Anti-HIV Antibody 10-1074 Variants

Information

  • Patent Application
  • 20220119504
  • Publication Number
    20220119504
  • Date Filed
    September 12, 2019
    5 years ago
  • Date Published
    April 21, 2022
    2 years ago
Abstract
The present disclosure provides optimized broadly-neutralizing anti-HIV antibodies, having modified light chain variable regions and/or heavy chain variable regions leading to improved biophysical characteristics. The present disclosure also provides methods for producing these anti-HIV antibodies and methods of use thereof.
Description
FIELD OF THE INVENTION

This invention relates generally to broad and potent antibodies against Human Immunodeficiency Virus (“HIV”) and more specifically to anti-HIV antibody 10-1074 variants and the use thereof.


BACKGROUND OF THE INVENTION

HIV causes acquired immunodeficiency syndrome (AIDS), a condition in humans characterized by clinical features including wasting syndromes, central nervous system degeneration and profound immunosuppression that results in life-threatening opportunistic infections and malignancies. Since its discovery in 1981, HIV type 1 (HIV-1) has led to the death of at least 25 million people worldwide. It is predicted that 20-60 million people will become infected over the next two decades even if there is a 2.5% annual decrease in HIV infections. There is a need for therapeutic agents and methods for treatment or inhibition of HIV infection.


Some HIV infected individuals show broadly neutralizing IgG antibodies in their serum. Yet, little is known regarding the specificity and activity of these antibodies, despite their potential importance in designing effective vaccines. In animal models, passive transfer of neutralizing antibodies can contribute to protection against virus challenge. Neutralizing antibody responses also can be developed in HIV-infected individuals, but the detailed composition of the serologic response is yet to be fully uncovered.


SUMMARY OF INVENTION

The present disclosure relates to a new category of broadly-neutralizing anti-HIV antibodies, having modified light chain variable regions and/or heavy chain variable regions leading to improved biophysical characteristics, as well as methods of production and methods of use thereof.


Accordingly, in a first aspect, the present disclosure provides an isolated anti-HIV antibody, or antigen-binding portion thereof, including a light chain variable region having a light chain amino acid sequence that is at least 75% identical to a polypeptide sequence selected from the group consisting of the light chain variable regions of SEQ ID NOs: 3-13, 22, 24-28, 35-39, 43-45, and 47. The isolated anti-HIV antibody, or antigen-binding portion thereof includes one or more light chain substitutions at one or more residues located within or outside the light chain variable region. The one or more residues are selected from the group consisting of LmdV:Y2, LmdV:R7, LmdV:P9, LmdV:E17, LmdV:H46, LmdV:P81.1, LmdV:I81.3, LmdV:N82, LmdV:R88, LmdV:D110, and LmdV:A142.


In another aspect, the present disclosure provides an isolated anti-HIV antibody, or antigen-binding portion thereof, including a heavy chain variable region having a heavy chain amino acid sequence that is at least 75% identical to a polypeptide sequence selected from the group consisting of the heavy chain variable regions of SEQ ID NOs: 61-94. The isolated anti-HIV antibody, or antigen-binding portion thereof includes one or more heavy chain substitutions at one or more residues located within or outside of the heavy chain variable region. The one or more residues are selected from the group consisting of HV:D29, HV:S47, HV:N75, HV:V79, HV:R82, HV:L89, HV:T108, and HV:K141.


In another aspect, the present disclosure provides an isolated anti-HIV antibody, or antigen-binding portion thereof, including a light chain variable region having a light chain amino acid sequence that is at least 75% identical to a polypeptide sequence selected from the group consisting of the light chain variable regions of SEQ ID NOs: 3-13, 22, 24-28, 35-39, 43-45, and 47. The isolated anti-HIV antibody, or antigen-binding portion thereof includes one or more light chain substitutions at one or more residues selected from the group consisting of LmdV:Y2, LmdV:R7, LmdV:P9, LmdV:E17, LmdV:H46, LmdV:P81.1, LmdV:I81.3, LmdV:N82, LmdV:R88, LmdV:D110, and LmdV:A142. The anti-HIV antibody, or antigen-binding portion thereof, further includes a heavy chain variable region having a heavy chain amino acid sequence is at least 75% identical to a polypeptide sequence selected from the group consisting of the heavy chain variable regions of SEQ ID NOs: 61-94. The isolated anti-HIV antibody, or antigen-binding portion thereof includes one or more heavy chain substitutions at one or more residues selected from the group consisting of HV:D29, HV:S47, HV:N75, HV:V79, HV:R82, HV:L89, HV:T108, and HV:K141.


In some embodiments, the isolated anti-HIV antibody, or antigen-binding portion thereof includes the one or more light chain substitutions selected from the group consisting of LmdV:Y2P, LmdV:R7P, LmdV:P9S, LmdV:E17Q, LmdV:H46Q, LmdV:P81.1N, LmdV:I81.3S, LmdV:N82G, LmdV:R88T, LmdV:D110E, and LmdV:A142G or conservative substitutions thereof (i.e., LmdV:P9C, LmdV:P9T, LmdV:E17N, LmdV:H46N, LmdV:P81.1Q, LmdV:R88C, LmdV:R88S).


In some embodiments, the isolated anti-HIV antibody, or antigen-binding portion thereof includes the one or more heavy chain substitutions selected from the group consisting of HV:D29G, HV:S47P, HV:N75Q, HV:V79T, HV:R82V, HV:L89F, HV:T108R, and HV:K141Q or conservative substitutions thereof (i.e., HV:L89W, HV:L89Y, HV:T108H, HV:T108K, HV:K141N).


In some embodiments, the isolated anti-HIV antibody, or antigen-binding portion thereof, includes the one or more light chain substitutions selected from the group consisting of LmdV:Y2P, LmdV:R7P, LmdV:P9S, LmdV:E17Q, LmdV:H46Q, LmdV:P81.1N, LmdV:I81.3S, LmdV:N82G, LmdV:R88T, LmdV:D110E, and LmdV:A142G or conservative substitutions thereof (i.e., LmdV:P9C, LmdV:P9T, LmdV:E17N, LmdV:H46N, LmdV:P81.1Q, LmdV:R88C, LmdV:R88S) and the one or more heavy chain substitutions selected from the group consisting of HV:D29G, HV:S47P, HV:N75Q, HV:V79T, HV:R82V, HV:L89F, HV:T108R, and HV:K141Q or conservative substitutions thereof (i.e., HV:L89W, HV:L89Y, HV:T108H, HV:T108K, HV:K141N).


In some embodiments, the light chain amino acid sequence is at least 75% identical to the light chain variable region of SEQ ID NO.: 3 and includes a LmdV:Y2P substitution or a conservative substitution of proline at LmdV:Y2.


In some embodiments, the heavy chain amino acid sequence is at least 75% identical to to the heavy chain variable region of SEQ ID NO.: 63 and includes an HV:V79T substitution or a conservative substitution of threonine at HV:V79.


In some embodiments, the heavy chain amino acid sequence is at least 75% identical to to the heavy chain variable region of SEQ ID NO.: 64 and includes an HV:R82V substitution or a conservative substitution of valine at HV:R82.


In some embodiments, the heavy chain amino acid sequence is at least 75% identical to to the heavy chain variable region of SEQ ID NO.: 65 and includes an HV:L89F substitution or a conservative substitution of phenylalanine of HV:L89.


In some embodiments, the heavy chain amino acid sequence is at least 75% identical to to the heavy chain variable region of SEQ ID NO.: 66 and includes an HV:T108R substitution or a conservative substitution of arginine at HV:T108.


In some embodiments, the light chain amino acid sequence is at least 75% identical to the light chain variable region of SEQ ID NO.: 22 and includes a LmdV:Y2P substitution or a conservative substitution of proline at LmdV:Y2, and the heavy chain amino acid sequence is at least 75% identical to the heavy chain variable region of SEQ ID NO.: 69 and includes an HV:R82V substitution or a conservative substitution of valine at HV:R82, and an HV:T108R substitution or a conservative substitution of arginine at HV:T108.


In some embodiments, the heavy chain amino acid sequence is at least 75% identical to the heavy chain variable region of SEQ ID NO.: 70 and includes an HV:V79T substitution or a conservative substitutions of threonine at HV:V79, an HV:L89F substitution or a conservative substitution of phenylalanine at HV:L89, and an HV:T108R substitution or a conservative substitution of arginine at HV:T108.


In some embodiments, the light chain amino acid sequence is at least 75% identical to the light chain variable region of SEQ ID NO.: 24 and comprises a LmdV:Y2P substitution or a conservative substitution of proline at LmdV:Y2, and the heavy chain amino acid sequence is at least 75% identical to the heavy chain variable region of SEQ ID NO.: 71 and includes an HV:V79T substitution or a conservative substitution of threonine at HV:V79, an HV:L89F substitution or a conservative substitution of phenylalanine at HV:L89, and an HV:T108R substitution or a conservative substitution of arginine at HV:T108.


In some embodiments, the isolated anti-HIV antibody, or antigen-binding portion thereof includes SEQ NO.: 3. In some embodiments, the isolated anti-HIV antibody, or antigen-binding portion thereof includes SEQ NO.: 63, 64, 65, 66, or 70. In some embodiments, the light chain variable region includes the light chain variable region of SEQ NO.: 22 and the heavy chain variable region includes the heavy chain variable region of SEQ No.: 69. In some embodiments, the light chain variable region includes the light chain variable region of SEQ NO.: 24 and the heavy chain variable region includes the heavy chain variable region of SEQ No.: 71.


In another aspect, the present disclosure also provides a pharmaceutical composition having the above-presented anti-HIV antibody or antigen-binding portion and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition further includes a second therapeutic agent. In some embodiments, the second therapeutic agent is an anti-HIV-1 broadly neutralizing antibody, such as 3BNC117.


In another aspect, the present disclosure additionally provides a nucleic acid, or a codon-optimized nucleic acid, encoding the above-presented anti-HIV antibody or antigen-binding portion thereof. Also provided is a vector or vector system having at least one above-presented nucleic acid and a cell having at least one above-presented nucleic acid.


In another aspect, the present disclosure provides a method of making recombinant anti-HIV antibody, or antigen-binding portion thereof. The method includes, among others, obtaining the cultured cell mentioned above, culturing the cell in a medium under conditions permitting expression of a polypeptide encoded by the vector and assembling of an antibody or fragment thereof, and purifying the antibody or fragment from the cultured cell or the medium of the cell.


In another aspect, the present disclosure provides a method of preventing or treating an HIV infection or an HIV-related disease. The method includes, among others, identifying a patient in need of such prevention or treatment, and administering to said patient a first therapeutic agent having a therapeutically effective amount of at least one above presented anti-HIV antibody of or an antigen-binding portion thereof. The method can further include administering a second therapeutic agent. The second therapeutic agent can be administered before, concurrently with or after the administration of the anti-HIV antibody or antigen-binding portion thereof. In some embodiments, the second therapeutic agent is an anti-HIV-1 broadly neutralizing antibody, such as 3BNC117.


In another aspect, the present disclosure further provides a kit having a pharmaceutically acceptable dose unit of a pharmaceutically effective amount of at least one isolated anti-HIV antibody presented above or antigen-binding portion thereof. The kit can further include a pharmaceutically acceptable dose unit of a pharmaceutically effective amount of an anti-HIV agent. The two pharmaceutically acceptable dose units can optionally take the form of a single pharmaceutically acceptable dose unit. An exemplary anti-HIV agent can be selected from the group consisting of a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, an entry or fusion inhibitor, and an integrase inhibitor. In some embodiments, the anti-HIV agent is an anti-HIV broadly neutralizing antibody, such as 3BNC117.


The foregoing summary is not intended to define every aspect of the disclosure, and additional aspects are described in other sections, such as the following detailed description. The entire document is intended to be related as a unified disclosure, and it should be understood that all combinations of features described herein are contemplated, even if the combination of features are not found together in the same sentence, or paragraph, or section of this document. Other features and advantages of the invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the disclosure, are given by way of illustration only, because various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.





BRIEF DESCRIPTION OF THE DRAWINGS


FIGS. 1A and 1B (collectively “FIG. 1”) show the characterization of anti-HIV antibody 10-1074 variants MS-194 (FIG. 1A) and MS-203 (FIG. 1B) by high-performance size exclusion chromatography (“HP-SEC”) before and after viral neutralization. Peaks in the HP-SEC profiles corresponding to the oligomeric species formed during viral inactivation are indicated by arrows.



FIG. 2 shows quantification of the degree of aggregation represented by the level of high molecular weight (“HMW”) and oligomeric species following each of the purification steps for the 10-1074 antibody variants MS-194, MS-200, MS-201, and MS-203.



FIG. 3 shows the level of HMW during incubation at 40° C. for up to 13 weeks for the 10-1074 antibody variants MS-194, MS-200, MS-201, and MS-203.



FIG. 4 shows the level of sub-visible particle formation during 6 weeks and 13 weeks for the 10-1074 antibody variants MS-194, MS-200, MS-201, and MS-203.



FIGS. 5A, 5B, and 5C (collectively “FIG. 5”) show delayed viral rebound with 3BNC117 and 10-1074 combination therapy during analytical treatment interruption (ATI). FIG. 5A shows the study design of the Phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during ATI. Red and blue triangles represent 3BNC117 and 10-1074 infusions, respectively. FIG. 5B shows plasma HIV-1 RNA levels (black; left y-axis) and bNAb serum concentrations (3BNC117, red; 10-1074, blue; right y-axis) in the 9 bNAb-sensitive participants (left) and the 2 participants with pre-existing resistance against one of the antibodies (right). Red and blue triangles indicate 3BNC117 and 10-1074 infusions, respectively. Serum antibody concentrations were determined by TZM-bl assay. Grey shaded areas indicate time on ART. Lower limit of detection of HIV-1 RNA was 20 copies/ml. FIG. 5C shows Kaplan-Meier plots summarizing time to viral rebound for the participants with HIV-1 RNA<20 copies/ml 2 weeks before and at the start of ATI (n=11, left), for the participants sensitive to both antibodies (n=9, center), and for the participants that showed pre-existing resistance to one of the antibodies (n=2, right). Y-axis indicates percentage of participants that maintain viral suppression. X-axis indicates weeks after start of ATI. Participants receiving the combination of 3BNC117+10-1074 are indicated by the blue line. Dotted red lines indicate a cohort of individuals receiving 3BNC117 alone during ATI (n=13) and dotted black lines indicate a cohort of participants who underwent ATI without intervention (n=52).



FIGS. 6A, 6B, 6C, 6D, 6E, and 6F (collectively “FIG. 6”) show demographics, CD4+ T cells during study period in participants and pharamacokinetics of 3BNC117 and 10-1074. FIG. 6A is a table showing baseline participant demographics. *NNRTI—Non-nucleoside reverse transcriptase inhibitor. FIG. 6B shows absolute CD4+ T cell counts and percentage of CD4+ T cells among CD3+ T cells at screening (n=15), day 0 (n=15), at the time of viral rebound (n=13) and at the end of the study are shown (n=15) (see also Supplementary Table 2). The last available time point after resuppression was used as end of the study time point for the participants that reinitiated ART. Red lines indicate mean, and error bars indicate standard deviation. P values were obtained using a two-tailed paired t-test comparing CD4+ T cell counts between day 0 and the time of viral rebound. FIGS. 6C and 6D show 3BNC117 (red) and 10-1074 (blue) levels in serum (n=15) as determined by TZM-bl assay (FIG. 6C) and ELISA (FIG. 6D). Curves indicate mean serum antibody concentrations and error bars represent standard deviation. Red and blue triangles indicate 3BNC117 and 10-1074 infusions, respectively. In the TZM-bl assay, lower limits of detection were 0.46 μg/ml and 0.01 μg/ml for 3BNC117 and 10-1074, respectively (FIG. 6C). In the ELISA, lower limits of detection were 0.78 μg/ml and 0.41 μg/ml, respectively (FIG. 6D). In cases where participants only received 2 infusions due to early viral rebound (9245, 9249 and 9253), only antibody concentrations up to the second infusion were included. The half-life of each bNAb is indicated in days. FIGS. 6E and 6F show half-lives of both antibodies as measured by TZM-bl assay (FIG. 6E) and ELISA (FIG. 6F). Each dot represents a single participant. The half-lives of both antibodies from the 15 participants enrolled in the study are represented. Black lines indicate the mean value and standard deviation (n=15). P values were obtained using a two-tailed unpaired t-test comparing the two antibodies.



FIGS. 7A, 7B, and 7C (collectively “FIG. 7”) show amino acid variants at 10-1074 contact sites and bNAb sensitivity of reactivated latent and rebound viruses. FIG. 7A is a set of charts showing Env contact sites of 10-1074 at the G(D/N)IR motif (positions 324-327, according to HXB2 numbering) and the glycan at the potential N-linked glycosylation site at position 332 (N×S/T motif at positions 332-334). The diagram shows the 7 bNAb-sensitive participants that rebounded before week 30 (left) and the 2 individuals with preexisting resistance to one of the 2 antibodies (right). LR indicates latent reservoir viruses isolated by Q2VOA, and RB indicates rebound viruses isolated by SGA (plasma) or viral outgrowth (PBMCs). Each amino acid is represented by a color, and the frequency of each amino acid is indicated by the height of the rectangle. Shaded rectangles indicate the lack of variation between latent reservoir virus and rebound virus at the indicated position. Full-color rectangles represent amino acid residues with changes in distribution between reservoir and rebound viruses. FIGS. 7B and 7C are dot plots indicating IC80 (μg/ml) of 3BNC117 (FIG. 7B, left panel) and 10-1074 (FIG. 7C, right panel) against latent and rebound viruses determined by TZM-bl neutralization assay. Q2VOA-derived latent viruses from week −2 and week 12 are shown as black and grey circles, respectively. For outgrowth culture-derived rebound viruses, the highest IC80 determined is shown as red circle. For 9246, 9252, 9245 and 9251 viruses could not be obtained from rebound outgrowth cultures and pseudoviruses were made from env sequences from Q2VOA and plasma SGA.



