQ ID NO: 17)

87
PR-1569579L
hBDI-9E8.4 VL (PDGF)
LK-long
hBDB-4G8.3 VL (VEGF)

(SEQ ID NO: 2)

(SEQ ID NO: 18)

88
PR-1572102H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 17)

(SEQ ID NO: 1)

89
PR-1572102L
hBDB-4G8.3 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 18)

(SEQ ID NO: 2)

90
PR-1572103H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 17)

(SEQ ID NO: 1)

91
PR-1572103L
hBDB-4G8.3 VL (VEGF)
GS-L11
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 18)

(SEQ ID NO: 2)

92
PR-1572104H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 17)

(SEQ ID NO: 1)

93
PR-1572104L
hBDB-4G8.3 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 18)

(SEQ ID NO: 2)

94
PR-1572105H
hBDB-4G8.3 VH (VEGF)
HG-short
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 17)

(SEQ ID NO: 1)

95
PR-1572105L
hBDB-4G8.3 VL (VEGF)
LK-long
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 18)

(SEQ ID NO: 2)

96
PR-1572106H
hBDB-4G8.3 VH (VEGF)
HG-long
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 17)

(SEQ ID NO: 1)

97
PR-1572106L
hBDB-4G8.3 VL (VEGF)
LK-short
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 18)

(SEQ ID NO: 2)

210
PR-1575573H
hBDI-9E8.4 VH (PDGF)
HG-long
hBDB-4G8.3 VH (VEGF)

(SEQ ID NO: 1)

(SEQ ID NO: 17)

98
PR-1575573L
hBDI-9E8.4 VL (PDGF)
LK-short
hBDB-4G8.3 VL (VEGF)

(SEQ ID NO: 2)

(SEQ ID NO: 18)

99
PR-1575832H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4E VH (PDGF)

(SEQ ID NO: 17)

(SEQ ID NO: 11)

100
PR-1575832L
hBDB-4G8.3 VL (VEGF)
GS-L10
hBDI-9E8.4E VL (PDGF)

(SEQ ID NO: 18)

(SEQ ID NO: 12)

101
PR-1575834H
hBDB-4G8.3 VH (VEGF)
HG-short
hBDI-9E8.4E VH (PDGF)

(SEQ ID NO: 17)

(SEQ ID NO: 11)

102
PR-1575834L
hBDB-4G8.3 VL (VEGF)
LK-long
hBDI-9E8.4E VL (PDGF)

(SEQ ID NO: 18)

(SEQ ID NO: 12)

103
PR-1575835H
hBDB-4G8.3 VH (VEGF)
HG-long
hBDI-9E8.4E VH (PDGF)

(SEQ ID NO: 17)

(SEQ ID NO: 11)

104
PR-1575835L
hBDB-4G8.3 VL (VEGF)
LK-short
hBDI-9E8.4E VL (PDGF)

(SEQ ID NO: 18)

(SEQ ID NO: 12)

105
PR-1577165H
hBEW-9A8.12 VH (VEGF)
GS-H10
hBDI-9E8.4E VH (PDGF)

(SEQ ID NO: 25)

(SEQ ID NO: 11)

106
PR-1577165L
hBEW-9A8.12 VL (VEGF)
GS-L10
hBDI-9E8.4E VL (PDGF)

(SEQ ID NO: 26)

(SEQ ID NO: 12)

107
PR-1577166H
hBEW-9A8.12 VH (VEGF)
HG-short
hBDI-9E8.4E VH (PDGF)

(SEQ ID NO: 25)

(SEQ ID NO: 11)

108
PR-1577166L
hBEW-9A8.12 VL (VEGF)
LK-long
hBDI-9E8.4E VL (PDGF)

(SEQ ID NO: 26)

(SEQ ID NO: 12)

109
PR-1577547H
hBEW-9A8.12 VH (VEGF)
HG-long
hBDI-9E8.4E VH (PDGF)

(SEQ ID NO: 25)

(SEQ ID NO: 11)

110
PR-1577547L
hBEW-9A8.12 VL (VEGF)
LK-short
hBDI-9E8.4E VL (PDGF)

(SEQ ID NO: 26)

(SEQ ID NO: 12)

111
PR-1577548H
hBDI-9E8.4E VH (PDGF)
HG-short
hBEW-9A8.12 VH (VEGF)

(SEQ ID NO: 11)

(SEQ ID NO: 25)

112
PR-1577548L
hBDI-9E8.4E VL (PDGF)
LK-long
hBEW-9A8.12 VL (VEGF)

(SEQ ID NO: 12)

(SEQ ID NO: 26)

113
PR-1577550H
hBDI-9E8.4E VH (PDGF)
HG-long
hBEW-9A8.12 VH (VEGF)

(SEQ ID NO: 11)

(SEQ ID NO: 25)

114
PR-1577550L
hBDI-9E8.4E VL (PDGF)
LK-short
hBEW-9A8.12 VL (VEGF)

(SEQ ID NO: 12)

(SEQ ID NO: 26)

115
PR-1578137H
hBDI-9E8.4E VH (PDGF)
GS-H10
hBEW-9A8.12 VH (VEGF)

(SEQ ID NO: 11)

(SEQ ID NO: 25)

116
PR-1578137L
hBDI-9E8.4E VL (PDGF)
GS-L10
hBEW-9A8.12 VL (VEGF)

(SEQ ID NO: 12)

(SEQ ID NO: 26)

117
PR-1598261H
hBDB-4G8.2 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 27)

(SEQ ID NO: 1)