FIG. 8 shows a comparison of the circulating latent reservoir and rebound viruses. Maximum likelihood phylogenetic trees of full-length env sequences of viruses isolated from Q2VOA, rebound plasma SGA, and rebound PBMC outgrowth cultures from 3 out of 7 participants (9242, 9243 and 9252) that rebounded before week 30. Open and closed black rectangles indicate Q2VOA-derived viruses from week −2 and week 12, respectively. Viruses obtained at the time of rebound are indicated by red rectangles (plasma SGA) and red stars (rebound PBMC outgrowth cultures). Asterisks indicate nodes with significant bootstrap values (bootstrap support ≥70%). Boxes indicate IC80s (μg/ml) of 3BNC117 and 10-1074 against representative viruses throughout the phylogenetic tree and clones, when possible. Asterisks in boxes indicate IC100 values of >50 μg/ml.



FIGS. 9A and 9B (collectively “FIG. 9”) show distribution of the circulating latent reservoir and rebound viruses. FIG. 9A is a set of Venn diagrams showing sequence identity between env sequences obtained from Q2VOA at week −2 (blue) and week 12 (grey), and plasma SGA or rebound PBMC outgrowth culture at the time of viral rebound (red). Area of overlap is proportional to the number of identical sequences. Number of sequences obtained is indicated. FIG. 9B shows infectious units per million (IUPM) CD4+ T cells at weeks −2 and 12 as determined by Q2VOA. Participants with IUPMs higher and lower than 0.1 are shown on the top and bottom, respectively. The 2 time points were not statistically different (P=0.078 (paired t-test)).





DETAILED DESCRIPTION OF THE INVENTION

This disclosure is based, at least in part, on an unexpected discovery of a new category of broadly neutralizing antibodies (bNAbs) against HIV that can recognize carbohydrate-dependent epitopes, including complex-type N-glycan, on gp120.


Antibodies are essential for the success of most vaccines, and antibodies against HIV appear to be the only correlate of protection in the recent RV144 anti-HIV vaccine trial. Some HIV-1 infected patients develop broadly neutralizing serologic activity against the gp160 viral spike 2-4 years after infection, but these antibodies do not generally protect infected humans because autologous viruses escape through mutation. Nevertheless, broadly neutralizing activity puts selective pressure on the virus and passive transfer of broadly neutralizing antibodies (bNAbs) to macaques protects against SHIV infection. It has therefore been proposed that vaccines that elicit such antibodies may be protective against HIV infection in humans.


The development of single cell antibody cloning techniques revealed that bNAbs target several different epitopes on the HIV-1 gp160 spike. The most potent HIV-1 bNAbs recognize the CD4 binding site (CD4bs) (Science 333(6049):1633-1637; Nature 477(7365):466-470; Science 334(6060):1289-1293) and carbohydrate-dependent epitopes associated with the variable loops (Nature 477(7365):466-470; Science 326(5950):285-289; Science 334(6059):1097-1103; Nature 480(7377):336-343), including the V1/V2 (PG9/PG16) (Science 326(5950):285-289) and V3 loops (PGTs) (Nature 477(7365):466-470). Less is known about carbohydrate-dependent epitopes because the antibodies studied to date are either unique examples or members of small clonal families.


To better understand the neutralizing antibody response to HIV-1 and the epitope targeted by PGT antibodies, members of a large clonal family dominating the gp160-specific IgG memory response from the clade A-infected patient who produced PGT121 have been isolated. The isolation of PGT121 is described in greater details in PCT/US13/65696. PGT121 antibodies can be divided into two groups, a PGT121-like and a 10-1074-like group, according to sequence, binding affinity, neutralizing activity and recognition of carbohydrates and the V3 loop. 10-1074 and related family members exhibit unusual potent neutralization, including broad reactivity against newly-transmitted viruses. Unlike previously-characterized carbohydrate-dependent bNAbs, PGT121 binds to complex-type, rather than high-mannose, N-glycans in glycan microarray experiments. The 10-1074 group exhibits remarkable potency and breadth despite not binding detectably to protein-free glycans. Crystal structures of un-liganded PGT121, 10-1074, and their germline precursor reveal that differential carbohydrate recognition maps to a cleft between CDRH2 and CDRH3, which was occupied by a complex-type N-glycan in a separate PGT121 structure. Swapping glycan contact residues between PGT121 and 10-1074 confirmed the importance of these residues in neutralizing activities.


Because the biophysical stability of monoclonal antibodies is an important determinant of their usefulness and commercial value, this disclosure presents the processes to optimize biophysical characteristics of the 10-1074 broadly neutralizing antibody. For example, a series of substitutions were carried out to identify potentially destabilizing residues in the Fv region of the 10-1074 broadly neutralizing antibody. These residues may, by themselves or in combination, lead to instability at low pH, increase susceptibility to chemical degradation, or lead to aggregation during production or long-term storage. Based on this analysis, a series of variants are designed for maintaining potency while optimizing desired characteristics using combinatorial residue replacement techniques. The optimization process is divided into different stages with the first being identification of single residues in the framework region which are potentially responsible for destabilization. Specifically, anti-HIV 10-1074 antibody variants (shown in Tables 2-7 and 9) were produced by transient expression, each containing a single residue modification of the identified amino acids. The variants were characterized for retention of neutralization activity and for desired biophysical characteristics as shown in Tables 8-16. Five distinct amino acid residues, LmdV:Y2, HV:V79, HV:R82, HV:L89, and HV:T108, were identified that showed an increase in desirable biophysical characteristics and did not impact neutralization. The residues were used to produce a library of variants (shown in Tables 2-7 and 12) encompassing all possible combinations of the five amino acids. The variants were again produced by transient expression, and the purified combinatorial variants were analyzed for retention of neutralization activity and desired biophysical characteristics. From the combinatorial library three variants, MS-200, MS-201, and MS-202 were identified for more in-depth analysis including expression, purification, and storage stability to identify combinatorial variants with optimized characteristics which included increased thermal stability, increased resistance to chemical unfolding, increased solubility, and increased resistance to aggregation during storage.


Isolated Anti-HIV Antibodies, Pharmaceutical Compositions, and Kits


Accordingly, in one aspect, this disclosure provides an isolated anti-HIV antibody, or antigen-binding portion thereof, including a light chain variable region having a light chain amino acid sequence that is at least 75% (i.e., 80%, 85%, 90%, 95%, 97%, 98%, 99%) identical to a polypeptide sequence selected from the group consisting of the light chain variable regions of SEQ ID NOs: 3-13, 22, 24-28, 35-39, 43-45, and 47 (Table 2). The isolated anti-HIV antibody, or antigen-binding portion thereof may include one or more light chain substitutions at one or more residues located within or outside the light chain variable region. The residues for substitution are can be one or more of LmdV:Y2, LmdV:R7, LmdV:P9, LmdV:E17, LmdV:H46, LmdV:P81.1, LmdV:I81.3, LmdV:N82, LmdV:R88, LmdV:D110, and LmdV:A142.


Also provided is an isolated anti-HIV antibody, or antigen-binding portion thereof, including a heavy chain variable region having a heavy chain amino acid sequence that is at least 75% (i.e., 80%, 85%, 90%, 95%, 97%, 98%, 99%) identical to a polypeptide sequence selected from the group consisting of the heavy chain variable regions of SEQ ID NOs: 61-94 (Table 3). The isolated anti-HIV antibody, or antigen-binding portion thereof includes one or more heavy chain substitutions at one or more residues located within or outside of the heavy chain variable region. The residues for substitution can be one or more of HV:D29, HV:S47, HV:N75, HV:V79, HV:R82, HV:L89, HV:T108, and HV:K141.


In another aspect, the present disclosure provides an isolated anti-HIV antibody, or antigen-binding portion thereof, including a light chain variable region having a light chain amino acid sequence that is at least 75% (i.e., 80%, 85%, 90%, 95%, 97%, 98%, 99%) identical to a polypeptide sequence selected from the group consisting of the light chain variable regions of SEQ ID NOs: 3-13, 22, 24-28, 35-39, 43-45, and 47 (Table 2). The isolated anti-HIV antibody, or antigen-binding portion thereof includes one or more light chain substitutions at one or more residues of LmdV:Y2, LmdV:R7, LmdV:P9, LmdV:E17, LmdV:H46, LmdV:P81.1, LmdV:I81.3, LmdV:N82, LmdV:R88, LmdV:D110, and LmdV:A142. The anti-HIV antibody, or antigen-binding portion thereof, further includes a heavy chain variable region having a heavy chain amino acid sequence is at least 75% (i.e., 80%, 85%, 90%, 95%, 97%, 98%, 99%) identical to a polypeptide sequence selected from the group consisting of the heavy chain variable regions of SEQ ID NOs: 61-94 (Table 3). The isolated anti-HIV antibody, or antigen-binding portion thereof includes one or more heavy chain substitutions at one or more residues of HV:D29, HV:S47, HV:N75, HV:V79, HV:R82, HV:L89, HV:T108, and HV:K141.


In some embodiments, the isolated anti-HIV antibody, or antigen-binding portion thereof includes the one or more light chain substitutions of LmdV:Y2P, LmdV:R7P, LmdV:P9S, LmdV:E17Q, LmdV:H46Q, LmdV:P81.1N, LmdV:I81.3S, LmdV:N82G, LmdV:R88T, LmdV:D110E, and LmdV:A142G or conservative substitutions thereof (i.e., LmdV:P9C, LmdV:P9T, LmdV:E17N, LmdV:H46N, LmdV:P81.1Q, LmdV:R88C, LmdV:R88S).


In some embodiments, the isolated anti-HIV antibody, or antigen-binding portion thereof includes the one or more heavy chain substitutions of HV:D29G, HV:S47P, HV:N75Q, HV:V79T, HV:R82V, HV:L89F, HV:T108R, and HV:K141Q or conservative substitutions thereof (i.e., HV:L89W, HV:L89Y, HV:T108H, HV:T108K, HV:K141N).


In some embodiments, the isolated anti-HIV antibody, or antigen-binding portion thereof, includes the one or more light chain substitutions of LmdV:Y2P, LmdV:R7P, LmdV:P9S, LmdV:E17Q, LmdV:H46Q, LmdV:P81.1N, LmdV:I81.3S, LmdV:N82G, LmdV:R88T, LmdV:D110E, and LmdV:A142G or conservative substitutions thereof (i.e., LmdV:P9C, LmdV:P9T, LmdV:E17N, LmdV:H46N, LmdV:P81.1Q, LmdV:R88C, LmdV:R88S) and the one or more heavy chain substitutions of HV:D29G, HV:S47P, HV:N75Q, HV:V79T, HV:R82V, HV:L89F, HV:T108R, and HV:K141Q or conservative substitutions thereof (i.e., HV:L89W, HV:L89Y, HV:T108H, HV:T108K, HV:K141N).


In some embodiments, the light chain amino acid sequence is at least 75% (i.e., 80%, 85%, 90%, 95%, 97%, 98%, 99%) identical to the light chain variable region of SEQ ID NO.: 3 and includes a LmdV:Y2P substitution or a conservative substitution of proline at LmdV:Y2.


In some embodiments, the heavy chain amino acid sequence is at least 75% (i.e., 80%, 85%, 90%, 95%, 97%, 98%, 99%) identical to the heavy chain variable region of SEQ ID NO.: 63 and includes an HV:V79T substitution or a conservative substitution of threonine at HV:V79.


In some embodiments, the heavy chain amino acid sequence is at least 75% (i.e., 80%, 85%, 90%, 95%, 97%, 98%, 99%) identical to the heavy chain variable region of SEQ ID NO.: 64 and includes an HV:R82V substitution or a conservative substitution of valine at HV:R82.


In some embodiments, the heavy chain amino acid sequence is at least 75% (i.e., 80%, 85%, 90%, 95%, 97%, 98%, 99%) identical to the heavy chain variable region of SEQ ID NO.: 65 and includes an HV:L89F substitution or a conservative substitution of phenylalanine of HV:L89.


In some embodiments, the heavy chain amino acid sequence is at least 75% (i.e., 80%, 85%, 90%, 95%, 97%, 98%, 99%) identical to the heavy chain variable region of SEQ ID NO.: 66 and includes an HV:T108R substitution or a conservative substitution of arginine at HV:T108.


In some embodiments, the light chain amino acid sequence is at least 75% (i.e., 80%, 85%, 90%, 95%, 97%, 98%, 99%) identical to the light chain variable region of SEQ ID NO.: 22 and includes a LmdV:Y2P substitution or a conservative substitution of proline at LmdV:Y2, and the heavy chain amino acid sequence is at least 75% (i.e., 80%, 85%, 90%, 95%, 97%, 98%, 99%) identical to the heavy chain variable region of SEQ ID NO.: 69 and includes an HV:R82V substitution or a conservative substitution of valine at HV:R82, and an HV:T108R substitution or a conservative substitution of arginine at HV:T108.


In some embodiments, the heavy chain amino acid sequence is at least 75% (i.e., 80%, 85%, 90%, 95%, 97%, 98%, 99%) identical to the heavy chain variable region of SEQ ID NO.: 70 and includes an HV:V79T substitution or a conservative substitutions of threonine at HV:V79, an HV:L89F substitution or a conservative substitution of phenylalanine at HV:L89, and an HV:T108R substitution or a conservative substitution of arginine at HV:T108.


In some embodiments, the light chain amino acid sequence is at least 75% (i.e., 80%, 85%, 90%, 95%, 97%, 98%, 99%) identical to the light chain variable region of SEQ ID NO.: 24 and comprises a LmdV:Y2P substitution or a conservative substitution of proline at LmdV:Y2, and the heavy chain amino acid sequence is at least 75% (i.e., 80%, 85%, 90%, 95%, 97%, 98%, 99%) identical to the heavy chain variable region of SEQ ID NO.: 71 and includes an HV:V79T substitution or a conservative substitution of threonine at HV:V79, an HV:L89F substitution or a conservative substitution of phenylalanine at HV:L89, and an HV:T108R substitution or a conservative substitution of arginine at HV:T108.


In some embodiments, the isolated anti-HIV antibody, or antigen-binding portion thereof includes SEQ NO.: 3. In some embodiments, the isolated anti-HIV antibody, or antigen-binding portion thereof includes SEQ NO.: 63, 64, 65, 66, or 70. In some embodiments, the light chain variable region includes the light chain variable region of SEQ NO.: 22 and the heavy chain variable region includes the heavy chain variable region of SEQ No.: 69. In some embodiments, the light chain variable region includes the light chain variable region of SEQ NO.: 24 and the heavy chain variable region includes the heavy chain variable region of SEQ No.: 71.


Variable domain residue positions are numbered according to the AHo (Honegger, A., & Plückthun, A. (2001). Journal of Molecular Biology, 309(3), 657-70.) structure-based numbering system. An exemplary residue numbering of variable domains of MS-194 is shown in Table 1. The abbreviations used in Table 1 are described as follows. “Ldr” refers leader sequence (e.g., AKA signal sequence or signal peptide). “Mat. Linear” refers to the linear number of the mature form of protein chains. “LmdV” refers variable regions in light chains which are of the lambda type.


The term “antibody” (Ab) as used herein includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (for example, bispecific antibodies and polyreactive antibodies), and antibody fragments. Thus, the term “antibody” as used in any context within this specification is meant to include, but not be limited to, any specific binding member, immunoglobulin class and/or isotype (e.g., IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgD, IgE and IgM); and biologically relevant fragment or specific binding member thereof, including but not limited to Fab, F(ab′)2, Fv, and scFv (single chain or related entity). It is understood in the art that an antibody is a glycoprotein having at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen-binding portion thereof. A heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (CH1, CH2, and CH3). A light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The variable regions of both the heavy and light chains comprise framework regions (FWR) and complementarity determining regions (CDR). The four FWR regions are relatively conserved while CDR regions (CDR1, CDR2, and CDR3) represent hypervariable regions and are arranged from NH2 terminus to the COOH terminus as follows: FWR1, CDR1, FWR2, CDR2, FWR3, CDR3, and FWR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen while, depending on the isotype, the constant region(s) may mediate the binding of the immunoglobulin to host tissues or factors.


Also included in the definition of “antibody” as used herein are chimeric antibodies, humanized antibodies, and recombinant antibodies, human antibodies generated from a transgenic non-human animal, as well as antibodies selected from libraries using enrichment technologies available to the artisan.


The term “variable” refers to the fact that certain segments of the variable (V) domains differ extensively in sequence among antibodies. The V domain mediates antigen-binding and defines specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the amino acid span of the variable regions. Instead, the V regions consist of relatively invariant stretches called framework regions (FRs) of 15-30 amino acids separated by shorter regions of extreme variability called “hypervariable regions” that may be 9-12 amino acids long. The variable regions of native heavy and light chains each comprise four FRs, largely adopting a beta-sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the beta-sheet structure. The hypervariable regions in each chain are held together in close proximity by the FRs and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, for example, Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).


The term “hypervariable region” as used herein refers to the amino acid residues of an antibody that are responsible for antigen binding. The hypervariable region generally comprises amino acid residues from a “complementarity determining region” (“CDR”).


The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. The term “polyclonal antibody” refers to preparations that include different antibodies directed against different determinants (“epitopes”).


The monoclonal antibodies herein include “chimeric” antibodies in which a portion of the heavy and/or light chain is identical with, or homologous to, corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with, or homologous to, corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see, for example, U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). The described invention provides variable region antigen-binding sequences derived from human antibodies. Accordingly, chimeric antibodies of primary interest herein include antibodies having one or more human antigen-binding sequences (for example, CDRs) and containing one or more sequences derived from a non-human antibody, for example, an FR or C region sequence. In addition, chimeric antibodies included herein are those comprising a human variable region antigen-binding sequence of one antibody class or subclass and another sequence, for example, FR or C region sequence, derived from another antibody class or subclass.


A “humanized antibody” generally is considered to be a human antibody that has one or more amino acid residues introduced into it from a source that is non-human. These non-human amino acid residues often are referred to as “import” residues, which typically are taken from an “import” variable region. Humanization may be performed following the method of Winter and co-workers (see, for example, Jones et al., Nature, 321:522-525 (1986); Reichmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting import hypervariable region sequences for the corresponding sequences of a human antibody. Accordingly, such “humanized” antibodies are chimeric antibodies (see, for example, U.S. Pat. No. 4,816,567), where substantially less than an intact human variable region has been substituted by the corresponding sequence from a non-human species.


An “antibody fragment” comprises a portion of an intact antibody, such as the antigen-binding or variable region of the intact antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab′, F(ab′)2, and Fv fragments; diabodies; linear antibodies (see, for example, U.S. Pat. No. 5,641,870; Zapata et al., Protein Eng. 8(10): 1057-1062 [1995]); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.


“Fv” is the minimum antibody fragment that contains a complete antigen-recognition and antigen-binding site. This fragment contains a dimer of one heavy- and one light-chain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable regions (three loops each from the H and L chain) that contribute the amino acid residues for antigen-binding and confer antigen-binding specificity to the antibody. However, even a single variable region (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.


“Single-chain Fv” (“sFv” or “scFv”) are antibody fragments that comprise the VH and VL antibody domains connected into a single polypeptide chain. The sFv polypeptide can further comprise a polypeptide linker between the VH and VL domains that enables the sFv to form the desired structure for antigen binding. For a review of sFv, see, for example, Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994); Borrebaeck 1995, infra.


The term “diabodies” refers to small antibody fragments prepared by constructing sFv fragments with short linkers (about 5-10 residues) between the VH and VL domains such that inter-chain but not the intra-chain pairing of the V domains is achieved, resulting in a bivalent fragment, i.e., fragment having two antigen-binding sites. Bispecific diabodies are heterodimers of two “crossover” sFv fragments in which the VH and VL domains of the two antibodies are present on different polypeptide chains. Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).


Domain antibodies (dAbs), which can be produced in fully human form, are the smallest known antigen-binding fragments of antibodies, ranging from about 11 kDa to about 15 kDa. DAbs are the robust variable regions of the heavy and light chains of immunoglobulins (VH and VL, respectively). They are highly expressed in microbial cell culture, show favorable biophysical properties including, for example, but not limited to, solubility and temperature stability, and are well suited to selection and affinity maturation by in vitro selection systems such as, for example, phage display. DAbs are bioactive as monomers and, owing to their small size and inherent stability, can be formatted into larger molecules to create drugs with prolonged serum half-lives or other pharmacological activities. Examples of this technology have been described in, for example, WO9425591 for antibodies derived from Camelidae heavy chain Ig, as well in US20030130496 describing the isolation of single domain fully human antibodies from phage libraries.


Fv and sFv are the only species with intact combining sites that are devoid of constant regions. Thus, they are suitable for reduced nonspecific binding during in vivo use. sFv fusion proteins can be constructed to yield fusion of an effector protein at either the amino or the carboxy terminus of an sFv. See, for example, Antibody Engineering, ed. Borrebaeck, supra. The antibody fragment also can be a “linear antibody,” for example, as described in U.S. Pat. No. 5,641,870 for example. Such linear antibody fragments can be monospecific or bispecific.


In certain embodiments, antibodies of the described invention are bispecific or multispecific. Bispecific antibodies are antibodies that have binding specificities for at least two different epitopes. Exemplary bispecific antibodies can bind to two different epitopes of a single antigen. Other such antibodies can combine a first antigen-binding site with a binding site for a second antigen. Alternatively, an anti-HIV arm can be combined with an arm that binds to a triggering molecule on a leukocyte, such as a T-cell receptor molecule (for example, CD3), or Fc receptors for IgG (Fc gamma R), such as Fc gamma RI (CD64), Fc gamma RII (CD32) and Fc gamma RIII (CD16), so as to focus and localize cellular defense mechanisms to the infected cell. Bispecific antibodies also can be used to localize cytotoxic agents to infected cells. Bispecific antibodies can be prepared as full-length antibodies or antibody fragments (for example, F(ab′)2 bispecific antibodies). For example, WO 96/16673 describes a bispecific anti-ErbB2/anti-Fc gamma RIII antibody and U.S. Pat. No. 5,837,234 discloses a bispecific anti-ErbB2/anti-Fc gamma RI antibody. For example, a bispecific anti-ErbB2/Fc alpha antibody is reported in WO98/02463; U.S. Pat. No. 5,821,337 teaches a bispecific anti-ErbB2/anti-CD3 antibody. See also, for example, Mouquet et al., Polyreactivity Increases The Apparent Affinity Of Anti-HIV Antibodies By Heteroligation. Nature. 467, 591-5 (2010), and Mouquet et al., Enhanced HIV-1 neutralization by antibody heteroligation” Proc Natl Acad Sci USA. 2012 Jan. 17; 109(3):875-80.


Methods for making bispecific antibodies are known in the art. Traditional production of full-length bispecific antibodies is based on the co-expression of two immunoglobulin heavy chain-light chain pairs, where the two chains have different specificities (see, for example, Millstein et al., Nature, 305:537-539 (1983)). Similar procedures are disclosed in, for example, WO 93/08829, Traunecker et al., EMBO J., 10:3655-3659 (1991) and see also Mouquet et al., Enhanced HIV-1 neutralization by antibody heteroligation” Proc Natl Acad Sci USA. 2012 Jan. 17; 109(3):875-80.


Alternatively, antibody variable regions with the desired binding specificities (antibody-antigen combining sites) are fused to immunoglobulin constant domain sequences. The fusion is with an Ig heavy chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. According to some embodiments, the first heavy-chain constant region (CH1) containing the site necessary for light chain bonding, is present in at least one of the fusions. DNAs encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors and are co-transfected into a suitable host cell. This provides for greater flexibility in adjusting the mutual proportions of the three polypeptide fragments in embodiments when unequal ratios of the three polypeptide chains used in the construction provide the optimum yield of the desired bispecific antibody. It is, however, possible to insert the coding sequences for two or all three polypeptide chains into a single expression vector when the expression of at least two polypeptide chains in equal ratios results in high yields or when the ratios have no significant effect on the yield of the desired chain combination.


Techniques for generating bispecific antibodies from antibody fragments also have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. For example, Brennan et al., Science, 229: 81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab′)2 fragments. These fragments are reduced in the presence of the dithiol complexing agent, sodium arsenite, to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab′ fragments generated then are converted to thionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives then is reconverted to the Fab′-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab′-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.


Other modifications of the antibody are contemplated herein. For example, the antibody can be linked to one of a variety of nonproteinaceous polymers, for example, polyethylene glycol, polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol. The antibody also can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example, hydroxymethyl cellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively), in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), or in macroemulsions. Such techniques are disclosed in, for example, Remington's Pharmaceutical Sciences, 16th edition, Oslo, A., Ed., (1980).


Typically, the antibodies of the described invention are produced recombinantly, using vectors and methods available in the art. Human antibodies also can be generated by in vitro activated B cells (see, for example, U.S. Pat. Nos. 5,567,610 and 5,229,275). General methods in molecular genetics and genetic engineering useful in the present disclosure are described in the current editions of Molecular Cloning: A Laboratory Manual (Sambrook, et al., 1989, Cold Spring Harbor Laboratory Press), Gene Expression Technology (Methods in Enzymology, Vol. 185, edited by D. Goeddel, 1991. Academic Press, San Diego, Calif.), “Guide to Protein Purification” in Methods in Enzymology (M. P. Deutscher, ed., (1990) Academic Press, Inc.); PCR Protocols: A Guide to Methods and Applications (Innis et al. 1990. Academic Press, San Diego, Calif.), Culture of Animal Cells: A Manual of Basic Technique, 2nd Ed. (R. I. Freshney. 1987. Liss, Inc. New York, N.Y.), and Gene Transfer and Expression Protocols, pp. 109-128, ed. E. J. Murray, The Humana Press Inc., Clifton, N.J.). Reagents, cloning vectors, and kits for genetic manipulation are available from commercial vendors such as BioRad, Stratagene, Invitrogen, ClonTech and Sigma-Aldrich Co.


Human antibodies also can be produced in transgenic animals (for example, mice) that are capable of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production. For example, it has been described that the homozygous deletion of the antibody heavy-chain joining region (JH) gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production. Transfer of the human germ-line immunoglobulin gene array into such germ-line mutant mice results in the production of human antibodies upon antigen challenge. See, for example, Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90:2551 (1993); Jakobovits et al., Nature, 362:255-258 (1993); Bruggemann et al., Year in Immuno., 7:33 (1993); U.S. Pat. Nos. 5,545,806, 5,569,825, 5,591,669 (all of GenPharm); U.S. Pat. No. 5,545,807; and WO 97/17852. Such animals can be genetically engineered to produce human antibodies comprising a polypeptide of the described invention.


Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments were derived via proteolytic digestion of intact antibodies (see, for example, Morimoto et al., Journal of Biochemical and Biophysical Methods 24:107-117 (1992); and Brennan et al., Science, 229:81 (1985)). However, these fragments can now be produced directly by recombinant host cells. Fab, Fv and ScFv antibody fragments can all be expressed in and secreted from E. coli, thus allowing the facile production of large amounts of these fragments. Fab′-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab′)2 fragments (see, for example, Carter et al., Bio/Technology 10:163-167 (1992)). According to another approach, F(ab′)2 fragments can be isolated directly from recombinant host cell culture. Fab and F(ab′)2 fragment with increased in vivo half-life comprising a salvage receptor binding epitope residues are described in U.S. Pat. No. 5,869,046. Other techniques for the production of antibody fragments will be apparent to the skilled practitioner.


Other techniques that are known in the art for the selection of antibody fragments from libraries using enrichment technologies, including but not limited to phage display, ribosome display (Hanes and Pluckthun, 1997, Proc. Nat. Acad. Sci. 94: 4937-4942), bacterial display (Georgiou, et al., 1997, Nature Biotechnology 15: 29-34) and/or yeast display (Kieke, et al., 1997, Protein Engineering 10: 1303-1310) may be utilized as alternatives to previously discussed technologies to select single chain antibodies. Single-chain antibodies are selected from a library of single chain antibodies produced directly utilizing filamentous phage technology. Phage display technology is known in the art (e.g., see technology from Cambridge Antibody Technology (CAT)) as disclosed in U.S. Pat. Nos. 5,565,332; 5,733,743; 5,871,907; 5,872,215; 5,885,793; 5,962,255; 6,140,471; 6,225,447; 6,291650; 6,492,160; 6,521,404; 6,544,731; 6,555,313; 6,582,915; 6,593,081, as well as other U.S. family members, or applications which rely on priority filing GB 9206318, filed 24 May 1992; see also Vaughn, et al. 1996, Nature Biotechnology 14: 309-314). Single chain antibodies may also be designed and constructed using available recombinant DNA technology, such as a DNA amplification method (e.g., PCR), or possibly by using a respective hybridoma cDNA as a template.


Variant antibodies also are included within the scope of the invention. Thus, variants of the sequences recited in the application also are included within the scope of the invention. Further variants of the antibody sequences having improved affinity can be obtained using methods known in the art and are included within the scope of the invention. For example, amino acid substitutions can be used to obtain antibodies with further improved affinity. Alternatively, codon optimization of the nucleotide sequence can be used to improve the efficiency of translation in expression systems for the production of the antibody.


Such variant antibody sequences will share 70% or more (i.e., 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or greater) sequence identity with the sequences disclosed in the application. Such sequence identity is calculated with regard to the full length of the reference sequence (i.e., the sequence recited in the application). Percentage identity, as referred to herein, is as determined using BLAST version 2.1.3 using the default parameters specified by the NCBI (the National Center for Biotechnology Information) [Blosum 62 matrix; gap open penalty=11 and gap extension penalty=1]. For example, peptide sequences provided by this disclosure include at least about 5, 10, 15, 20, 30, 40, 50, 75, 100, 150, or more contiguous peptides of one or more of the sequences disclosed herein as well as all intermediate lengths therebetween. As used herein, the term “intermediate lengths” is meant to describe any length between the quoted values, such as 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, etc.; 21, 22, 23, etc.; 30, 31, 32, etc.; 50, 51, 52, 53, etc.; 100, 101, 102, 103, etc.; 150, 151, 152, 153, etc.


The present disclosure provides for antibodies, either alone or in combination with other antibodies, such as, but not limited to, VRC01, anti-V3 loop, CD4bs, and CD4i antibodies as well as PG9/PG16-like antibodies, that have broad neutralizing activity in serum.


According to another embodiment, the present disclosure provides methods for the preparation and administration of an HIV antibody composition that is suitable for administration to a human or non-human primate patient having HIV infection, or at risk of HIV infection, in an amount and according to a schedule sufficient to induce a protective immune response against HIV, or reduction of the HIV virus, in a human.


According to another embodiment, the present disclosure provides a vaccine comprising at least one antibody of the disclosure and a pharmaceutically acceptable carrier. According to one embodiment, the vaccine is a vaccine comprising at least one antibody described herein and a pharmaceutically acceptable carrier. The vaccine can include a plurality of the antibodies having the characteristics described herein in any combination and can further include antibodies neutralizing to HIV as are known in the art.


It is to be understood that compositions can be a single or a combination of antibodies disclosed herein, which can be the same or different, in order to prophylactically or therapeutically treat the progression of various subtypes of HIV infection after vaccination. Such combinations can be selected according to the desired immunity. When an antibody is administered to an animal or a human, it can be combined with one or more pharmaceutically acceptable carriers, excipients or adjuvants as are known to one of ordinary skilled in the art. The composition can further include broadly neutralizing antibodies known in the art, including but not limited to, VRC01, b12, anti-V3 loop, CD4bs, and CD4i antibodies as well as PG9/PG16-like antibodies.


Further, with respect to determining the effective level in a patient for treatment of HIV, in particular, suitable animal models are available and have been widely implemented for evaluating the in vivo efficacy against HIV of various gene therapy protocols (Sarver et al. (1993b), supra). These models include mice, monkeys, and cats. Even though these animals are not naturally susceptible to HIV disease, chimeric mice models (for example, SCID, bg/nu/xid, NOD/SCID, SCID-hu, immunocompetent SCID-hu, bone marrow-ablated BALB/c) reconstituted with human peripheral blood mononuclear cells (PBMCs), lymph nodes, fetal liver/thymus or other tissues can be infected with lentiviral vector or HIV, and employed as models for HIV pathogenesis. Similarly, the simian immune deficiency virus (SIV)/monkey model can be employed, as can the feline immune deficiency virus (FIV)/cat model. The pharmaceutical composition can contain other pharmaceuticals, in conjunction with a vector according to the invention, when used to therapeutically treat AIDS. These other pharmaceuticals can be used in their traditional fashion (i.e., as agents to treat HIV infection).


According to another embodiment, the present disclosure provides an antibody-based pharmaceutical composition comprising an effective amount of an isolated HIV antibody, or an affinity matured version, which provides a prophylactic or therapeutic treatment choice to reduce infection of the HIV virus. The pharmaceutical composition may further include a second therapeutic agent. In some embodiments, the second therapeutic agent can be an anti-HIV-1 broadly neutralizing antibody. The anti-HIV-1 broadly neutralizing antibody can be one of 10-259, 10-303, 10-410, 10-847, 10-996, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369, 10-1074GM, GL, 10E8, 12A12, 12A21, 2F5, 2G12, 35022, 3BC176, 3BNC117, 3BNC55, 3BNC60, 3BNC62, 447-52D, 4E10, 5H/11-BMV-D5, 8ANC195, b12, CAP256-VRC26.01, CAP256-VRC26.02, CAP256-VRC26.03, CAP256-VRC26.04, CAP256-VRC26.05, CAP256-VRC26.06, CAP256-VRC26.07, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.10, CAP256-VRC26.11, CAP256-VRC26.12, CH01, CH02, CH03, CH04, CH103, HGN194, HJ16, HK20, M66.6, NIH45-46, PCDN-33A, PCDN-33B, PCDN-38A, PG9, PG16, PGDM1400, PGDM1401, PGDM1402, PGDM1403, PGDM1404, PGDM1405, PGDM1406, PGDM1407, PGDM1408, PGDM1409, PGDM1410, PGDM1411, PGDM1412, PGT121, PGT122, PGT123, PGT125, PGT126, PGT127, PGT128, PGT130, PGT131, PGT135, PGT136, PGT137, PGT141, PGT142, PGT143, PGT145, PGT151, PGT152, VRC-CH30, VRC-CH31, VRC-CH32, VRC-CH33, VRC-CH34, VRC-PG04, VRC-CH04b, VRC-PG20, VRC01, VRC02, VRC03, VRC07, VRC23, and Z13. In some embodiments, the anti-HIV-1 broadly neutralizing antibody is 3BNC117. 3BNC117 is a next-generation bNAb that targets the CD4 binding site on HIV envelope gp160. It is a recombinant human IgG1 kappa monoclonal antibody cloned from an HIV-infected viremic controller. A long-acting version of 3BNC117 is known as 3BNC117-LS. 3BNC117 was described in US patent U.S. Pat. No. 9,783,594.


The antibody-based pharmaceutical composition of the present disclosure may be formulated by any number of strategies known in the art (e.g., see McGoff and Scher, 2000, Solution Formulation of Proteins/Peptides: In McNally, E. J., ed. Protein Formulation and Delivery. New York, N.Y.: Marcel Dekker; pp. 139-158; Akers and Defilippis, 2000, Peptides and Proteins as Parenteral Solutions. In: Pharmaceutical Formulation Development of Peptides and Proteins. Philadelphia, Pa.: Talyor and Francis; pp. 145-177; Akers et al., 2002, Pharm. Biotechnol. 14:47-127). A pharmaceutically acceptable composition suitable for patient administration will contain an effective amount of the antibody in a formulation which both retains biological activity while also promoting maximal stability during storage within an acceptable temperature range. The pharmaceutical compositions can also include, depending on the formulation desired, pharmaceutically acceptable diluents, pharmaceutically acceptable carriers and/or pharmaceutically acceptable excipients, or any such vehicle commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solutions, dextrose solution, and Hank's solution. The amount of an excipient that is useful in the pharmaceutical composition or formulation of this disclosure is an amount that serves to uniformly distribute the antibody throughout the composition so that it can be uniformly dispersed when it is to be delivered to a subject in need thereof. It may serve to dilute the antibody to a concentration which provides the desired beneficial palliative or curative results while at the same time minimizing any adverse side effects that might occur from too high a concentration. It may also have a preservative effect. Thus, for the antibody having high physiological activity, more of the excipient will be employed. On the other hand, for any active ingredient(s) that exhibit a lower physiological activity, a lesser quantity of the excipient will be employed.