118
PR-1598261L
hBDB-4G8.2 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 28)

(SEQ ID NO: 2)

119
PR-1598262H
hBDB-4G8.4 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 29)

(SEQ ID NO: 1)

120
PR-1598262L
hBDB-4G8.4 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 30)

(SEQ ID NO: 2)

121
PR-1598263H
hBDB-4G8.5 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 31)

(SEQ ID NO: 1)

122
PR-1598263L
hBDB-4G8.5 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 32)

(SEQ ID NO: 2)

123
PR-1598264H
hBDB-4G8.12 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 33)

(SEQ ID NO: 1)

124
PR-1598264L
hBDB-4G8.12 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 34)

(SEQ ID NO: 2)

125
PR-1598265H
hBDB-4G8.13 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 19)

(SEQ ID NO: 1)

126
PR-1598265L
hBDB-4G8.13 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 20)

(SEQ ID NO: 2)

127
PR-1598266H
hBDB-4G8.14 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 21)

(SEQ ID NO: 1)

128
PR-1598266L
hBDB-4G8.14 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 22)

(SEQ ID NO: 2)

129
PR-1610560H
hBDB-4G8.5 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)

(SEQ ID NO: 31)

(SEQ ID NO: 13)

130
PR-1610560L
hBDB-4G8.5 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)

(SEQ ID NO: 32)

(SEQ ID NO: 14)

131
PR-1610561H
hBEW-9E10.1 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)

(SEQ ID NO: 35)

(SEQ ID NO: 15)

132
PR-1610561L
hBEW-9E10.1 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)

(SEQ ID NO: 36)

(SEQ ID NO: 16)

133
PR-1610562H
hBEW-9E10.1 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)

(SEQ ID NO: 35)

(SEQ ID NO: 13)

134
PR-1610562L
hBEW-9E10.1 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)

(SEQ ID NO: 36)

(SEQ ID NO: 14)

135
PR-1610563H
hBEW-9E10.6 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)

(SEQ ID NO: 37)

(SEQ ID NO: 13)

136
PR-1610563L
hBEW-9E10.6 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)

(SEQ ID NO: 38)

(SEQ ID NO: 14)

137
PR-1610564H
hBEW-1B10.1 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)

(SEQ ID NO: 39)

(SEQ ID NO: 13)

138
PR-1610564L
hBEW-1B10.1 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)

(SEQ ID NO: 40)

(SEQ ID NO: 14)

139
PR-1611291H
hBDB-4G8.5 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)

(SEQ ID NO: 31)

(SEQ ID NO: 15)

140
PR-1611291L
hBDB-4G8.5 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)

(SEQ ID NO: 32)

(SEQ ID NO: 16)

141
PR-1611292H
hBEW-1B10.1 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)

(SEQ ID NO: 39)

(SEQ ID NO: 15)

142
PR-1611292L
hBEW-1B10.1 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)

(SEQ ID NO: 40)

(SEQ ID NO: 16)

143
PR-1611293H
hBEW-1E3.4 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)

(SEQ ID NO: 41)

(SEQ ID NO: 15)

144
PR-1611293L
hBEW-1E3.4 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)

(SEQ ID NO: 42)

(SEQ ID NO: 16)

145
PR-1611294H
hBEW-1E3.4 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 41)

(SEQ ID NO: 1)

146
PR-1611294L
hBEW-1E3.4 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 42)

(SEQ ID NO: 2)

147
PR-1611295H
CL-33675 VH (PDGF)
GS-H10
hBEW-9E10.1 VH (VEGF)

(SEQ ID NO: 15)

(SEQ ID NO: 35)

148
PR-1611295L
CL-33675 VL (PDGF)
GS-L10(dR)
hBEW-9E10.1 VL (VEGF)

(SEQ ID NO: 16)

(SEQ ID NO: 36)

149
PR-1611296H
CL-33675 VH (PDGF)
GS-H10
hBEW-9E10.6 VH (VEGF)

(SEQ ID NO: 15)

(SEQ ID NO: 37)

150
PR-1611296L
CL-33675 VL (PDGF)
GS-L10(dR)
hBEW-9E10.6 VL (VEGF)

(SEQ ID NO: 16)

(SEQ ID NO: 38)

151
PR-1611297H
CL-33675 VH (PDGF)
GS-H10
hBEW-1E3.4 VH (VEGF)

(SEQ ID NO: 15)

(SEQ ID NO: 41)

152
PR-1611297L
CL-33675 VL (PDGF)
GS-L10(dR)
hBEW-1E3.4 VL (VEGF)

(SEQ ID NO: 16)

(SEQ ID NO: 42)

153
PR-1611298H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBEW-9E10.1 VH (VEGF)

(SEQ ID NO: 1)

(SEQ ID NO: 35)

154
PR-1611298L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBEW-9E10.1 VL (VEGF)

(SEQ ID NO: 2)

(SEQ ID NO: 36)

155
PR-1611299H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBEW-9E10.6 VH (VEGF)

(SEQ ID NO: 1)

(SEQ ID NO: 37)

156
PR-1611299L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBEW-9E10.6 VL (VEGF)

(SEQ ID NO: 2)

(SEQ ID NO: 38)

157
PR-1611300H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBEW-1B10.1 VH (VEGF)

(SEQ ID NO: 1)

(SEQ ID NO: 39)

158
PR-1611300L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBEW-1B10.1 VL (VEGF)

(SEQ ID NO: 2)

(SEQ ID NO: 40)