The above-described antibodies and antibody compositions or vaccine compositions, comprising at least one or a combination of the antibodies described herein, can be administered for the prophylactic and therapeutic treatment of HIV viral infection.


The present disclosure also relates to isolated polypeptides comprising the novel amino acid sequences of the light chain regions and heavy chain variable regions, listed in Tables 2-3. In other related embodiments, this disclosure provides polypeptide variants having the amino acid sequences of the light chain regions and heavy chain variable regions of the HIV antibodies that share at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or greater sequence identity compared to a polypeptide sequence, listed in Tables 2-3, as determined using the methods described herein (i.e., BLAST analysis using standard parameters). One skilled in this art will recognize that these values can be appropriately adjusted to determine corresponding identity of proteins encoded by taking into amino acid similarity and the like. In other related embodiments, this disclosure provides polypeptide variants having the amino acid sequences of the light chain regions and heavy chain variable regions of the HIV antibodies that share at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or greater sequence identity compared to a polypeptide sequence, listed in Tables 2-3, and having the amino acid sequences of the CDR regions identical or substantially identical to those listed in Table 4 or to the amino acid sequences of the CDR regions of the unmodified 10-1074-LS antibody (or MS-193). In other related embodiments, this disclosure provides polypeptide variants having the amino acid sequences of the light chain regions and heavy chain variable regions of the HIV antibodies that share at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or greater sequence identity compared to a polypeptide sequence, listed in Tables 2-3, and having the amino acid sequences of the CDR regions identical or substantially identical to those listed in Table 4 or to the amino acid sequences of the CDR regions of the unmodified 10-1074-LS antibody (or MS-193), such that polypeptide variants retain 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or greater binding affinity to the HIV virus. The term “substantially identical” refers to the identity of a sequence to another sequence greater than about 85%.


The term “polypeptide” is used in its conventional meaning, i.e., as a sequence of amino acids. The polypeptides are not limited to a specific length of the product. Peptides, oligopeptides, and proteins are included within the definition of polypeptide, and such terms can be used interchangeably herein unless specifically indicated otherwise. This term also includes post-expression modifications of the polypeptide, for example, glycosylations, acetylations, phosphorylations and the like, as well as other modifications known in the art, both naturally occurring and non-naturally occurring. A polypeptide can be an entire protein or a subsequence thereof. Particular polypeptides of interest in the context of this disclosure are amino acid subsequences comprising CDRs, VH, and VL, being capable of binding an antigen or HIV-infected cell.


A polypeptide “variant,” as the term is used herein, is a polypeptide that typically differs from a polypeptide specifically disclosed herein in one or more substitutions, deletions, additions and/or insertions. Such variants can be naturally occurring or can be synthetically generated, for example, by modifying one or more of the above polypeptide sequences of the disclosure and evaluating one or more biological activities of the polypeptide as described herein and/or using any of some techniques well known in the art.


For example, certain amino acids can be substituted for other amino acids in a protein structure without appreciable loss of its ability to bind other polypeptides (for example, antigens) or cells. Since it is the binding capacity and nature of a protein that defines that protein's biological functional activity, certain amino acid sequence substitutions can be made in a protein sequence, and, accordingly, its underlying DNA coding sequence, whereby a protein with like properties is obtained. It is thus contemplated that various changes can be made in the peptide sequences of the disclosed compositions, or corresponding DNA sequences that encode said peptides without appreciable loss of their biological utility or activity.


Variant antibody sequences include those wherein conservative substitutions have been introduced by modification of polynucleotides encoding polypeptides of the invention. Amino acids can be classified according to physical properties and contribution to secondary and tertiary protein structure. A “conservative substitution” is recognized in the art as a substitution of one amino acid for another amino acid that has similar properties. Exemplary conservative substitutions are set out below:












CONSERVATIVE SUBSTITUTION I










Side chain characteristic
Amino acid







Aliphatic




Non-polar
G A P I L V



Polar - uncharged
C S T M N Q



Polar - charged
D E K R



Aromatic
H F W Y



Other
N Q D E










Alternatively, conservative amino acids can be grouped as described in Lehninger, [Biochemistry, Second Edition; Worth Publishers, Inc. NY, N.Y. (1975), pp. 71-77] as set out below:












CONSERVATIVE SUBSTITUTION II










Side chain characteristic
Amino acid







Non-polar (hydrophobic)




A. Aliphatic:
A L I V P



B. Aromatic:
F W



C. Sulfur-containing:
M



D. Borderline:
G



Uncharged-polar



A. Hydroxyl:
S T Y



B. Amides:
N Q



C. Sulfhydryl:
C



D. Borderline:
G



Positively Charged (Basic):
K R H



Negatively Charged (Acidic):
D E










As still another alternative, exemplary conservative substitutions are set out below:












CONSERVATIVE SUBSTITUTIONS III










Original residue
Exemplary substitution







Ala (A)
Val, Leu, Ile



Arg (R)
Lys, Gln, Asn



Asn (N)
Gln, His, Lys, Arg



Asp (D)
Glu



Cys (C)
Ser



Gln (Q)
Asn



Glu (E)
Asp



His (H)
Asn, Gln, Lys, Arg



Ile (I)
Leu, Val, Met, Ala, Phe,



Leu (L)
Ile, Val, Met, Ala, Phe



Lys (K)
Arg, Gln, Asn



Met (M)
Leu, Phe, Ile



Phe (F)
Leu, Val, Ile, Ala



Pro (P)
Gly



Ser (S)
Thr



Thr (T)
Ser



Trp (W)
Tyr



Tyr (Y)
Trp, Phe, Thr, Ser



Val (V)
Ile, Leu, Met, Phe, Ala










A conservative substitution of an existing substitution refers to a conservative substitution of the substituting residue. For example, a conservative substitution of LmdV:Y2P refers to a conservative substitution (i.e., glycine (G)) of proline (P) at position LmdV:Y2. In another example, a conservative substitution of HV:V79T refers to a conservative substitution (i.e., serine (S), cysteine (C)) of threonine (T) at position HV:V79.


“Homology” or “sequence identity” refers to the percentage of residues in the polynucleotide or polypeptide sequence variant that are identical to the non-variant sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent homology. In particular embodiments, polynucleotide and polypeptide variants have at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% polynucleotide or polypeptide homology with a polynucleotide or polypeptide described herein.


Such variant polypeptide sequences will share 70% or more (i.e. 80%, 85%, 90%, 95%, 97%, 98%, 99% or more) sequence identity with the sequences recited in the application. In additional embodiments, the described invention provides polypeptide fragments comprising various lengths of contiguous stretches of amino acid sequences disclosed herein. For example, peptide sequences provided by this disclosure include at least about 5, 10, 15, 20, 30, 40, 50, 75, 100, 150, or more contiguous peptides of one or more of the sequences disclosed herein as well as all intermediate lengths therebetween.


The disclosure also includes nucleic acid sequences encoding part or all of the light and heavy chains of the described inventive antibodies, and fragments thereof. Due to the redundancy of the genetic code, variants of these sequences will exist that encode the same amino acid sequences.


The present disclosure also includes isolated nucleic acid sequences encoding the polypeptides for the light and heavy chains of the HIV antibodies listed in Tables 2-3. In other related embodiments, the described invention provides polynucleotide variants that encode the peptide sequences of the heavy and light chains of the HIV antibodies listed in Tables 5-6. These polynucleotide variants have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, or greater, sequence identity compared to a polynucleotide sequence of this disclosure, as determined using the methods described herein (i.e., BLAST analysis using standard parameters). One skilled in this art will recognize that these values can be appropriately adjusted to determine corresponding identity of proteins encoded by two nucleotide sequences by taking into account codon degeneracy, amino acid similarity, reading frame positioning, and the like.


The terms “nucleic acid” and “polynucleotide” are used interchangeably herein to refer to single-stranded or double-stranded RNA, DNA, or mixed polymers. Polynucleotides can include genomic sequences, extra-genomic and plasmid sequences, and smaller engineered gene segments that express, or can be adapted to express polypeptides.


An “isolated nucleic acid” is a nucleic acid that is substantially separated from other genome DNA sequences as well as proteins or complexes such as ribosomes and polymerases, which naturally accompany a native sequence. The term encompasses a nucleic acid sequence that has been removed from its naturally occurring environment and includes recombinant or cloned DNA isolates and chemically synthesized analogs or analogs biologically synthesized by heterologous systems. A substantially pure nucleic acid includes isolated forms of the nucleic acid. Accordingly, this refers to the nucleic acid as originally isolated and does not exclude genes or sequences later added to the isolated nucleic acid by the hand of man.


A polynucleotide “variant,” as the term is used herein, is a polynucleotide that typically differs from a polynucleotide specifically disclosed herein in one or more substitutions, deletions, additions and/or insertions. Such variants can be naturally occurring or can be synthetically generated, for example, by modifying one or more of the polynucleotide sequences of the disclosure and evaluating one or more biological activities of the encoded polypeptide as described herein and/or using any of some techniques well known in the art.


Modifications can be made in the structure of the polynucleotides of the described invention and still obtain a functional molecule that encodes a variant or derivative polypeptide with desirable characteristics. When it is desired to alter the amino acid sequence of a polypeptide to create an equivalent or even an improved, variant or portion of a polypeptide of the invention, one skilled in the art typically will change one or more of the codons of the encoding DNA sequence.


Typically, polynucleotide variants contain one or more substitutions, additions, deletions and/or insertions, such that the immunogenic binding properties of the polypeptide encoded by the variant polynucleotide is not substantially diminished relative to a polypeptide encoded by a polynucleotide sequence specifically set forth herein.


In additional embodiments, the described invention provides polynucleotide fragments comprising various lengths of contiguous stretches of sequence identical to or complementary to one or more of the sequences disclosed herein. For example, polynucleotides are provided by this disclosure that comprise at least about 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 400, 500 or 1000 or more contiguous nucleotides of one or more of the sequences disclosed herein as well as all intermediate lengths therebetween and encompass any length between the quoted values, such as 16, 17, 18, 19, etc.; 21, 22, 23, etc.; 30, 31, 32, etc.; 50, 51, 52, 53, etc.; 100, 101, 102, 103, etc.; 150, 151, 152, 153, etc.; and including all integers through 200-500; 500-1,000.


In another embodiment of the invention, polynucleotide compositions are provided that are capable of hybridizing under moderate to high stringency conditions to a polynucleotide sequence provided herein, or a fragment thereof, or a complementary sequence thereof. Hybridization techniques are well known in the art of molecular biology. For purposes of illustration, suitable moderately stringent conditions for testing the hybridization of a polynucleotide of this disclosure with other polynucleotides include prewashing in a solution of 5×SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridizing at 50-60° C., 5×SSC, overnight; followed by washing twice at 65° C. for 20 minutes with each of 2×, 0.5×, and 0.2×SSC containing 0.1% SDS. One skilled in the art will understand that the stringency of hybridization can be readily manipulated, such as by altering the salt content of the hybridization solution and/or the temperature at which the hybridization is performed. For example, in another embodiment, suitable highly stringent hybridization conditions include those described above, with the exception that the temperature of hybridization is increased, for example, to 60-65° C. or 65-70° C.


In some embodiments, the polypeptide encoded by the polynucleotide variant or fragment has the same binding specificity (i.e., specifically or preferentially binds to the same epitope or HIV strain) as the polypeptide encoded by the native polynucleotide. In some embodiments, the described polynucleotides, polynucleotide variants, fragments, and hybridizing sequences, encode polypeptides that have a level of binding activity of at least about 50%, at least about 70%, and at least about 90% of that for a polypeptide sequence specifically set forth herein.


The polynucleotides of the described invention, or fragments thereof, regardless of the length of the coding sequence itself, can be combined with other DNA sequences, such as promoters, polyadenylation signals, additional restriction enzyme sites, multiple cloning sites, other coding segments, and the like, such that their overall length can vary considerably. A nucleic acid fragment of almost any length is employed. For example, illustrative polynucleotide segments with total lengths of about 10000, about 5000, about 3000, about 2000, about 1000, about 500, about 200, about 100, about 50 base pairs in length, and the like, (including all intermediate lengths) are included in many implementations of this invention.


Further included within the scope of the invention are vectors such as expression vectors, comprising a nucleic acid sequence according to the invention. Cells transformed with such vectors also are included within the scope of the invention.


The present disclosure also provides vectors and host cells comprising a nucleic acid of the invention, as well as recombinant techniques for the production of a polypeptide of the invention. Vectors of the invention include those capable of replication in any type of cell or organism, including, for example, plasmids, phage, cosmids, and minichromosomes. In some embodiments, vectors comprising a polynucleotide of the described invention are vectors suitable for propagation or replication of the polynucleotide, or vectors suitable for expressing a polypeptide of the described invention. Such vectors are known in the art and commercially available.


“Vector” includes shuttle and expression vectors. Typically, the plasmid construct also will include an origin of replication (for example, the ColE1 origin of replication) and a selectable marker (for example, ampicillin or tetracycline resistance), for replication and selection, respectively, of the plasmids in bacteria. An “expression vector” refers to a vector that contains the necessary control sequences or regulatory elements for expression of the antibodies including antibody fragment of the invention, in bacterial or eukaryotic cells.


As used herein, the term “cell” can be any cell, including, but not limited to, that of a eukaryotic, multicellular species (for example, as opposed to a unicellular yeast cell), such as, but not limited to, a mammalian cell or a human cell. A cell can be present as a single entity or can be part of a larger collection of cells. Such a “larger collection of cells” can comprise, for example, a cell culture (either mixed or pure), a tissue (for example, endothelial, epithelial, mucosa or other tissue), an organ (for example, lung, liver, muscle and other organs), an organ system (for example, circulatory system, respiratory system, gastrointestinal system, urinary system, nervous system, integumentary system or other organ system), or an organism (e.g., a bird, mammal, or the like).


Polynucleotides of the invention may be synthesized, in whole or in parts that are then combined, and inserted into a vector using routine molecular and cell biology techniques, including, for example, subcloning the polynucleotide into a linearized vector using appropriate restriction sites and restriction enzymes. Polynucleotides of the described invention are amplified by polymerase chain reaction using oligonucleotide primers complementary to each strand of the polynucleotide. These primers also include restriction enzyme cleavage sites to facilitate subcloning into a vector. The replicable vector components generally include but are not limited to, one or more of the following: a signal sequence, an origin of replication, and one or more marker or selectable genes.


In order to express a polypeptide of the invention, the nucleotide sequences encoding the polypeptide, or functional equivalents, may be inserted into an appropriate expression vector, i.e., a vector that contains the necessary elements for the transcription and translation of the inserted coding sequence. Methods well known to those skilled in the art may be used to construct expression vectors containing sequences encoding a polypeptide of interest and appropriate transcriptional and translational control elements. These methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. Such techniques are described, for example, in Sambrook, J. et al. (1989) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Plainview, N.Y., and Ausubel, F. M. et al. (1989) Current Protocols in Molecular Biology, John Wiley & Sons, New York. N.Y.


The present disclosure also provides kits useful in performing diagnostic and prognostic assays using the antibodies, polypeptides and nucleic acids of the present invention. Kits of the present invention include a suitable container comprising an HIV antibody, a polypeptide or a nucleic acid of the invention in either labeled or unlabeled form. In addition, when the antibody, polypeptide or nucleic acid is supplied in a labeled form suitable for an indirect binding assay, the kit further includes reagents for performing the appropriate indirect assay. For example, the kit may include one or more suitable containers including enzyme substrates or derivatizing agents, depending on the nature of the label. Control samples and/or instructions may also be included. The present disclosure also provides kits for detecting the presence of the HIV antibodies or the nucleotide sequence of the HIV antibody of the present disclosure in a biological sample by PCR or mass spectrometry.


In some embodiments, the kit includes a pharmaceutically acceptable dose unit of a pharmaceutically effective amount of at least one isolated anti-HIV antibody described herein or antigen-binding portion thereof. The kit can further include a pharmaceutically acceptable dose unit of a pharmaceutically effective amount of an anti-HIV agent. The two pharmaceutically acceptable dose units can optionally take the form of a single pharmaceutically acceptable dose unit. An exemplary anti-HIV agent can be selected from the group consisting of a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, an entry or fusion inhibitor, and an integrase inhibitor. In some embodiments, the anti-HIV agent is an anti-HIV broadly neutralizing antibody, such as 3BNC117.


“Label” as used herein refers to a detectable compound or composition that is conjugated directly or indirectly to the antibody so as to generate a “labeled” antibody. A label can also be conjugated to a polypeptide and/or a nucleic acid sequence disclosed herein. The label can be detectable by itself (for example, radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, can catalyze chemical alteration of a substrate compound or composition that is detectable. Antibodies and polypeptides of the described invention also can be modified to include an epitope tag or label, for example, for use in purification or diagnostic applications. Suitable detection means include the use of labels such as, but not limited to, radionucleotides, enzymes, coenzymes, fluorescers, chemiluminescers, chromogens, enzyme substrates or co-factors, enzyme inhibitors, prosthetic group complexes, free radicals, particles, dyes, and the like.


According to another embodiment, the present disclosure provides diagnostic methods. Diagnostic methods generally involve contacting a biological sample obtained from a patient, such as, for example, blood, serum, saliva, urine, sputum, a cell swab sample, or a tissue biopsy, with an HIV antibody and determining whether the antibody preferentially binds to the sample as compared to a control sample or predetermined cut-off value, thereby indicating the presence of the HIV virus.