159
PR-1611301H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBEW-1E3.4 VH (VEGF)

(SEQ ID NO: 1)

(SEQ ID NO: 41)

160
PR-1611301L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBEW-1E3.4 VH (VEGF)

(SEQ ID NO: 2)

(SEQ ID NO: 42)

161
PR-1612489H
hBDB-4G8.5 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 31)

(SEQ ID NO: 1)

162
PR-1612489L
hBDB-4G8.5 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 32)

(SEQ ID NO: 2)

163
PR-1612491H
hBEW-9E10.1 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 35)

(SEQ ID NO: 1)

164
PR-1612491L
hBEW-9E10.1 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 36)

(SEQ ID NO: 2)

165
PR-1612492H
hBEW-9E10.6 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)

(SEQ ID NO: 37)

(SEQ ID NO: 15)

166
PR-1612492L
hBEW-9E10.6 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)

(SEQ ID NO: 38)

(SEQ ID NO: 16)

167
PR-1612493H
hBEW-9E10.6 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 37)

(SEQ ID NO: 1)

168
PR-1612493L
hBEW-9E10.6 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 38)

(SEQ ID NO: 2)

169
PR-1612494H
hBEW-1B10.1 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 39)

(SEQ ID NO: 1)

170
PR-1612494L
BEW-1B10.1 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 40)

(SEQ ID NO: 2)

171
PR-1612495H
hBEW-1E3.4 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)

(SEQ ID NO: 41)

(SEQ ID NO: 13)

172
PR-1612495L
hBEW-1E3.4 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)

(SEQ ID NO: 42)

(SEQ ID NO: 14)

173
PR-1612496H
CL-33675 VH (PDGF)
GS-H10
hBDB-4G8.5 VH (VEGF)

(SEQ ID NO: 15)

(SEQ ID NO: 31)

174
PR-1612496L
CL-33675 VL (PDGF)
GS-L10(dR)
hBDB-4G8.5 VL (VEGF)

(SEQ ID NO: 16)

(SEQ ID NO: 32)

175
PR-1612498H
CL-33675 VH (PDGF)
GS-H10
hBEW-1B10.1 VH (VEGF)

(SEQ ID NO: 15)

(SEQ ID NO: 39)

176
PR-1612498L
CL-33675 VL (PDGF)
GS-L10(dR)
hBEW-1B10.1 VL (VEGF)

(SEQ ID NO: 16)

(SEQ ID NO: 40)

177
PR-1612499H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBDB-4G8.5 VH (VEGF)

(SEQ ID NO: 13)

(SEQ ID NO: 31)

178
PR-1612499L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBDB-4G8.5 VL (VEGF)

(SEQ ID NO: 14)

(SEQ ID NO: 32)

179
PR-1612500H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBEW-9E10.1 VH (VEGF)

(SEQ ID NO: 13)

(SEQ ID NO: 35)

180
PR-1612500L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBEW-9E10.1 VL (VEGF)

(SEQ ID NO: 14)

(SEQ ID NO: 36)

181
PR-1612501H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBEW-9E10.6 VH (VEGF)

(SEQ ID NO: 13)

(SEQ ID NO: 37)

182
PR-1612501L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBEW-9E10.6 VL (VEGF)

(SEQ ID NO: 14)

(SEQ ID NO: 38)

183
PR-1612502H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBEW-1B10.1 VH (VEGF)

(SEQ ID NO: 13)

(SEQ ID NO: 39)

184
PR-1612502L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBEW-1B10.1 VL (VEGF)

(SEQ ID NO: 14)

(SEQ ID NO: 40)

185
PR-1613183H
CL-34565 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)

(SEQ ID NO: 43)

(SEQ ID NO: 15)

186
PR-1613183L
CL-34565 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)

(SEQ ID NO: 44)

(SEQ ID NO: 16)

187
PR-1613184H
CL-34565 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)

(SEQ ID NO: 43)

(SEQ ID NO: 1)

188
PR-1613184L
CL-34565 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)

(SEQ ID NO: 44)

(SEQ ID NO: 2)

189
PR-1613185H
CL-34565 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)

(SEQ ID NO: 43)

(SEQ ID NO: 13)

190
PR-1613185L
CL-34565 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)

(SEQ ID NO: 44)

(SEQ ID NO: 14)

191
PR-1613186H
CL-33675 VH (PDGF)
GS-H10
CL-34565 VH (VEGF)

(SEQ ID NO: 15)

(SEQ ID NO: 43)

192
PR-1613186L
CL-33675 VL (PDGF)
GS-L10(dR)
CL-34565 VL (VEGF)

(SEQ ID NO: 16)

(SEQ ID NO: 44)

193
PR-1613187H
hBDI-9E8.4 VH (PDGF)
GS-H10
CL-34565 VH (VEGF)

(SEQ ID NO: 1)

(SEQ ID NO: 43)

194
PR-1613187L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
CL-34565 VL (VEGF)

(SEQ ID NO: 2)

(SEQ ID NO: 44)

195
PR-1613188H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBDB-4G8.5 VH (VEGF)

(SEQ ID NO: 1)

(SEQ ID NO: 31)

196
PR-1613188L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBDB-4G8.5 VL (VEGF)

(SEQ ID NO: 2)

(SEQ ID NO: 32)

197
PR-1613189H
hBFU-3E2.1 VH (PDGF)
GS-H10
CL-34565 VH (VEGF)

(SEQ ID NO: 13)

(SEQ ID NO: 43)