According to another embodiment, the present disclosure provides methods to detect the presence of the HIV antibodies of the present disclosure in a biological sample from a patient. Detection methods generally involve obtaining a biological sample from a patient, such as, for example, blood, serum, saliva, urine, sputum, a cell swab sample, or a tissue biopsy and isolating HIV antibodies or fragments thereof, or the nucleic acids that encode an HIV antibody, and assaying for the presence of an HIV antibody in the biological sample. Also, the present disclosure provides methods to detect the nucleotide sequence of an HIV antibody in a cell. The nucleotide sequence of an HIV antibody may also be detected using the primers disclosed herein. The presence of the HIV antibody in a biological sample from a patient may be determined by utilizing known recombinant techniques and/or the use of a mass spectrometer.


In another embodiment, the present disclosure provides a method for detecting an HIV antibody comprising a heavy chain comprising a highly conserved consensus sequence and a light chain comprising a highly conserved consensus sequence in a biological sample, comprising obtaining an immunoglobulin-containing biological sample from a mammalian subject, isolating an HIV antibody from said sample, and identifying the highly conserved consensus sequences of the heavy chain and the light chain. The biological sample may be blood, serum, saliva, urine, sputum, a cell swab sample, or a tissue biopsy. The amino acid sequences may be determined by methods known in the art including, for example, PCR and mass spectrometry.


The term “assessing” includes any form of measurement, and includes determining if an element is present or not. The terms “determining,” “measuring,” “evaluating,” “assessing” and “assaying” are used interchangeably and include quantitative and qualitative determinations. Assessing may be relative or absolute. “Assessing the presence of” includes determining the amount of something present, and/or determining whether it is present or absent. As used herein, the terms “determining,” “measuring,” and “assessing,” and “assaying” are used interchangeably and include both quantitative and qualitative determinations.


Method of Reducing Viral Replication


Methods for reducing an increase in HIV virus titer, virus replication, virus proliferation or an amount of an HIV viral protein in a subject are further provided. According to another aspect, a method includes administering to the subject an amount of an HIV antibody effective to reduce an increase in HIV titer, virus replication or an amount of an HIV protein of one or more HIV strains or isolates in the subject.


According to another embodiment, the present disclosure provides a method of reducing viral replication or spread of HIV infection to additional host cells or tissues comprising contacting a mammalian cell with the antibody, or a portion thereof, which binds to an antigenic epitope on gp120.


Method of Treatment


According to another embodiment, the present disclosure provides a method for treating a mammal infected with a virus infection, such as, for example, HIV, comprising administering to said mammal a pharmaceutical composition comprising the HIV antibodies disclosed herein. According to one embodiment, the method for treating a mammal infected with HIV comprises administering to said mammal a pharmaceutical composition that comprises an antibody of the present disclosure, or a fragment thereof. The compositions of the disclosure can include more than one antibody having the characteristics disclosed (for example, a plurality or pool of antibodies). It also can include other HIV neutralizing antibodies as are known in the art, for example, but not limited to, 10-259, 10-303, 10-410, 10-847, 10-996, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369, 10-1074GM, GL, 10E8, 12A12, 12A21, 2F5, 2G12, 35022, 3BC176, 3BNC117, 3BNC55, 3BNC60, 3BNC62, 447-52D, 4E10, 5H/11-BMV-D5, 8ANC195, b12, CAP256-VRC26.01, CAP256-VRC26.02, CAP256-VRC26.03, CAP256-VRC26.04, CAP256-VRC26.05, CAP256-VRC26.06, CAP256-VRC26.07, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.10, CAP256-VRC26.11, CAP256-VRC26.12, CH01, CH02, CH03, CH04, CH103, HGN194, HJ16, HK20, M66.6, NIH45-46, PCDN-33A, PCDN-33B, PCDN-38A, PG9, PG16, PGDM1400, PGDM1401, PGDM1402, PGDM1403, PGDM1404, PGDM1405, PGDM1406, PGDM1407, PGDM1408, PGDM1409, PGDM1410, PGDM1411, PGDM1412, PGT121, PGT122, PGT123, PGT125, PGT126, PGT127, PGT128, PGT130, PGT131, PGT135, PGT136, PGT137, PGT141, PGT142, PGT143, PGT145, PGT151, PGT152, VRC-CH30, VRC-CH31, VRC-CH32, VRC-CH33, VRC-CH34, VRC-PG04, VRC-CH04b, VRC-PG20, VRC01, VRC02, VRC03, VRC07, VRC23, and Z13.


The method can further include administering a second therapeutic agent, such as a therapeutically effective amount of the second therapeutic agent. The second therapeutic agent can be administered before, concurrently with or after the administration of the anti-HIV antibody or antigen-binding portion thereof. In some embodiments, the second therapeutic agent is an anti-HIV-1 broadly neutralizing antibody. Examples of anti-HIV-1 broadly neutralizing antibodies are provided above. In some embodiments, the anti-HIV-1 broadly neutralizing antibody is 3BNC117.


Passive immunization has proven to be an effective and safe strategy for the prevention and treatment of viral diseases. (See, for example, Keller et al., Clin. Microbiol. Rev. 13:602-14 (2000); Casadevall, Nat. Biotechnol. 20:114 (2002); Shibata et al., Nat. Med. 5:204-10 (1999); and Igarashi et al., Nat. Med. 5:211-16 (1999). Passive immunization using human monoclonal antibodies provides an immediate treatment strategy for emergency prophylaxis and treatment of HIV.


Subjects at risk for HIV-related diseases or disorders include patients who have come into contact with an infected person or who have been exposed to HIV in some other way. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of HIV-related disease or disorder, such that a disease or disorder is prevented or, alternatively, delayed in its progression.


For in vivo treatment of human and non-human patients, the patient is administered or provided a pharmaceutical formulation including an HIV antibody of this disclosure. When used for in vivo therapy, the antibodies of this disclosure are administered to the patient in therapeutically effective amounts (i.e., amounts that eliminate or reduce the patient's viral burden). The antibodies are administered to a human patient, in accord with known methods, such as intravenous administration, for example, as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intraarticular, intrasynovial, intrathecal, oral, topical, or inhalation routes. The antibodies can be administered parenterally, when possible, at the target cell site, or intravenously. In some embodiments, the antibody is administered by an intravenous or subcutaneous administration. Therapeutic compositions of the disclosure may be administered to a patient or subject systemically, parenterally, or locally. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.


For parenteral administration, the antibodies may be formulated in a unit dosage injectable form (solution, suspension, emulsion) in association with a pharmaceutically acceptable, parenteral vehicle. Examples of such vehicles include, but are not limited, water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Nonaqueous vehicles include, but are not limited to, fixed oils and ethyl oleate. Liposomes can be used as carriers. The vehicle may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, such as, for example, buffers and preservatives. The antibodies can be formulated in such vehicles at concentrations of about 1 mg/ml to 150 mg/ml.


The dose and dosage regimen depends upon a variety of factors readily determined by a physician, such as the nature of the infection, for example, its therapeutic index, the patient, and the patient's history. Generally, a therapeutically effective amount of an antibody is administered to a patient. In some embodiments, the amount of antibody administered is in the range of about 0.1 mg/kg to about 50 mg/kg of patient body weight. Depending on the type and severity of the infection, about 0.1 mg/kg to about 50 mg/kg body weight (for example, about 0.1-15 mg/kg/dose) of antibody is an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion. The progress of this therapy is readily monitored by conventional methods and assays and based on criteria known to the physician or other persons of skill in the art. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.


Other therapeutic regimens may be combined with the administration of the HIV antibody of the present disclosure. The combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities. Such combined therapy can result in a synergistic therapeutic effect. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.


The terms “treating” or “treatment” or “alleviation” are used interchangeably and refer to both therapeutic treatment and prophylactic or preventative measures; wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented. A subject or mammal is successfully “treated” for an infection if, after receiving a therapeutic amount of an antibody according to the methods of the present disclosure, the patient shows observable and/or measurable reduction in or absence of one or more of the following: reduction in the number of infected cells or absence of the infected cells; reduction in the percent of total cells that are infected; and/or relief to some extent, one or more of the symptoms associated with the specific infection; reduced morbidity and mortality, and improvement in quality of life issues. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.


The term “effective amount,” “effective dose,” or “effective dosage” is defined as an amount sufficient to achieve or at least partially achieve a desired effect. A “therapeutically effective amount” or “therapeutically effective dosage” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. A “prophylactically effective amount” or a “prophylactically effective dosage” of a drug is an amount of the drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or of suffering a recurrence of disease, inhibits the development or recurrence of the disease. The ability of a therapeutic or prophylactic agent to promote disease regression or inhibit the development or recurrence of the disease can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.


Administration “in combination with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order.


“Carriers” as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include, but not limited to, buffers such as phosphate, citrate, acetate and other organic acids; antioxidants including, but not limited to, ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as, but not limited to, serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as, but not limited to, polyvinylpyrrolidone; amino acids such as, but not limited to, glycine, glutamine, asparagine, arginine, proline or lysine; monosaccharides, disaccharides, and other carbohydrates including, but not limited to, glucose, mannose, or dextrins; chelating agents such as, but not limited to, EDTA; sugar alcohols such as, but not limited to, mannitol, sorbitol, sucrose or trehalose; salt-forming counterions such as, but not limited to, sodium; and/or nonionic surfactants such as, but not limited to, TWEEN; polyethylene glycol (PEG), poloxamers, i.e. Pluronic F-68 and polysorbates, i.e. polysorbate 20 or polysorbate 80


Definitions

To aid in understanding the detailed description of the compositions and methods according to the disclosure, a few express definitions are provided to facilitate an unambiguous disclosure of the various aspects of the disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.


The term “recombinant” when made in reference to a nucleic acid molecule refers to a nucleic acid molecule which is comprised of segments of nucleic acid joined together by means of molecular biological techniques. The term “recombinant,” when made in reference to a protein or a polypeptide, refers to a protein molecule which is expressed using a recombinant nucleic acid molecule.


The term “operably linked” refers to a functional linkage between a nucleic acid expression control sequence (such as a promoter, or array of transcription factor binding sites) and a second nucleic acid sequence, wherein the expression control sequence directs transcription of the nucleic acid corresponding to the second sequence.


As used herein, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multi-cellular organism.


As used herein, the term “in vivo” refers to events that occur within a multi-cellular organism such as a non-human animal.


The terms “prevent,” “preventing,” “prevention,” “prophylactic treatment” and the like refer to reducing the probability of developing a disorder or condition in a subject, who does not have, but is at risk of or susceptible to developing a disorder or condition.


As used herein, “administering” refers to the physical introduction of a composition comprising a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Routes of administration described herein include intravenous, intraperitoneal, intramuscular, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. Alternatively, a composition described herein can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.


The term “agent” is used herein to denote a chemical compound, a mixture of chemical compounds, a biological macromolecule (such as a nucleic acid, an antibody, a protein or portion thereof, e.g., a peptide), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. The activity of such agents may render it suitable as a “therapeutic agent,” which is a biologically, physiologically, or pharmacologically active substance (or substances) that acts locally or systemically in a subject.


The terms “therapeutic agent,” “therapeutic capable agent,” or “treatment agent” are used interchangeably and refer to a molecule or compound that confers some beneficial effect upon administration to a subject. The beneficial effect includes enablement of diagnostic determinations; amelioration of a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder or condition; and generally counteracting a disease, symptom, disorder or pathological condition.


“Combination” therapy, as used herein, unless otherwise clear from the context, is meant to encompass administration of two or more therapeutic agents in a coordinated fashion, and includes, but is not limited to, concurrent dosing. Specifically, combination therapy encompasses both co-administration (e.g., administration of a co-formulation or simultaneous administration of separate therapeutic compositions) and serial or sequential administration, provided that administration of one therapeutic agent is conditioned in some way on administration of another therapeutic agent. For example, one therapeutic agent may be administered only after a different therapeutic agent has been administered and allowed to act for a prescribed period of time. See, e.g., Kohrt et al. (2011) Blood 117:2423.


Where a value of ranges is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges which may independently be included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the disclosure.


It is noted here that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.


The terms “including,” “comprising,” “containing,” or “having” and variations thereof are meant to encompass the items listed thereafter and equivalents thereof as well as additional subject matter unless otherwise noted.


The phrases “in one embodiment,” “in various embodiments,” “in some embodiments,” and the like are used repeatedly. Such phrases do not necessarily refer to the same embodiment, but they may unless the context dictates otherwise.


The terms “and/or” or “/” means any one of the items, any combination of the items, or all of the items with which this term is associated.


The word “substantially” does not exclude “completely,” e.g., a composition which is “substantially free” from Y may be completely free from Y. Where necessary, the word “substantially” may be omitted from the definition of the invention.


As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In some embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value). Unless indicated otherwise herein, the term “about” is intended to include values, e.g., weight percents, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment.


As used herein, the term “each,” when used in reference to a collection of items, is intended to identify an individual item in the collection but does not necessarily refer to every item in the collection. Exceptions can occur if explicit disclosure or context clearly dictates otherwise.


The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.


All methods described herein are performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. In regard to any of the methods provided, the steps of the method may occur simultaneously or sequentially. When the steps of the method occur sequentially, the steps may occur in any order, unless noted otherwise.


In cases in which a method comprises a combination of steps, each and every combination or sub-combination of the steps is encompassed within the scope of the disclosure, unless otherwise noted herein.


Each publication, patent application, patent, and other reference cited herein is incorporated by reference in its entirety to the extent that it is not inconsistent with the present disclosure. Publications disclosed herein are provided solely for their disclosure prior to the filing date of the present invention. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.


It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.


EXAMPLES
Example 1

Identification and Characterization of the Variants of the 10-1074 Broadly Neutralizing Antibody—Round 1


The first round variants, including MS-203, MS-204, MS-205, MS-206, MS-207, MS-208, MS-209, MS-210, MS-211, MS-212, MS-213, MS-214, MS-215, MS-216, MS-217, MS-218, MS-219, MS-220, and MS-224, as shown in Table 9, were produced using transient expression in HEK293 cells and purified by protein A chromatography. The characterization methods used to analyze the variants are listed in Table 8, including size exclusion chromatography (SEC), differential scanning fluorimetry (DSF), low pH stability, and relative solubility assay (RSA). The antibodies were buffer exchanged into phosphate-buffered saline and used for analysis. Assays used for analysis of the first round variants included SEC to quantify monomer and high molecular weight species following purification, DSF to characterize stability of the CH2 and Fab domains during thermal ramping, and retention of neutralization capacity.


The monomer content of the variants ranged from a low of 60.8% to a high of 96.3%. The monomer content of the unmodified 10-1074-LS (or MS-194) was 91.5% with the remainder of material for all variants being high molecular weight species (HMW). Variants with less than 10% HMW were considered for the second round combinatorial variants. In addition to SEC analysis, differential scanning fluorimetry was used to define molecules with increased thermodynamic stability. For the 10-1074-LS (or MS-194) parental molecule, only a single Tm was measured indicating that the CH2 and Fab domains unfolded at the same temperature. Similar results were observed for some of the variants. A few, though, also showed the presence of both a Tm1 and a second melting transition termed Tm2, because modifications that help to stabilize the Fab domain were made in the Fv domain of the antibodies, resulting in the increased thermal transition. Antibodies that did not show a consistent Tm2 for both replicates of the DSF analysis were not considered for Round 2 combinations.


Neutralization activity was also measured to ensure retention of activity of the bnAb variants. Results are shown in Table 10 for neutralization against six pseudoviruses of HIV (e.g., Du156.12, WIT04160.33, CNE17, CNE30, CAAN5342.A2, Du172.17), which are representative of the broader set of viruses against which 10-1074 is active. Antibodies with more than a 3-fold increase in the IC50 or IC80 value for a particular pseudovirus were considered inactive and discarded from further consideration. As evidenced by the data, only one variant, MS-208, lost neutralization activity and was not selected for further development.


The final set of amino acids for further development was based on the combination of amount purified, percent high molecular weight, increase in thermodynamic stability by DSF, and retention of neutralization activity. An example of the reasoning for the selection of residues for combinatorial analysis is described in Table 11. Five amino acid residues selected for further development are MS-203 (LmdV: Y2P), MS-216 (HV: V79T), MS-217 (HV: R82V), MS-218 (HV: L89F) and MS-219 (HV: T108R).


Example 2

Identification and Characterization of the Variants of the 10-1074 Broadly Neutralizing Antibody—Round 2


The second round combinatorial variants were designed based on the first round variants as described in the prior section. The combinatorial variants tested in the second round of optimization are shown in Table 12 and consist of ten double combinations, ten triple combinations, five quadruples and one quintuple combination consisting of all five amino acid modifications. These variants include MS-200, MS-201, MS-202, MS-225, MS-226, MS-227, MS-228, MS-229, MS-230, MS-231, MS-232, MS-233, MS-234, MS-235, MS-236, MS-237, MS-238, MS-239, MS-240, MS-241, MS-242, MS-243, MS-244, and MS-245. The combinatorial variants were produced using transient expression in HEK293 cells and purified by protein A chromatography. The antibodies were buffer exchanged into phosphate-buffered saline before being used for analysis. Assays used for analysis of the second round variants included SEC to quantify monomer and high molecular weight species following purification, differential scanning fluorimetry to characterize stability of the CH2 and Fab domains during thermal ramping, chemical unfolding, low pH stability, solubility, and retention of neutralization capacity.


Results of the initial screening consisting of SEC analysis for dimer and oligomer content and DSF for increased thermodynamic stability are shown in Table 13. For example, MS-200 has lower HMW than the control variant MS-194. MS-200 also has a Tm1=70.15° C. and a Tm2=74.62° C., suggesting it has improved thermal stability. Separation of the HMW species into dimer and oligomer species, with HMW species eluting earlier than dimer, provides a more refined view of the data. The data show that the dimer content was relatively unchanged from 10-1074-LS (or MS-194), while the oligomer content of the variants both increased up to 2-fold for a few variants and decreased up to approximately 7-fold for others. The variants were also characterized by DSF to identify those with increased thermodynamic stability as evidenced by the presence of distinct Tm2 unfolding temperatures.