198
PR-1613189L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
CL-34565 VL (VEGF)

(SEQ ID NO: 14)

(SEQ ID NO: 44)

199
PR-1613190H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBEW-1E3.4 VH (VEGF)

(SEQ ID NO: 13)

(SEQ ID NO: 41)

200
PR-1613190L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBEW-1E3.4 VL (VEGF)

(SEQ ID NO: 14)

(SEQ ID NO: 42)

201
PR-1629646H
hBEW-9E10.1 VH (VEGF)
HG-short
CL-33675 VH (PDGF)

(SEQ ID NO: 35)

(SEQ ID NO: 15)

202
PR-1629646L
hBEW-9E10.1 VL (VEGF)
LK-long
CL-33675 VL (PDGF)

(SEQ ID NO: 36)

(SEQ ID NO: 16)

203
PR-1629647H
hBEW-1B10.1 VH (VEGF)
HG-short
CL-33675 VH (PDGF)

(SEQ ID NO: 39)

(SEQ ID NO: 15)

204
PR-1629647L
hBEW-1B10.1 VL (VEGF)
LK-long
CL-33675 VL (PDGF)

(SEQ ID NO: 40)

(SEQ ID NO: 16)

205
PR-1629648H
hBEW-9E10.1 VH (VEGF)
HG-long
CL-33675 VH (PDGF)

(SEQ ID NO: 35)

(SEQ ID NO: 15)

206
PR-1629648L
hBEW-9E10.1 VL (VEGF)
LK-short
CL-33675 VL (PDGF)

(SEQ ID NO: 36)

(SEQ ID NO: 16)

207
PR-1629649H
hBEW-1B10.1 VH (VEGF)
HG-long
CL-33675 VH (PDGF)

(SEQ ID NO: 39)

(SEQ ID NO: 15)

208
PR-1629649L
hBEW-1B10.1 VL (VEGF)
LK-short
CL-33675 VL (PDGF)

(SEQ ID NO: 40)

(SEQ ID NO: 16)

TABLE 96

Sequences of Exemplary DVD-Ig Binding Proteins

SEQ

ID NO
DVD-Ig
Sequence

45
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1563988H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW

GQGTMVTVSSGGGGSGGGGSEVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY

WVRQAPGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT

AVYYCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAA

LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP

EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNHYTQKSLSLSPGK

46
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS

1563988L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGGSGGG

GSGDTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNL

ESGVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

47
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1563990H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW

GQGTMVTVSSASTKGPEVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQ

APGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYY

CARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV

VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGK

48
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS

1563990L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPDT

VLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESGVP

ARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVFIF

PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS

LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

49
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1563998H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW

GQGTMVTVSSASTKGPEVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQ

APGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYY

CARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV

VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGK

50
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS

1563998L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPSV

FIFPPDTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASN

LESGVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVA

APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS

KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

51
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1564009H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW

GQGTMVTVSSASTKGPSVFPLAPEVQLVQSGSELKKPGASVKVSCKASGYTFTNYG

MYWVRQAPGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAE

DTAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGT

AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ

TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS

RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL

HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV

FSCSVMHEALHNHYTQKSLSLSPGK

51
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS

1564009L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPDT

VLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESGVP

ARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVFIF

PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS

LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

53
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1564010H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM

GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP

VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNHYTQKSLSLSPGK

54
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1564010L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG

SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR

PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

55
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1564011H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI

RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT

YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV

VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGK

56
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1564011L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF

VLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGI

PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPSVFI

FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY

SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

57
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1564012H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI

RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT

YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV

VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGK

58
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1564012L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVF

IFPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ

RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

59
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1564013H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG

MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM

DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR

TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH

QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNHYTQKSLSLSPGK

60
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1564013L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF

VLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGI

PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPSVFI

FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY

SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

61
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIRQPPGKALEWLANIWWDD

1564883H
DKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWG

(DVD3896H)a
QGTTVTVSSASTKGPEIQLVQSGTEVKKPGESLKISCKASGYTFTNYGMYWVKQMP

GKGLEYMGWINTETGKPTYADDFKGRFTFSLDKSFNTAFLQWSSLKASDTAMYFCA

RTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGK

62
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVSWYQQKPGQPPKNVIYGNDQRP

1564883L
SGVPDRFSGSGSGNSATLTISSLQAEDVAVYFCQSYDSDIDIVFGGGTKVEIKGTVAA

(DVD3896L)a
PSVFIFPPETVLTQSPATLSVSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYG

ASNLESGVPARFSGSGSGTDFTLTISSLQSEDFAVYFCQQSWNDPFTFGQGTRLEIKRT

VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ

DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

63
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIRQPPGKALEWLANIWWDD

1564893H
DKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWG

(DVD3897H)a
QGTTVTVSSASTKGPEIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQAP

GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFCA

RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGK

64
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVSWYQQKPGQPPKNVIYGNDQRP

1564893L
SGVPDRFSGSGSGNSATLTISSLQAEDVAVYFCQSYDSDIDIVFGGGTKVEIKGTVAA

(DVD3897L)a
PSVFIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGA

SNLESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTV

AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD

SKDSTYSLSSTLTLSKADYEK

209
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIRQPPGKALEWLANIWWDD

1564896H
DKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWG

(DVD3898H)a
QGTTVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQAP

GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYFCA

RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGK

65
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVSWYQQKPGQPPKNVIYGNDQRP

1564896L
SGVPDRFSGSGSGNSATLTISSLQAEDVAVYFCQSYDSDIDIVFGGGTKVEIKGTVAA

(DVD3898L)a
PSVFIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYG

ASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRT

VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ

DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

66
PR-
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTFGMGVGWIRQAPGKGLEWLANIWWD

1564898H
DDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCARISTGISSYYVMDAW

(DVD3899H)a
GQGTLVTVSSASTKGPEIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQA

PGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFC

ARTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK

PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV

VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK

EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS

DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA

LHNHYTQKSLSLSPGK

67
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAPKNVIYGNDQRP

1564898L
SGVPSRFSGSGSGNSATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVEIKGTVAAP

(DVD3899L)a
SVFIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGAS

NLESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTV

AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD

SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

68
PR-
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTFGMGVGWIRQAPGKGLEWLANIWWD

1564899H
DDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCARISTGISSYYVMDAW

(DVD3900H)a
GQGTLVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQ

APGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYF

CARTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV

VVDVSHEDPEVKTNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGK

69
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAPKNVIYGNDQRP

1564899L
SGVPSRFSGSGSGNSATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVEIKGTVAAP

(DVD3900L)a
SVFIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYGA

SNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRTV

AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD

SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

70
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1565023H
DDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWG

(DVD3901H)a
QGTTVTVSSASTKGPEIQLVQSGTEVKKPGESLKISCKASGYTFTNYGMYWVKQMP

GKGLEYMGWINTETGKPTYADDFKGRFTFSLDKSFNTAFLQWSSLKASDTAMYFCA

RTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGK

71
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVSWYQQKPGQPPKNVIYADDQRP

1565023L
SGVPDRFSGSGSGNSASLTISSLQAEDVAVYFCQSYDINIDIVFGGGTKVEIKGTVAAP

(DVD3901L)a
SVFIFPPETVLTQSPATLSVSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGA

SNLESGVPARFSGSGSGTDFTLTISSLQSEDFAVYFCQQSWNDPFTFGQGTRLEIKRTV

AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD

SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

72
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1565029H
DDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWG

(DVD3902H)a
QGTTVTVSSASTKGPEIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQAP

GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFCA

RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGK

73
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVSWYQQKPGQPPKNVIYADDQRP

1565029L
SGVPDRFSGSGSGNSASLTISSLQAEDVAVYFCQSYDINIDIVFGGGTKVEIKGTVAAP

(DVD3902L)a
SVFIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGAS

NLESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTV

AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD

SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

74
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1565030H
DDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWG

(DVD3903H)a
QGTTVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQAP

GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYFCA

RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGK

75
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVSWYQQKPGQPPKNVIYADDQRP

1565030L
SGVPDRFSGSGSGNSASLTISSLQAEDVAVYFCQSYDINIDIVFGGGTKVEIKGTVAAP

(DVD3903L)a
SVFIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYGA

SNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRTV

AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD

SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

76
PR-
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTYGMGVGWIRQAPGKGLEWLANIWW

1565031H
DDDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCARIESIGTTYSFDYW

(DVD3904H)a
GQGTLVTVSSASTKGPEIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQA

PGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFC

ARTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK

PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV

VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK

EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS

DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA

LHNHYTQKSLSLSPGK

77
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAPKNVIYADDQRPS

1565031L
GVPSRFSGSGSGNSASLTISSLQPEDFATYFCQSYDINIDIVFGQGTKVEIKGTVAAPSV

(DVD3904L)a
FIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGASNL

ESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

78
PR-
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTYGMGVGWIRQAPGKGLEWLANIWW

1565032H
DDDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCARIESIGTTYSFDYW

(DVD3905H)a
GQGTLVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQ

APGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYF

CARTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV

VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGK

79
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAPKNVIYADDQRPS

1565032L
GVPSRFSGSGSGNSASLTISSLQPEDFATYFCQSYDINIDIVFGQGTKVEIKGTVAAPSV

(DVD3905L)a
FIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYGASN

LESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRTVA

APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS

KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

80
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIRQPPGKALEWLANIWWDD

1565035H
DKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWG

(DVD3906H)a
QGTTVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQAP

GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYFCA

RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGK

81
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAPKNVIYGNDQRP

1565035L
SGVPSRFSGSGSGNSATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVEIKGTVAAP

(DVD3906L)a
SVFIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYGA

SNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRTV

AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD

SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

82
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1565033H
DDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWG

(DVD3907H)a
QGTTVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQAP

GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYFCA

RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNHYTQKSLSLSPGK

83
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAPKNVIYADDQRPS

1565033L
GVPSRFSGSGSGNSASLTISSLQPEDFATYFCQSYDINIDIVFGQGTKVEIKGTVAAPSV

(DVD3907L)a
FIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGASNL

ESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

84
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1569574H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM

GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP

VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

85
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1569574L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG

SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR

PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

86
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1569579H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI

RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT

YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV

VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNAYTQKSLSLSPGK

87
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1569579L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVF

IFPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ

RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

88
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1572102H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM

GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP

VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

89
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1572102L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG

SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR

PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

90
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1572103H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM

GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP

VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

91
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1572103L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG

SGGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ

RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

92
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1572104H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM

GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP

VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

93
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1572104L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGSGGGGS

GGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ

RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

94
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1572105H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI

RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT

YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV

VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNAYTQKSLSLSPGK

95
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1572105L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVF

IFPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ

RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

96
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1572106H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG

MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM

DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR

TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH

QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNAYTQKSLSLSPGK

97
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1572106L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF

VLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGI

PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPSVFI

FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY

SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

210
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1575573H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG

MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM

DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR

TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH

QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNAYTQKSLSLSPGK

98
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1575573L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF

VLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGI

PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPSVFI

FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY

SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

99
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1575832H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM

GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP

VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

100
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1575832L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG

SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQR

PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

101
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1575834H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI

RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT

YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV

VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNAYTQKSLSLSPGK

102
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1575834L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVF

IFPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQ

RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

103
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1575835H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG

MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM

DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR

TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH

QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNAYTQKSLSLSPGK

104
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1575835L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF

VLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPSGI

PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPSVFI

FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY

SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

105
PR-
EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1577165H
TGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARVDYDGSFWFAY

WGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD

TATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC

LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV

NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT

CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL

NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG

FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNAYTQKSLSLSPGK

106
PR-
DTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLESGV

1577165L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRGGSGGGGS

GEFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRP

SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

107
PR-
EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1577166H
TGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARVDYDGSFWFAY

WGQGTLVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR

QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATY

YCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK

PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV

VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK

EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS

DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA

LHNAYTQKSLSLSPGK

108
PR-
DTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLESGV

1577166L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAAPSVFI

FPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQ

RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

109
PR-
EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1577547H
TGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARVDYDGSFWFAY

WGQGTLVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM

GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP

VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

110
PR-
DTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLESGV

1577547L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAAPEFVL

TQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPSGIPD

RFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPSVFIFP

PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL

SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

111
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1577548H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW

GQGTMVTVSSASTKGPEVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQ

APGQGLEWMGWINTETGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYY

CARVDYDGSFWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNAYTQKSLSLSPGK

112
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPS

1577548L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPSV

FIFPPDTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNL

ESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

113
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1577550H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW

GQGTMVTVSSASTKGPSVFPLAPEVQLVQSGAEVKKPGASVKVSCKASGYTFTNYG

MYWVRQAPGQGLEWMGWINTETGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRS

DDTAVYYCARVDYDGSFWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA

LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP

EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

114
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPS

1577550L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPDT

QLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLESGVPS

RFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAAPSVFIFP

PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL

SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

115
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1578137H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW

GQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMY

WVRQAPGQGLEWMGWINTETGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDD

TAVYYCARVDYDGSFWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG

CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV

TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK

GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNAYTQKSLSLSPGK

116
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPS

1578137L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRGGSGGG

GSGDTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLE

SGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

117
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE

1598261H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD

YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM

GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP

VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNHYTQKSLSLSPGK

118
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV

1598261L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRGGSGGGGS

GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP

SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

119
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET

1598262H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY

WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG

VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG

CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV

TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK

GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNHYTQKSLSLSPGK

120
PR-
AIQLTQSPSSLSASVGDRVTITCRASESVSTHMHWYQQKPGKAPKLLIYGASNLESGV

1598262L
PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSWNDPFTFGQGTKLEIKRGGSGGGGS

GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP

SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

121
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET

1598263H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY

WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG

VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG

CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV

TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK

GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNHYTQKSLSLSPGK

122
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV

1598263L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRGGSGGGGS

GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP

SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

123
PR-
EIQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET

1598264H
GKPTYADDFKGRFTFTLDTSTSTAYMELRSLRSDDTAVYFCARTNYYYRSYIFYFDY

WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG

VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG

CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV

TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK

GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNHYTQKSLSLSPGK

124
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1598264L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG

SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR

PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

125
PR-
EIQLVQSGTEVKKPGESLKISCKASGYTFTNYGMYWVKQMPGKGLEYMGWINTETG

1598265H
KPTYADDFKGRFTFSLDKSFNTAFLQWSSLKASDTAMYFCARTNYYYRSYIFYFDY

WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG

VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG

CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV

TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK

GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNHYTQKSLSLSPGK

126
PR-
ETVLTQSPATLSVSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG

1598265L
VPARFSGSGSGTDFTLTISSLQSEDFAVYFCQQSWNDPFTFGQGTRLEIKRGGSGGGG

SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR

PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

127
PR-
EIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQAPGKGLEYMGWINTET

1598266H
GKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFCARTNYYYRSYIFYFDY

WGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD

TATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC

LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV

NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT

CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL

NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG

FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNHYTQKSLSLSPGK

128
PR-
DTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGASNLESGV

1598266L
PSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRGGSGGGGS

GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP

SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

129
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET

1610560H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY

WGQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYM

YWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSEDT

AVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALG

CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV

TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK

GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNAYTQKSLSLSPGK

130
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV

1610560L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKGGSGGGGSG

GETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESG

VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPSV

FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST

YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

131
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET

1610561H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA

YWGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG

VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

132
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV

1610561L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG

GEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRA

SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

133
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET

1610562H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA

YWGQGTLVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESY

MYWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSE

DTAVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

134
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV

1610562L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG

GETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESG

VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPSV

FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST

YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

135
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWIDTE

1610563H
TGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDTAVYYCARWSGDTTGIRGPWF

AYWGQGTLVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESY

MYWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSE

DTAVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

136
PR-
DIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV

1610563L
PSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG

GETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESG

VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPSV

FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST

YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

137
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV

1610564H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT

TVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQ

APGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFC

ARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNAYTQKSLSLSPGK

138
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG

1610564L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKGGSGGGGS

GGETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLES

GVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

139
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET

1611291H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY

WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG

VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

140
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV

1611291L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKGGSGGGGSG

GEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRA

SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

141
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV

1611292H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT

TVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQ

PPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYY

CARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNAYTQKSLSLSPGK

142
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG

1611292L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKGGSGGGGS

GGEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQR

ASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

143
PR-
EIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMYWVKQAPGQGLEYMGWINTEA

1611293H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWGYISDNSYGWFDY

WGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD

TATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG

CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV

TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK

GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNAYTQKSLSLSPGK

144
PR-
ATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNLASG

1611293L
VPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKGGSGGGGS

GGEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQR

ASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

145
PR-
EIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMYWVKQAPGQGLEYMGWINTEA

1611294H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWGYISDNSYGWFDY

WGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV

GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD

TATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC

LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV

NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT

CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL

NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG

FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNAYTQKSLSLSPGK

146
PR-
ATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNLASG

1611294L
VPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKGGSGGGGS

GGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ

RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

147
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1611295H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW

GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY

WVKQAPGQGLEYMGWIDTETGRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT

AVYFCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR

TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH

QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNAYTQKSLSLSPGK

148
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS

1611295L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG

SGGDIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQ

NGVPSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

149
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1611296H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW

GQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMY

WVRQAPGQGLEWMGWIDTETGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDT

AVYYCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR

TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH

QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNAYTQKSLSLSPGK

150
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS

1611296L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG

SGGDIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQ

NGVPSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

151
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1611297H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW

GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMY

WVKQAPGQGLEYMGWINTEAGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT

AVYFCARWGYISDNSYGWFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA

LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP

EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

152
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS

1611297L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG

SGGATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNL

ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

153
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1611298H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW

GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY

WVKQAPGQGLEYMGWIDTETGRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT

AVYFCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR

TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH

QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNAYTQKSLSLSPGK

154
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS

1611298L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG

SGGDIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQ

NGVPSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

155
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1611299H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW

GQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMY

WVRQAPGQGLEWMGWIDTETGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDT

AVYYCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR

TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH

QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNAYTQKSLSLSPGK

156
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS

1611299L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG

SGGDIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQ

NGVPSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

157
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1611300H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW

GQGTMVTVSSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMA

WFRQAPGKGLEWVASITTSGVGTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDT

AVYYCARGYGAMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK

PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV

VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK

EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS

DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA

LHNAYTQKSLSLSPGK

158
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS

1611300L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG

SGGDIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRL

ADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

159
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1611301H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW

GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMY

WVKQAPGQGLEYMGWINTEAGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT

AVYFCARWGYISDNSYGWFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA

LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP

EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

160
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS

1611301L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG

SGGATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNL

ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

161
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET

1612489H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY

WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG

VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG

CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV

TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK

GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNAYTQKSLSLSPGK

162
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV

1612489L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKGGSGGGGSG

GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP

SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

163
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET

1612491H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA

YWGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG

VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV

DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG

CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV

TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK

GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNAYTQKSLSLSPGK

164
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV

1612491L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG

GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP

SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

165
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWIDTE

1612492H
TGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDTAVYYCARWSGDTTGIRGPWF

AYWGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM

GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP

VDTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAA

LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP

EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

166
PR-
DIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV

1612492L
PSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG

GEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRA

SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

167
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWIDTE

1612493H
TGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDTAVYYCARWSGDTTGIRGPWF

AYWGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM

GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP

VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

168
PR-
DIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV

1612493L
PSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG

GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP

SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

169
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV

1612494H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT

TVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQ

PPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYY

CARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD

YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP

SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV

DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL

HNAYTQKSLSLSPGK

170
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG

1612494L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKGGSGGGGS

GGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ

RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

171
PR-
EIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMYWVKQAPGQGLEYMGWINTEA

1612495H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWGYISDNSYGWFDY

WGQGTLVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYM

YWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSEDT

AVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALG

CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV

TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK

GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNAYTQKSLSLSPGK

172
PR-
ATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNLASG

1612495L
VPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKGGSGGGGS

GGETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLES

GVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

173
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1612496H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW

GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY

WVRQAPGQGLEYMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT

AVYFCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

174
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS

1612496L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG

SGGATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLE

SGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

175
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1612498H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW

GQGTMVTVSSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMA

WFRQAPGKGLEWVASITTSGVGTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDT

AVYYCARGYGAMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK

PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV

VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK

EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS

DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA

LHNAYTQKSLSLSPGK

176
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS

1612498L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG

SGGDIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRL

ADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

177
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG

1612499H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG

QGTTVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWV

RQAPGQGLEYMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVY

FCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL

VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN

HKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC

VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN

GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF

YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM

HEALHNAYTQKSLSLSPGK

178
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV

1612499L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS

GGATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLES

GVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRTVAAPSV

FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST

YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

179
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG

1612500H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG

QGTTVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWV

KQAPGQGLEYMGWIDTETGRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVY

FCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC

LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV

NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT

CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL

NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG

FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNAYTQKSLSLSPGK

180
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV

1612500L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS

GGDIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLTYNANGLQN

GVPSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

181
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG

1612501H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG

QGTTVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMYW

VRQAPGQGLEWMGWIDTETGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDTA

VYYCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA

LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP

EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

182
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV

1612501L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS

GGDIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLTYNANGLQN

GVPSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

183
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG

1612502H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG

QGTTVTVSSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWF

RQAPGKGLEWVASITTSGVGTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAV

YYCARGYGAMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF

PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN

TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVD

VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY

KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI

AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH

NAYTQKSLSLSPGK

184
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV

1612502L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS

GGDIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLA

DGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

185
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGLEWMGWIDTE

1613183H
TGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRNYMFYF

DYWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG

MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM

DPVDTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGT

AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ

TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS

RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL

HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV

FSCSVMHEALHNAYTQKSLSLSPGK

186
PR-
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILESGV

1613183L
PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKGGSGGGGSG

GEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRA

SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

187
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGLEWMGWIDTE

1613184H
TGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRNYMFYF

DYWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG

MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM

DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR

TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH

QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNAYTQKSLSLSPGK

188
PR-
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILESGV

1613184L
PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKGGSGGGGSG

GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP

SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

189
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGLEWMGWIDTE

1613185H
TGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRNYMFYF

DYWGQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTES

YMYWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRS

EDTAVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAA

LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP

EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

190
PR-
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILESGV

1613185L
PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKGGSGGGGSG

GETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESG

VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPSV

FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST

YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

191
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1613186H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW

GQGTMVTVSSGGGGSGGGGSEVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMY

WVRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT

AVYYCARTNYYYRNYMFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR

TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH

QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNAYTQKSLSLSPGK

192
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS

1613186L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG

SGGEIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILE

SGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

193
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1613187H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW

GQGTMVTVSSGGGGSGGGGSEVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMY

WVRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT

AVYYCARTNYYYRNYMFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR

TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH

QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS

CSVMHEALHNAYTQKSLSLSPGK

194
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS

1613187L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG

SGGEIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILE

SGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

195
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD

1613188H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW

GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY

WVRQAPGQGLEYMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT

AVYFCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC

NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE

VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

196
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS

1613188L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG

SGGATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLE

SGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

197
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG

1613189H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG

QGTTVTVSSGGGGSGGGGSEVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW

VRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTA

VYYCARTNYYYRNYMFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAA

LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI

CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP

EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

VMHEALHNAYTQKSLSLSPGK

198
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV

1613189L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS

GGEIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILES

GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS

TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

199
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG

1613190H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG

QGTTVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMYWV

KQAPGQGLEYMGWINTEAGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAV

YFCARWGYISDNSYGWFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG

CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN

VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV

TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK

GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV

MHEALHNAYTQKSLSLSPGK

200
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV

1613190L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS

GGATQLTQSPSSLSASVGDRQVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNLA

SGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKRTVAAP

SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD

STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

201
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET

1629646H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA

YWGQGTLVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI

RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT

YYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV

VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNAYTQKSLSLSPGK

202
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV

1629646L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAPSVFI

FPPEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQR

ASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAA

PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK

DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

203
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV

1629647H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT

TVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKA

LEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIE

SSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP

VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK

VDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS

HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC

KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV

EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNA

YTQKSLSLSPGK

204
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG

1629647L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAAPSVF

IFPPEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQ

RASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVA

APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS

KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

205
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET

1629648H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA

YWGQGTLVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG

MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM

DPVDTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGT

AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ

TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS

RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL

HQDWLNGKEYKCKVSNKALPAPIEKTIMISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV

FSCSVMHEALHNAYTQKSLSLSPGK

206
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV

1629648L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAPEIVL

TQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRASGIPD

RFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAPSVFIFP

PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL

SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

207
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV

1629649H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT

TVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI

RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT

YYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV

KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH

KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV

VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNAYTQKSLSLSPGK

208
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG

1629649L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAAPEIV

LTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRASGIP

DRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAPSVFI

FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY

SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Example 18
PR-1610561 Cell Lines

Chimeric, humanized, and affinity matured antibodies, and DVD-Ig binding proteins were expressed using pHybE vectors. Transient expression of PR-1610561 in HEK cells was also achieved using a vector similar to pHybE-hCg1,z,non-a,mut(234,235) V2. See U.S. Pat. No. 8,187,836.

CHO cell lines producing PR-1610561 have been generated. The growth and productivity of the CHO cell lines were similar to those of other DVD-Ig molecules. All cell lines passed a screening for acceptable product quality by MS, SEC, and CIEX. CHO cell lines were produced using pBJ and pCD plasmid vectors encoding the amino acid sequences of PR-1610561. See US 2014/0295497.

Example 19
Epitope Binning

Antibodies and binding proteins disclosed herein are tested in a label-free cell-based competition assay in order to determine which antibodies and binding proteins are capable of binding to the same antigen (e.g., VEGF, PDGF, or one of their receptors) simultaneously. If antibodies or binding proteins are not able to bind simultaneously (therefore possibly competing for the same or similar epitope), those antibodies or binding proteins are assigned to the same “epitope bin.” If antibodies or binding proteins are capable of binding simultaneously and therefore do not compete for antigen binding, those antibodies or binding proteins are assigned to different epitope bins.

INCORPORATION BY REFERENCE

The contents of all cited references (including literature references, patents, patent applications, and websites) that maybe cited throughout this application are hereby expressly incorporated by reference in their entirety for any purpose, as are the references cited therein. To the extent those references contradict or are inconsistent with any statements in this application, the text of the application will control. The disclosure will employ, unless otherwise indicated, conventional techniques of immunology, molecular biology and cell biology, and pathology, which are well known in the art.

EQUIVALENTS

The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting of the inventions described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced herein.

	Number	Date	Country
	62291964	Feb 2016	US
	62175546	Jun 2015	US

BINDING PROTEINS AGAINST VEGF, PDGF, AND/OR THEIR RECEPTORS

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