To better differentiate the variants by DSF, an alternative analysis of the data was devised which took advantage of the change between Tm1 and Tm2 and the area under the thermal unfolding curves. As indicated by the data in Table 14 termed DSF Shoulder Score, the variants may have similar Tm2 values, but different shoulder score values with the increased values indicative of greater stability. For example, the DSF Shoulder Score values for MS-200, MS-201, and MS-202 are 16.12, 29.39, and 22.49, respectively, which are significantly larger than the Shoulder Score value, 7.65, of the control antibody variant MS-194, suggesting the variants MS-200, MS-201, and MS-203 are more stable than the control antibody variant MS-194. Thermodynamic stability was also assessed by chemical unfolding which asses the intrinsic resistance of the native state against unfolding as measured by the mid-point of the denaturation curve. The higher the value, the greater the stability. Together with the DSF shoulder score, a much finer differentiation of the intrinsic thermodynamic stability of the antibodies was obtained. In addition to the intrinsic stability, the resistance to aggregation during low pH incubation, neutralization, and solubility of the variants was also analyzed. While the parental 10-1074-LS (or MS-194) aggregated with up to 40% HMW formation, some variants showed only 2-3% HMW formation. Solubility was also increased for some variants, with up to a 42% increase in solubility over the parental molecule.


The neutralization capacity of a subset of the combinatorial variants was also examined to ensure no loss in neutralization occurred. As shown in Table 15, a reduced set of variants were tested against a representative set of 12 pseudoviruses, including SC422661.8, WITO4160.33, CAAN5342.A2, DU156.12, DU172.17, CNE17, CNE30, CNE53, 235-47, X1193_c1, X1254_c3, and 3301.v1.c24. Variants with a Tm2 were selected for the testing. Of the variants that were tested they all retained neutralization activity against the set of pseudoviruses examined.


The final set of variants for in-depth biophysical analysis was defined based on the biophysical attributes since the reduced set of antibodies defined in Table 15 all retained neutralization activity. The specific reasons for exclusion of bnAbs from the set for in-depth analysis are described in Table 16, and the final set is shown below.


















LIGHT CHAIN
HEAVY CHAIN



ORIGINAL NAME
MODIFICATIONS
MODIFICATIONS



















MS-200
10-1074_ROUND2_XTEND.015
LMDV: Y2P
HV: R82V, HV: T108R


MS-201
10-1074_ROUND2_XTEND.019

HV: V79T, HV: L89F,





HV: T108R


MS-202
10-1074_ROUND2_XTEND.023
LMDV: Y2P
HV: V79T, HV: L89F,





HV: T108R









In-Depth Analysis of the Final Variant Set


The final optimized variant was based on the final variant set defined above. Analysis performed was downstream purification (FIGS. 1-2), accelerated stability (FIGS. 3-4). For the downstream purification analysis and accelerated stability, molecules were produced using transient expression in a CHO-S cell line.


The results from the in-depth analysis indicate that MS-202 was the best performing molecule of the optimized variants. While both MS-200, MS-201, and MS-202 have similar rates of dimer formation at 40° C., MS-202 shows better resistance to sub-visible particle formation over a 13 week period.


Production of Antibodies


Antibody materials were cloned and produced as previously described (Durocher, Y., Perret, S., & Kamen, A. (2002). Nucleic Acids Research, 30(2), E9). bNAbs antibody materials were generated from transient expression of two suspension cell lines, Human Embryonic Kidney 293 (HEK293) and Chinese Hamster Ovary (CHO). The pTT5 mammalian expression vectors containing either a light chain (LC) or heavy chain (HC) coding region were co-transfected into HEK293 cells at a viable cell density (VCD) of 1*10{circumflex over ( )}6 cells/mL using polyethyleneimine (PEI) (Durocher, Perret, & Kamen, 2002) then two-fold diluted with pre-warmed medium to ⅕ shake flask volume. Expression duration was 5-7 days at 37° C., 5% CO2, and 85% humidity at a shaking speed of 130 RPM with an orbit of 19 mm. The ExpiCHO-S™ “max titer” method was followed essentially as described by ThermoFisher (catalog number A29133, document part number A29518). The pcDNA3.4 expression vectors containing either LC or HC coding regions were co-transfected into CHO-S cells at a VCD of 6*10{circumflex over ( )}6 using expifectamine. The expression duration was 12 days at 32° C., 5% CO2, and 85% humidity at a shaking speed of 130 RPM with an orbit of 19 mm. All clarified supernatants were produced by pelleting the cells at 3000 g for 20 minutes followed by 0.22 m filtration. Antibodies were purified from the clarified supernatants using Mab Select SuRe protein A resin. A sodium phosphate, sodium chloride buffer system with an arginine wash and an acetate pH 3.5 elution was utilized. Protein A elutions were neutralized with tris and buffer exchanged into 20 mM sodium phosphate, 150 mM NaCl, pH 7.4.


Neutralization Assays


Virus neutralization was evaluated using a luciferase-based assayin TZM.bl cells (J Virol 79(16):10108-10125). The HIV-1 pseudoviruses tested contained mostly tier-2 and tier-3 viruses (Journal of Virology 84(3):1439-1452). High-mannose-only pseudoviruses were produced in wild-type cells treated with 25 μM kifunensine (Enzo Life Sciences) or in HEK 293S GnTI−/− cells. Non-linear regression analysis was used to calculate concentrations at which half-maximal inhibition was observed (IC50 values). Neutralization activities were also evaluated with a previously characterized PBMC-based assay using infection with primary HIV-1 variants (n=95) isolated from clade B-infected donors with known seroconversion dates either between 1985 and 1989 (“historical seroconverters”, n=14) or between 2003 and 2006 (“contemporary seroconverters”, n=21) (Journal of Virology 85(14):7236-7245; Nat Med 16(9):995-997). Neutralization activity for each antibody was calculated using GraphPad Prism software (v5.0b) as the area under the best-fit curve, which fits the proportion of viruses neutralized over IC50 values ranging from 0.001 to 50 μg/ml.


HP-SEC


High-Performance Size Exclusion Chromatography (“HP-SEC”) separates proteins based on differences in their hydrodynamic volumes. Molecules with larger hydrodynamic protein volumes elute earlier than molecules with smaller volumes. Undiluted samples were loaded onto a Waters XBridge Protein BEH SEC 200 Å column (3.5 μm, 7.8×300 mm), separated isocratically with a 100 mM sodium phosphate, 250 mM sodium chloride, pH 6.8 running buffer, and the eluent was monitored by UV absorbance at 280 nm. Purity was determined by calculating the percentage of each separated component as compared to the total integrated area.


DSF


The DSF technique consists of measuring the fluorescence intensity of a hydrophobic probe at gradually increasing temperatures to determine the transition temperature and exposure of the hydrophobic regions of a protein. The measurements from this technique, reported as transition temperatures, correlate well with data obtained from differential scanning calorimetry (DSC). DSF is a high throughput technique that is used to estimate a protein's relative thermodynamic stability and by ranking the results, can be used as a tool to select candidates with more favorable stability properties. Thermal transition temperature(s) by DSF were measured according to the method previously described (Feng H, et al. J Pharm Sci, 2010; 99:4, 1707-1720). The analysis was carried out in PBS buffer (20 mM sodium phosphate and 150 mM sodium chloride pH 7.1) at a final protein concentration of 0.15 mg/mL and a final Sypro Orange concentration of 3×. Protein and Sypro Orange were mixed at a 1:1 volumetric ratio in a 96 well PCR plate and analyzed using a Roche Light Cycler 480 instrument equipped with Thermal Shift Analysis Software. Thermal curves were generated by heating the samples from 20-95° C. at a ramp rate of 4.4° C./s and 10 acquisitions per ° C., at Ex=465 nm Em=580 nm. Transition temperatures and shoulder scores were determined using the first derivative of the melting curve.


Low pH Stability


The pH of protein samples at 1 mg/mL in 20 mM PBS was lowered to approximately pH 3.3 using 2 M acetic acid. After a 30 minute incubation, samples were neutralized to approximately pH 5 using 2 M Tris base. Samples were measured for high molecular weight species using the SE-HPLC method and measured in duplicate. As a control, protein samples had PBS added that was the same volume of the 2 M acetic acid and 2 M Tris base and measured for high molecular weight species.


Relative Solubility


Solubility was assessed according to the method previously described (Vishal M. Toprani, Sangeeta B. Joshi, Lisa A. Kueltzo, Richard M. Schwartz, C. Russell Middaugh, David B. Volkin). A micro-polyethylene glycol precipitation assay as a relative solubility screening tool for monoclonal antibody design and formulation development (J. Pharm. Sci 2016; 105:8: 2319-2327). Analysis was done in PBS buffer (20 mM sodium phosphate and 150 mM sodium chloride pH 7.1) and a final PEG 10,000 concentration of 7.9%. Protein at 1 mg/mL was diluted into the PEG solution at a 1:4 ratio and incubated at room temperature overnight in a 96 well 0.22 m filter plate. After PEG incubation, samples are passed through the filter by centrifugation and the remaining soluble protein is measured by a protein A titer assay.


Chemical Unfolding


Thirty-two guanidine hydrochloride (GND) concentrations in PBS ranging from 0 to 6 M GND were prepared using a liquid handling robot. Then, the protein samples at 1 mg/mL in 20 mM PBS were transferred to each GND concentration to achieve a final protein concentration of 0.05 mg/mL. After a 24 hr incubation, the samples were measured on a SpectraMax M5 plate reader (excitation: 280 nm, emission: 300-450 nm). The measured fluorescence intensity at 373 nm was corrected for scattering and stray light by subtraction of a small amount of the summed intensity measured between 300 and 320 nm (used as a surrogate for signal due to scattering) and then ratioed to the total intensity measured between 320 and 440 nm to correct for total intensity fluctuations. Then, the chemical unfolding curve was generated by graphing each corrected intensity against the GND concentration. The inflection point of the curve was calculated and reported for each protein sample from this curve. Samples were completed in triplicate.


Sub-Visible Particle Analysis


Sub-visible particles were measured using a Flowcam 8100 benchtop microflow imaging system equipped with an 80 μm flow cell and a 10× magnification lens and controlled by the Visual Spreadsheet software. Samples were equilibrated to room temperature and gently swirled to mix thoroughly. Single readings of 100 μl per sample were collected, and total particle concentration above 2 μm was recorded.


Example 3

Characterization for the Formation of Oligomeric Species and HMW of the 10-1074 Variants During Viral Inactivation and the Purification Steps



FIG. 1 shows the characterization of anti-HIV antibody 10-1074 variants MS-194 (FIG. 1A) and MS-203 (FIG. 1B) by high-performance size exclusion chromatography (“HP-SEC”) before and after viral neutralization. Peaks in the HP-SEC profiles corresponding to the oligomeric species formed during viral inactivation are indicated by arrows. FIG. 2 shows quantification of the degree of aggregation represented by the level of high molecular weight (“HMW”) and oligomeric species following each of the purification steps for the 10-1074 antibody variants MS-194, MS-200, MS-201, and MS-203.


Molecules MS-194, MS-200, MS-201, and MS-203, were produced using the ExpiCHO-S™ “max titer” method essentially as described by ThermoFisher (catalog number A29133, document part number A29518). The pcDNA3.4 expression vectors containing either light chain or heavy chain coding regions were co-transfected into CHO-S cells at a VCD of 6*10{circumflex over ( )}6 using expifectamine. The expression duration was 12 days at 32° C., 5% CO2 and 85% humidity at a shaking speed of 130 RPM with an orbit of 19 mm. All clarified supernatants were produced by pelleting the cells at 3000 g for 20 minutes followed by 0.22 μm filtration.


Antibodies were purified from the clarified supernatants using MabSelect SuRe protein A resin. Equilibrated with a Tris and sodium chloride buffer. Following loading of the column, the column was washed with a Tris buffer containing 0.5M sodium chloride. Bound mAb was eluted with a 0.1 M acetate buffer at pH 3.6 and neutralized. The stability of each molecule during viral inactivation was ascertained by titrating the eluate to pH 3.5, followed by incubating for 1 hour followed by neutralization with Tris buffer. The remainder of the Protein A elutions were also neutralized with a tris buffer system immediately following elution. Further purification was achieved by loading the neutralized eluent onto a Fractogel SO3 cation-exchange resin (EMD Millipore Corporation) and eluting with a sodium chloride gradient. The peak containing the mAb was collected, concentrated to 20 mg/mL, and buffer exchanged into 10 mM acetate, 9% sucrose, pH 5.2.


The percent high molecular weight and oligomer were determined for each sample using HP-SEC analysis as previously described. As shown in FIGS. 1A and 1B and quantified in FIG. 2 the MS-194 antibody shows a significant increase in oligomer during the low pH viral inactivation while molecules MS-200, MS-201, and MS-203 showed no increase in HMW or oligomer content during the viral inactivation process.


Example 4

Characterization of Stability of the 10-1074 Variants



FIG. 3 shows the level of HMW during incubation at 40° C. for up to 13 weeks for the 10-1074 antibody variants MS-194, MS-200, MS-201, and MS-203. The figure shows a similar rate of dimer formation during incubation at 40° C. for up to 13 weeks. FIG. 4 shows the level of sub-visible particle formation during 6 weeks and 13 weeks for the 10-1074 antibody variants MS-194, MS-200, MS-201, and MS-203. The figure shows that antibodies MS-200, MS-201 and MS-203 particulated to a much smaller degree than MS-194. After 6 weeks, MS-194 showed 6× more particles than MS-200, MS-201, and MS-203, while after 13 weeks MS-200 and MS-203 had approximately 2× less than MS-194 and MS-203 showed 4× less particle formation.


Monoclonal antibodies MS-194, MS-200, MS-201 and MS-203 purified by cation-exchange chromatography and buffer exchanged as previously described were buffer exchanged into 20 mM acetate, 9% sucrose and concentrated to 100 mg/mL at a final pH of 5.2. A 500 μL aliquot of each sample was placed in a 4 mL Type I glass vial, sealed with a rubber stopper and aluminum crimp seal. The samples were incubated for up to 13 weeks at 40° C. Samples were removed at the indicated time points and the vials resealed and placed back in the incubator. The % HMW was determined using HP-SEC and sub-visible particles determined using the FlowCam instrument as described above.


Example 5

Combination Therapy with Anti-HIV-1 Antibodies


Although anti-HIV-1 antibodies constitute a potential alternative to ARTS, treatment of viremic individuals with a single antibody also results in emergence of resistant viral variants ((Caskey, M. et al. Nature 522, 487-491 (2015); Caskey, M. et al. Nat. Med. 23, 185-191 (2017); Lynch, R. M. et al. Sci. Transl. Med. 7, 319ra206 (2015)). Moreover, combinations of first-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) had little measurable effect on the infection. This disclosure presents the results from a phase 1b clinical trial (NCT02825797) in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption (ATI) (Mendoza et al., Nature. 2018 September; 561(7724): 479-484; Bar-On et al., Nature Medicine 24:1701-1707 (2018)). Participants received three infusions of 30 mg/kg of each antibody at 0, 3, and 6 weeks. Infusions of the two antibodies were generally well tolerated. The nine enrolled individuals with antibody-sensitive latent viral reservoirs maintained suppression for 15 to >30 weeks (median=21 weeks). In the four individuals with dual antibody-sensitive viruses, immunotherapy resulted in an average reduction in HIV-1 viral load of 2.05 log10 copies per ml that remained significantly reduced for three months following the first of up to three infusions. In addition, none developed viruses resistant to both antibodies. It was concluded that the combination of anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 could maintain long-term suppression in the absence of ART in individuals with antibody-sensitive viral reservoirs.


Study Design


An open-label phase 1b study was conducted in HIV-1-infected participants who were virologically suppressed on antiretroviral therapy (ART) (http://www.clinicaltrials.gov; NCT02825797; EudraCT: 2016-002803-25) (Mendoza et al., Nature. 2018 September; 561(7724): 479-484; Bar-On et al., Nature Medicine 24:1701-1707 (2018)). Study participants were enrolled sequentially according to eligibility criteria. Participants received 3BNC117 and 10-1074 intravenously at a dose of 30 mg/kg body weight of each antibody, at weeks 0, 3, and 6, unless viral rebound occurred. ART was discontinued 2 days after the first infusion of antibodies (day 2). Plasma HIV-1 viral RNA levels were monitored weekly and ART was resumed if viral load increased to ≥200 copies/ml or CD4+ T cell counts decreased to <350 cells/μl in two consecutive measurements. Time of viral rebound was determined by the first viral load >200 copies/ml. Study participants were followed for 30 weeks after the first infusion. Safety data are reported until the end of study follow-up. All participants provided written informed consent before participation in the study, and the study was conducted in accordance with Good Clinical Practice (GCP). The protocol was approved by the Federal Drug Administration (FDA) in the USA, the Paul-Ehrlich-Institute in Germany, and the Institutional Review Boards (IRBs) at the Rockefeller University and the University of Cologne.


Study Participants


Study participants were recruited at the Rockefeller University Hospital, New York, USA, and the University Hospital Cologne, Cologne, Germany. Eligible participants were adults aged 18-65 years, HIV-1-infected, on ART for a minimum of 24 months, with plasma HIV-1 RNA levels of <50 copies/ml for at least 18 months (one viral blip of >50 but <500 copies/ml during this 18-month period was allowed), plasma HIV-1 RNA levels <20 copies/ml at the screening visit, and a current CD4+ T cell count >500 cells/μl. In addition, participants were pre-screened for sensitivity of latent proviruses against 3BNC117 and 10-1074 by bulk PBMC viral outgrowth culture as described below. Sensitivity was defined as an IC50<2 μg/ml for both 3BNC117 and 10-1074 against outgrowth virus. Participants on an NNRTI-based ART regimen were switched to an integrase inhibitor-based regimen (dolutegravir plus tenofovir disoproxil fumarate/emtricitabine) 4 weeks before treatment interruption due to the prolonged half-life of NNRTIs. Exclusion criteria included reported CD4+ T cell nadir of <200 cells/μl, concomitant hepatitis B or C infection, previous receipt of monoclonal antibodies of any kind, clinically relevant physical findings, medical conditions or laboratory abnormalities, and pregnancy or lactation.


Study Procedures


3BNC117 and 10-1074 were administered intravenously at a dose level of 30 mg/kg (Mendoza et al., Nature. 2018 September; 561(7724): 479-484; Bar-On et al., Nature Medicine 24:1701-1707 (2018)). The appropriate stock volume of 3BNC117 and 10-1074 was calculated according to body weight and diluted in sterile normal saline to a total volume of 250 ml per antibody. Monoclonal antibody infusions were administered sequentially and intravenously over 60 minutes. Study participants were observed at the Rockefeller University Hospital or the University Hospital Cologne for one hour after the last antibody infusion. Participants returned for weekly follow-up visits during the ATI period for safety assessments, which included physical examination and measurements of clinical laboratory parameters such as hematology, chemistries, urinalysis, and pregnancy tests (for women). Plasma HIV-1 RNA levels were monitored weekly during the ATI period, and CD4+ T cell counts were measured every 1 to 2 weeks. After ART was re-initiated, participants returned for follow up every 2 weeks until viral re-suppression was achieved, and every 8 weeks thereafter. Study investigators evaluated and graded adverse events according to the DAIDS AE Grading Table (version 2.0, November 2014) and determined causality. Leukapheresis was performed at the Rockefeller University Hospital or at the University Hospital Cologne at week −2 and week 12. Blood samples were collected before and at multiple times after 3BNC117 and 10-1074 infusions. Samples were processed within 4 h of collection, and serum and plasma samples were stored at −80° C. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation. The absolute number of PBMCs was determined by an automated cell counter (Vi-Cell XR; Beckman Coulter) or manually, and cells were cryopreserved in fetal bovine serum plus 10% DMSO.


Plasma HIV-1 RNA Levels


HIV-1 RNA levels in plasma were measured at the time of screening, at week −2, day 0 (before infusion), weekly during ATI, and every two weeks to every eight weeks after viral rebound had occurred. HIV-1 RNA levels were determined using the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 Assay (version 2.0) or the Roche COBAS HIV-1 quantitative nucleic acid test (COBAS 6800), which quantitate HIV-1 RNA over a range of 2×101 to 1×107 copies/ml. These assays were performed at LabCorp or at the University Hospital Cologne.


CD4+ T Cells


CD4+ T-cell counts were determined by a clinical flow cytometry assay, performed at LabCorp or at the University Hospital Cologne, at screening, week 0 (before infusion), weeks 2, 3, 5, 6, 8, 10, and weekly thereafter, while participants remained off ART.


Determination of Baseline Neutralizing Antibody Activity


Purified IgG (Protein G Sepharose 4 Fast Flow, GE Life Sciences) obtained before antibody infusions was tested against a panel of 12 HIV-1 pseudoviruses as described previously (Schoofs T et al. Science 352, 997-1001 (2016)).


Measurement of 3BNC117 and 10-1074 Serum Levels


Blood samples were collected before, at the end of each 3BNC117 infusion and at the end of each 10-1074 infusion at weeks 0, 3, and 6, and weekly during the ATI period, up to week 30. Serum levels of 3BNC117 and 10-1074 were determined by a TZM-bl assay and by ELISA from samples obtained before and after each antibody infusion, and approximately every three weeks during follow up as well as at the time of viral rebound.


3BNC117 and 10-1074 serum concentrations were measured by a validated sandwich ELISA. High bind polystyrene plates were coated with 4 μg/ml of an anti-idiotypic antibody specifically recognizing 3BNC117 (anti-ID 1F1-2E3 mAb) or 2 μg/ml of an anti-idiotypic antibody specifically recognizing 10-1074 (anti-ID 3A1-4E11 mAb), and incubated overnight at 2-8° C. After washing, plates were blocked with 5% Milk Blotto (w/v), 5% NGS (v/v), and 0.05% Tween 20 (v/v) in PBS. Serum samples, QCs and standards were added (1:50 minimum dilution in 5% Milk Blotto (w/v), 5% NGS (v/v), and 0.05% Tween 20 (v/v) in PBS) and incubated at room temperature. 3BNC117 or 10-1074 were detected using a horseradish peroxidase (HRP)-conjugated mouse anti-human IgG kappa-chain-specific antibody (Abcam) for 3BNC117 or an HRP-conjugated goat antihuman IgG Fc-specific antibody for 10-1074 (Jackson ImmunoResearch) and the HRP substrate tetra-methylbenzidine. 3BNC117 and 10-1074 concentrations were then calculated from a standard curve of 3BNC117 or 10-1074 run on the same plate using a 5-PL curve-fitting algorithm (Softmax Pro, v5.4.5). Standard curves and positive controls were created from the drug product lots of 3BNC117 and 10-1074 used in the clinical study. The capture anti-idiotypic mAbs were produced using a stable hybridoma cell line (Duke Protein Production Facility). The lower limit of quantitation for the 3BNC117 ELISA is 0.78 μg/ml and for the 10-1074 ELISA is 0.41 μg/ml. The lower limit of detection was determined to be 0.51 μg/ml and 0.14 μg/ml in HIV-1 seropositive serum for the 3BNC117 and 10-1074 ELISA, respectively. For values that were detectable (i.e., positive for mAb) but were below the lower limit of quantitation, values are reported as <0.78 μg/ml and <0.41 μg/ml for 3BNC117 and 10-1074 ELISA, respectively. If day 0 baseline samples had measurable levels of antibody by the respective assays, the background measured antibody level was subtracted from subsequent results. In addition, samples with antibody levels measured to be within 3-fold from background were excluded from the analysis of PK parameters.


Serum concentrations of active 3BNC117 and 10-1074 were also measured using a validated luciferase-based neutralization assay in TZM-bl cells as previously described (Sarzotti-Kelsoe M et al. J Immunol Methods 409, 131-146 (2014)). Briefly, serum samples were tested using a primary 1:20 dilution with a 5-fold titration series against HIV-1 Env pseudoviruses Q769.d22 and X2088_c9, which are highly sensitive to neutralization by 3BNC117 and 10-1074, respectively, while fully resistant against the other administered antibody. In the case of the post-infusion time points of 10-1074, instances where serum ID50 titers against X2088_c9 were >100,000, serum samples were also tested against a less sensitive strain, Du422. To generate standard curves, 3BNC117 and 10-1074 clinical drug products were included in every assay set-up using a primary concentration of 10 μg/ml with a 5-fold titration series. Serum concentrations of 3BNC117 and 10-1074 for each sample were calculated as follows: serum ID50 titer (dilution)×3BNC117IC50 or 10-1074 IC50 titer (μg/ml)=serum concentration of 3BNC117 or 10-1074 (μg/ml). Env pseudoviruses were produced using an ART-resistant backbone vector that reduces background inhibitory activity of antiretroviral drugs if present in the serum sample (SG3ΔEnv/K101P.Q148H.Y181C). Virus pseudotyped with the envelope protein of murine leukemia virus (MuLV) was utilized as a negative control. Antibody concentrations were calculated using the serum ID80 titer and monoclonal antibody IC80 if non-specific activity against MuLV was detected (ID50>20; 9246, week 30; 9248, baseline, d0, wk 18). All assays were performed in a laboratory meeting GCLP standards.


Pre-Screening Bulk PBMC Culture


To test HIV-1 viral strains for sensitivity to 3BNC117 and 10-1074, bulk viral outgrowth cultures were performed by co-culturing isolated CD4+ T cells with MOLT-4/CCR-5 cells or CD8+ T cell-depleted donor lymphoblasts. PBMCs for pre-screening were obtained up to 72 weeks (range 54-505 days) before enrollment under separate protocols approved by the IRBs of The Rockefeller University and the University of Cologne. Sensitivity was determined by TZM-bl neutralization assay as described below. Culture supernatants with IC50<2 μg/ml were deemed sensitive.


Quantitative and Qualitative Viral Outgrowth Assay (Q2VOA)


The quantitative and qualitative viral outgrowth assay (Q2VOA) was performed using isolated PBMCs from leukapheresis at week −2 and week 12 as previously described (Lorenzi J C et al. PNAS 113, E7908-E7916 (2016)). Briefly, isolated CD4+ T cells were activated with 1 μg/ml phytohemagglutinin (Life Technologies) and 100 U/ml IL-2 (Peprotech) and co-cultured with 1×106 irradiated PBMCs from a healthy donor in 24-well plates. A total of 6×107-6.2×108 cells were assayed for each individual at each of the 2 time points. After 24 hours, PHA was removed and 0.1×106 MOLT-4/CCR5 cells were added to each well. Cultures were maintained for 2 weeks, splitting by half the MOLT-4/CCR5 cells 7 days after the initiation of the culture and every other day after that. Positive wells were detected by measuring p24 by ELISA. The frequency of latently infected cells was calculated through the infectious units per million (IUPM) algorithm developed by the Siliciano lab (http://silicianolab.johnshopkins.edu).


Rebound Outgrowth Cultures


CD4+ T cells isolated from PBMCs from the rebound time points were cultured at limiting dilution exactly as described for Q2VOA. CD4+ T cells were activated with T cell activation beads (Miltenyi) at a concentration of 0.5×106 beads per 106 CD4+ T cells and 20 U/ml of IL-2. Rebound outgrowth was performed using PBMCS from the highest viral load sample (usually the repeat measurement ≥200 copies/ml). Viruses whose sequences matched the SGA env sequences, and therefore were identical to those present in plasma, as opposed to potentially reactivated PBMC-derived latent reservoir viruses, were selected to test for neutralization.


Viral Sensitivity Testing


Supernatants from p24-positive bulk PBMC cultures, rebound PBMC outgrowth cultures and Q2VOA wells were tested for sensitivity to 3BNC117 and 10-1074 by TZM-bl neutralization assay as previously described (Sarzotti-Kelsoe M et al. J Immunol Methods 409, 131-146 (2014)).


Sequencing


HIV-1 RNA extraction and single genome amplification were performed as previously described (Salazar-Gonzalez J F et al. J Virol 82, 3952-3970 (2008)). In brief, HIV-1 RNA was extracted from plasma samples or Q2VOA-derived virus supernatants using the MinElute Virus Spin kit (Qiagen) followed by first strand cDNA synthesis using SuperScript III reverse transcriptase (Invitrogen). cDNA synthesis for plasma-derived HIV-1 RNA was performed using the antisense primer envB3out Fidelity Platinum Taq (Invitrogen) and run at 94° C. for 2 min; 35 cycles of 94° C. for 15 s, 55° C. for 30 s, and 68° C. for 4 min; and 68° C. for 15 min. Second round PCR was performed with 1 μl of first PCR product as template and High Fidelity Platinum Taq at 94° C. for 2 min; 45 cycles of 94° C. for 15 s, 55° C. for 30 s, and 68° C. for 4 min; and 68° C. for 15 min. cDNA synthesis for Q2VOA-derived HIV-1 RNA was performed using the antisense primer R3B6R


Study Outcomes


Combination bNab Infusion is Well Tolerated


To evaluate the effects of the combination of 3BNC117 and 10-1074 on maintaining HIV-1 suppression during ATI, a Phase 1b clinical trial was conducted (FIG. 5A) (Mendoza et al., Nature. 2018 September; 561(7724): 479-484). HIV-1-infected individuals on ART were pre-screened for 3BNC117 and 10-1074 sensitivity of bulk outgrowth culture-derived viruses using the TZM-bl neutralization assay. Consistent with previous results, 64% and 71% of the outgrowth viruses were sensitive to 3BNC117 and 10-1074, respectively, and 48% were sensitive to both (IC50≤2 μg/ml).


Study eligibility criteria included ongoing ART for at least 24 months with plasma HIV-1 RNA levels of <50 copies/ml for at least 18 months (with one blip <500 copies/ml allowed) and <20 copies/ml at screening, as well as CD4+ T cell counts >500 cells/μl. Enrolled participants received 3 infusions of 30 mg/kg each of 3BNC117+10-1074 at 3-week intervals beginning 2 days before treatment interruption (FIG. 5A). Individuals whose regimens contained non-nucleoside reverse transcriptase inhibitors were switched to an integrase inhibitor-based regimen 4 weeks before discontinuing ART (FIG. 6A). Viral load and CD4+ T cell counts were monitored every 1-2 weeks. ART was reinitiated, and antibody infusions were discontinued if viremia of >200 copies/ml was confirmed. Time of viral rebound was defined as the first of two consecutive viral loads >200 copies/ml. Fifteen individuals were enrolled, but four of them showed viral loads of >20 copies/ml two weeks before or at the time of the first bNAb infusion, and they were excluded from efficacy analyses.


Antibody infusions were generally safe and well-tolerated with no reported serious adverse events or antibody-related adverse events except for mild fatigue in two participants. The mean CD4+ T cell count was 685 and 559 cells/μl at the time of first antibody infusion and at rebound, respectively (FIG. 6B). Re-initiation of ART after viral rebound resulted in resuppression of viremia. It was concluded that combination therapy with 3BNC117+10-1074 is generally safe and well-tolerated.


Combination bNAbs Maintain Viral Suppression


For the 11 individuals who had complete viral suppression (HIV-1 RNA<20 copies/ml) during the screening period and at day 0, combination antibody therapy was associated with maintenance of viral suppression for 5 to >30 weeks (FIGS. 5B and 5C) (Mendoza et al., Nature. 2018 September; 561(7724): 479-484). The median time to rebound was 21 weeks compared to 2.3 weeks for historical controls who participated in non-interventional ATI studies and 6-10 weeks for monotherapy with 3BNC117 (FIG. 5C). Altogether, 9 of the 11 participants maintained viral suppression for over 15 weeks, while 2 rebounded at weeks 5 and 7 (FIGS. 5B and 5C).


Quantitative and qualitative viral outgrowth assays (Q2VOA) were used to retrospectively analyze the replication-competent latent viral reservoir in all individuals. Phylogenetic analysis showed that the trial participants were infected with epidemiologically distinct clade B viruses. Q2VOA analysis revealed that the pre-infusion latent reservoir in the two individuals rebounding early, 9245 and 9251, harbored 10-1074- or 3BNC117-resistant viruses, respectively (FIG. 7). Therefore, these two individuals were effectively subjected to antibody monotherapy because there was pre-existing resistance in the reservoir to one of the two bNAbs. Consistent with this idea, the delay in rebound in these two participants was within the range anticipated for antibody monotherapy (FIG. 5C). In addition, all four of the individuals excluded from the analysis due to incomplete viral suppression showed pre-existing resistance or viruses that were not fully neutralized by one or both of the antibodies and these individuals rebounded before week 12.


To examine the viruses arising in the early rebounding individuals, single genome analysis (SGA) on rebound plasma was performed. Pseudoviruses constructed from plasma SGA were tested for bNAb sensitivity in the TZM-bl assay. In addition to the pre-existing sequences associated with resistance in the 10-1074 target site (N332T+S334N, FIG. 7A), rebound viruses in 9245 also carried an extended V5 loop and potential N-linked glycosylation sites that could interfere with 3BNC117 binding. Conversely, genetic features associated with resistance to 3BNC117 were found in the pre-infusion reservoir of 9251 and were accompanied by mutations in the 10-1074 target site in the rebounding viruses (S334N, FIG. 7A). For both individuals, resistance of rebound viruses to both antibodies was confirmed by the TZM-bl neutralization assay (FIGS. 7B and 7C). Thus, bulk outgrowth cultures used for screening failed to detect pre-existing resistance in the reservoir of 2 of the 11 individuals studied. This result is not surprising given that bulk cultures are dominated by a limited number of rapidly growing viral species which may not be representative of the diversity in the latent reservoir.


Similarly, participant 91C33, who failed to respond to antibody infusions, had preexisting circulating viruses that were resistant to both antibodies (Bar-On et al., Nature Medicine 24:1701-1707 (2018)). These viruses carried mutations in 3BNC117 contact sites (N280S and A281H) and in 10-1074 contact sites (N332T and S334N). Two individuals, 91C35 and 9341, responded to antibody therapy with a decrease in viremia of −1.58 and −1.32 log10 copies per ml but HIV-1 RNA levels returned to baseline within 3 and 4 weeks, respectively. 91C35 was found to have pre-infusion circulating viruses with reduced sensitivity to 3BNC117, and carried a CD4 contact residue mutation (A281T) that was associated with viral escape from 3BNC11720. Pre-infusion viruses derived from bulk CD4+ T cell outgrowth cultures of 9341 showed a 10-1074 IC80 that was 1.3 log10 higher than the geometric mean IC80 of all other enrolled viremic individuals. In both of these cases, rebounding viruses were resistant to both antibodies and carried mutations resulting in the loss of the potential N-linked glycosylation site at position 332 that is critical for 10-1074 binding. In addition, rebound viruses from 91C35 and 9341 contained G471E and N276D mutations, respectively, that are associated with increased resistance to 3BNC117. These mutations were not found in the pre-infusion circulating viruses described above or in the additional 113 pre-infusion env sequences that were analyzed from these two participants. Thus, 91C35 and 9341 were infected with viruses with reduced sensitivity to one of the two antibodies and resemble individuals that received antibody monotherapy, both in the magnitude of the drop in viremia and time required to return to baseline viremia. It was concluded that the bulk outgrowth cultures used for initial screening failed to detect partial or complete preexisting resistance against one or both of the antibodies in three of the seven individuals studied.


The four remaining individuals showed no detectable pre-existing resistant viruses in circulation and experienced significantly suppressed viremia until day 94 after the first antibody infusion with an average maximum drop in viral load of −2.05 log10 copies per ml (Bar-On et al., Nature Medicine 24:1701-1707 (2018)). The individual in this group with the highest initial viral load (97,800 copies per ml; patient 9343) was the first to rebound at eight weeks. The two individuals with the lowest initial viral loads, 91C22 and 9342 (750 and 2,550 copies per ml, respectively), demonstrated suppression to near or below the limit of detection for 12 and 16 weeks, respectively. Finally, viremia in participant 91C34 was reduced for a period of 12 weeks, however it never dropped below 810 copies per ml. Despite the persistent viremia, no resistance against both antibodies developed in this individual for as long as bNAb serum levels were above 10 μg/ml. In three of the four initially sensitive individuals, rebound viremia was associated with the appearance of viruses that were resistant to 10-1074, but these individuals remained sensitive to 3BNC117. This is consistent with the relatively shorter half-life of 3BNC117, which means that participants were effectively exposed to 10-1074 monotherapy at the end of the observation period. In accordance with the increased resistance to 10-1074, rebound viruses carried mutations in 10-1074 contact sites. By contrast, there was no accumulation of de novo mutations in 3BNC117 contact sites. 91C22, the participant with the lowest initial viral load, only returned to baseline viremia after both antibodies were below the limit of detection, and rebound viruses remained sensitive to both antibodies. Overall none of the four participants that were initially sensitive to the two antibodies developed de novo resistance to 3BNC117 over a cumulative observation period of over one year (56 weeks), despite the residual viremia observed in three of these participants and frequent recombination events between circulating viruses.


The median time to rebound in the 7 individuals that had no detectable resistant viruses in the pre-infusion latent reservoir, and rebounded during the study period, was also 21 weeks and different from 6-10 weeks for monotherapy with 3BNC117 (FIG. 5C) (Mendoza et al., Nature. 2018 September; 561(7724): 479-484). In these participants, viral suppression was maintained for 15 to 26 weeks after ART discontinuation. The two remaining participants (9254 and 9255) completed the study follow-up at 30 weeks without experiencing rebound. Notably, viral rebound never occurred when the concentration of both administered antibodies was above 10 μg/ml. The average 3BNC117 serum concentration (determined by TZM-bl assay) at the time of rebound in sensitive individuals that rebounded during study follow-up was 1.9 μg/ml (FIG. 5B). In contrast, the average serum concentration of 10-1074 at rebound was 14.8 μg/ml (FIG. 5B). The difference in the antibody concentrations at the time of rebound is consistent with the longer half-life of 10-1074 which resulted in a period of 10-1074 monotherapy (FIG. 5B). Finally, these 9 individuals showed little or no preexisting neutralizing antibodies against a diagnostic panel of viruses before bNAb infusion.


Rebound and Latent Viruses


To examine the relationship between rebound viruses and the circulating latent reservoir, env sequences obtained from plasma rebound viruses were compared by SGA with sequences obtained by Q2VOA from both pre-infusion and week 12 samples. In addition, sensitivity of rebound outgrowth viruses and/or pseudoviruses to 3BNC117 and 10-1074 was measured by the TZM-bl neutralization assay (FIGS. 7B and 7C). A total of 154 viral env sequences obtained by plasma SGA were analyzed and compared to 408 sequences obtained from the latent reservoir by Q2VOA. Although rebound and reservoir viruses clustered together for each individual, no identical sequences between the two compartments in any of the individuals studied were found (FIGS. 8 and 9A). The difference could be accounted for by distinct requirements for HIV-1 reactivation in vitro and in vivo, compartmentalization of reservoir viruses, HIV-1 mutation during the course of the trial, and/or by viral recombination in some individuals. Whether or not bNAb therapy influences selection for recombination events remains to be determined.


Similar to 3BNC117 monotherapy, the vast majority of rebounding viruses clustered within low diversity lineages consistent with expansion of 1-2 recrudescent viruses (FIG. 8). In contrast, rebound viruses are consistently polyclonal during ATI in the absence of antibody therapy. Thus, the antibodies restrict the outgrowth of latent viruses in vivo.


The emerging viruses in 6 of the 7 individuals that rebounded when the mean 3BNC117 and 10-1074 concentrations were 1.9 and 14.8 μg/ml, respectively, carried resistance-associated mutations in the 10-1074 target site (FIGS. 5B and 8A). Consistent with the sequence data, these rebound viruses were generally resistant to 10-1074 by the TZM-bl neutralization assay but remained sensitive to 3BNC117 (FIGS. 7B and 7C). The level of sensitivity to 3BNC117 in these emerging viruses was similar to that found in the reservoir viruses in each of the individuals (FIG. 7B). One individual, 9244, showed rebound viruses that remained sensitive to both antibodies in TZM-bl neutralization assays. Rebound occurred when 3BNC117 and 10-1074 concentrations in serum of this individual were undetectable and 11.6 μg/ml, respectively (FIG. 5B). The sensitivity of the plasma rebound viruses was similar to that of latent pre-infusion and week 12 viruses obtained in viral outgrowth cultures (FIGS. 7B and 7C). Therefore, this individual did not develop resistance to either of the antibodies despite prolonged exposure to both. In conclusion, none of the 9 individuals with pre-infusion reservoirs containing viruses that were sensitive to both antibodies developed double resistance during the observation period.


The Latent Reservoir


To determine whether there were changes in the circulating reservoir during the observation period, the results of Q2VOA assays performed at entry and 12 weeks after the start of ATI for 8 of the 9 individuals that remained suppressed for at least 12 weeks were compared (FIG. 9). Similar to previous reports, 63% of all viruses obtained by Q2VOA belonged to expanded clones. Comparison of the env sequences of the viruses that emerged in outgrowth cultures revealed that 60% of the sequences could be found at both time points. However, there were numerous examples of clones that appeared or disappeared between the time points, and some of these changes were significant. To determine the number of infectious units per million (IUPM, http://silicianolab.johnshopkins.edu/), 6.0×107-6.2×108 CD4+ T cells were assayed by Q2VOA for each time point for each individual (FIG. 9B). The difference between the 2 time points was never greater than 6.5-fold for any individual, and the 2 time points were not statistically different (P=0.078). Moreover, time to rebound was not directly correlated with IUPM. Additional time points would be required to calculate the half-life of the reservoir in individuals receiving immunotherapy.


Discussion


First generation anti-HIV-1 bNAbs were generally ineffective in suppressing viremia in animal models and humans leading to the conclusion that this approach should not be pursued. bNAb monotherapy with 3BNC117 or VRC01 was not enough to maintain control during ATI in HIV-1-infected humans. In contrast, the combination of 3BNC117 and 10-1074 was sufficient to maintain viral suppression in sensitive individuals when the concentration of both antibodies remains above a certain level in serum, for example, above 10 μg/ml. Rebound occurred when 3BNC117 levels dropped below 10 μg/ml effectively leading to 10-1074 monotherapy, from which nearly all individuals rapidly escaped by mutations in the 10-1074 contact site. The observation that 9 individuals infected with distinct viruses were unable to develop double resistant viruses over a median 21 week period suggests that viral replication was severely limited by this antibody combination.


In human studies, monotherapy with 3BNC117 is associated with enhanced humoral immunity and accelerated clearance of HIV-1-infected cells. In addition, when administered early to SHIVAD8-infected macaques, combined 3BNC117+10-1074 immunotherapy induced host CD8+ T cell responses that contributed to the control of viremia in nearly 50% of the animals. However, virus-specific CD8+ T cells responsible for control of viremia in these macaques were not detected in the circulation, and their contribution to viral suppression was only documented after CD8+ T cell depletion. In most controller macaques, complete viral suppression was only established after rebound viremia that followed antibody clearance.


Two individuals in this study remained suppressed for over 30 weeks after ATI, 9254 and 9255. Neither one had detectable levels of ART in the blood or carried the B*27 and B*57 HLA alleles that are most frequently associated with elite control (Walker B D & Yu X G. Nat Rev Immunol 13, 487-498 (2013)). The first, 9254, reports starting ART within 4-5 months after probable exposure to the virus with an initial viral load of 860,000 copies/ml. Despite relatively early therapy and excellent virological control for 21 years on therapy, this individual had an IUPM of 0.68 by Q2VOA at the 12-week time point. The second individual, 9255, showed several viral blips that were spontaneously controlled beginning 15 weeks after ATI when antibody levels were waning. This individual was infected for at least 7 months before starting ART with an initial viral load of 85,800 copies/ml and had an IUPM of 1.4 at the 12-week time point. A small fraction of individuals on ART show spontaneous prolonged virologic control after ART was discontinued, and this number appears to increase when ART treatment was initiated during the acute phase of infection.


A significant fraction of the circulating latent reservoir is composed of expanded clones of infected T cells. These T cell clones appear to be dynamic in that the specific contribution of individual clones of circulating latently infected CD4+ T cells to the reservoir of individuals receiving ART fluctuates over time. Individuals that maintain viral suppression by antibody therapy appear to show similar fluctuations in reservoir clones that do not appear to be associated with antibody sensitivity. Whether the apparent differences observed in the reservoir during immunotherapy lead to changes in the reservoir half-life cannot be determined from the available data and will require reservoir assessments in additional individuals at multiple time points over an extended observation period.


Individuals harboring viruses sensitive to 3BNC117 and 10-1074 maintained viral suppression during ATI for a median of almost 4 months after the final antibody administration. In macaques, the therapeutic efficacy of anti-HIV-1 antibodies is directly related to their half-life, which can be extended by mutations that enhance Fc domain interactions with the neonatal Fc receptor. The mutations can increase the half-life of antibodies in humans by 2-4-fold. The data suggest that a single administration of combinations of bNAbs with extended half-lives could maintain suppression for 6-12 months in individuals harboring sensitive viruses.









TABLE 1







Residue numbering of anti-HIV antibody 10-1074 variant MS-194








MS-194_LC
MS-194_HC
















Mat.



Mat.



Residue
Linear #
Linear #
ASN #
Residue
Linear #
Linear #
ASN #

















M
1

Ldr: −19
M
1

Ldr: −19


G
2

Ldr: −18
G
2

Ldr: −18


W
3

Ldr: −17
W
3

Ldr: −17


S
4

Ldr: −16
S
4

Ldr: −16


C
5

Ldr: −15
C
5

Ldr: −15


I
6

Ldr: −14
I
6

Ldr: −14


I
7

Ldr: −13
I
7

Ldr: −13


L
8

Ldr: −12
L
8

Ldr: −12


F
9

Ldr: −11
F
9

Ldr: −11


L
10

Ldr: −10
L
10

Ldr: −10


V
11

Ldr: −9
V
11

Ldr: −9


A
12

Ldr: −8
A
12

Ldr: −8


T
13

Ldr: −7
T
13

Ldr: −7


A
14

Ldr: −6
A
14

Ldr: −6


T
15

Ldr: −5
T
15

Ldr: −5


G
16

Ldr: −4
G
16

Ldr: −4


V
17

Ldr: −3
V
17

Ldr: −3


H
18

Ldr: −2
H
18

Ldr: −2


S
19

Ldr: −1
S
19

Ldr: −1


S
20
1
LmdV: 1
Q
20
1
HV: 1


Y
21
2
LmdV: 2
V
21
2
HV: 2


V
22
3
LmdV: 3
Q
22
3
HV: 3



22.1
3.1
LmdV: 4
L
23
4
HV: 4



22.2
3.2
LmdV: 5
Q
24
5
HV: 5



22.3
3.3
LmdV: 6
E
25
6
HV: 6


R
23
4
LmdV: 7
S
26
7
HV: 7



23.1
4.1
LmdV: 8

26.1
7.1
HV: 8


P
24
5
LmdV: 9
G
27
8
HV: 9



24.1
5.1
LmdV: 10
P
28
9
HV: 10


L
25
6
LmdV: 111
G
29
10
HV: 11


S
26
7
LmdV: 12
L
30
11
HV: 12


V
27
8
LmdV: 13
V
31
12
HV: 13


A
28
9
LmdV: 14
K
32
13
HV: 14


L
29
10
LmdV: 15
P
33
14
HV: 15


G
30
11
LmdV: 16
S
34
15
HV: 16


E
31
12
LmdV: 17
E
35
16
HV: 17


T
32
13
LmdV: 18
T
36
17
HV: 18


A
33
14
LmdV: 19
L
37
18
HV: 19


R
34
15
LmdV: 20
S
38
19
HV: 20


I
35
16
LmdV: 21
V
39
20
HV: 21


S
36
17
LmdV: 22
T
40
21
HV: 22


C
37
18
LmdV: 23
C
41
22
HV: 23


G
38
19
LmdV: 24
S
42
23
HV: 24


R
39
20
LmdV: 25
V
43
24
HV: 25


Q
40
21
LmdV: 26
S
44
25
HV: 26



40.1
21.1
LmdV: 27
G
45
26
HV: 27



40.2
21.2
LmdV: 28

45.1
26.1
HV: 28



40.3
21.3
LmdV: 29
D
46
27
HV: 29


A
41
22
LmdV: 30
S
47
28
HV: 30


L
42
23
LmdV: 31
M
48
29
HV: 31


G
43
24
LmdV: 32
N
49
30
HV: 32


S
44
25
LmdV: 33
N
50
31
HV: 33



44.1
25.1
LmdV: 34

50.1
31.1
HV: 34



44.2
25.2
LmdV: 35

50.2
31.2
HV: 35



44.3
25.3
LmdV: 36

50.3
31.3
HV: 36



44.4
25.4
LmdV: 37

50.4
31.4
HV: 37



44.5
25.5
LmdV: 38

50.5
31.5
HV: 38


R
45
26
LmdV: 39
Y
51
32
HV: 39


A
46
27
LmdV: 40
Y
52
33
HV: 40


V
47
28
LmdV: 41
W
53
34
HV: 41


Q
48
29
LmdV: 42
T
54
35
HV: 42


W
49
30
LmdV: 43
W
55
36
HV: 43


Y
50
31
LmdV: 44
I
56
37
HV: 44


Q
51
32
LmdV: 45
R
57
38
HV: 45


H
52
33
LmdV: 46
Q
58
39
HV: 46


R
53
34
LmdV: 47
S
59
40
HV: 47


P
54
35
LmdV: 48
P
60
41
HV: 48


G
55
36
LmdV: 49
G
61
42
HV: 49


Q
56
37
LmdV: 50
K
62
43
HV: 50


A
57
38
LmdV: 51
G
63
44
HV: 51


P
58
39
LmdV: 52
L
64
45
HV: 52


I
59
40
LmdV: 53
E
65
46
HV: 53


L
60
41
LmdV: 54
W
66
47
HV: 54


L
61
42
LmdV: 55
I
67
48
HV: 55


I
62
43
LmdV: 56
G
68
49
HV: 56


Y
63
44
LmdV: 57
Y
69
50
HV: 57


N
64
45
LmdV: 58
I
70
51
HV: 58



64.1
45.1
LmdV: 59
S
71
52
HV: 59



64.2
45.2
LmdV: 60
D
72
53
HV: 60



64.3
45.3
LmdV: 61

72.1
53.1
HV: 61



64.4
45.4
LmdV: 62

72.2
53.2
HV: 62



64.5
45.5
LmdV: 63

72.3
53.3
HV: 63



64.6
45.6
LmdV: 64

72.4
53.4
HV: 64



64.7
45.7
LmdV: 65
R
73
54
HV: 65



64.8
45.8
LmdV: 66
E
74
55
HV: 66


N
65
46
LmdV: 67
S
75
56
HV: 67


Q
66
47
LmdV: 68
A
76
57
HV: 68


D
67
48
LmdV: 69
T
77
58
HV: 69


R
68
49
LmdV: 70
Y
78
59
HV: 70


P
69
50
LmdV: 71
N
79
60
HV: 71


S
70
51
LmdV: 72
P
80
61
HV: 72


G
71
52
LmdV: 73
S
81
62
HV: 73


I
72
53
LmdV: 74
L
82
63
HV: 74


P
73
54
LmdV: 75
N
83
64
HV: 75


E
74
55
LmdV: 76
S
84
65
HV: 76


R
75
56
LmdV: 77
R
85
66
HV: 77


F
76
57
LmdV: 78
V
86
67
HV: 78


S
77
58
LmdV: 79
V
87
68
HV: 79


G
78
59
LmdV: 80
I
88
69
HV: 80


T
79
60
LmdV: 81
S
89
70
HV: 81


P
80
61
LmdV: 81.1
R
90
71
HV: 82


D
81
62
LmdV: 81.2
D
91
72
HV: 83


I
82
63
LmdV: 81.3
T
92
73
HV: 84


N
83
64
LmdV: 82
S
93
74
HV: 85


F
84
65
LmdV: 83
K
94
75
HV: 86


G
85
66
LmdV: 84
N
95
76
HV: 87



85.1
66.1
LmdV: 85
Q
96
77
HV: 88



85.2
66.2
LmdV: 86
L
97
78
HV: 89


T
86
67
LmdV: 87
S
98
79
HV: 90


R
87
68
LmdV: 88
L
99
80
HV: 91


A
88
69
LmdV: 89
K
100
81
HV: 92


T
89
70
LmdV: 90
L
101
82
HV: 93


L
90
71
LmdV: 91
N
102
83
HV: 94


T
91
72
LmdV: 92
S
103
84
HV: 95


I
92
73
LmdV: 93
V
104
85
HV: 96


S
93
74
LmdV: 94
T
105
86
HV: 97


G
94
75
LmdV: 95
P
106
87
HV: 98


V
95
76
LmdV: 96
A
107
88
HV: 99


E
96
77
LmdV: 97
D
108
89
HV: 100


A
97
78
LmdV: 98
T
109
90
HV: 101


G
98
79
LmdV: 99
A
110
91
HV: 102


D
99
80
LmdV: 100
V
111
92
HV: 103


E
100
81
LmdV: 101
Y
112
93
HV: 104


A
101
82
LmdV: 102
Y
113
94
HV: 105


D
102
83
LmdV: 103
C
114
95
HV: 106


Y
103
84
LmdV: 104
A
115
96
HV: 107


Y
104
85
LmdV: 105
T
116
97
HV: 108


C
105
86
LmdV: 106
A
117
98
HV: 109


H
106
87
LmdV: 107
R
118
99
HV: 110


M
107
88
LmdV: 108
R
119
100
HV: 111


W
108
89
LmdV: 109
G
120
101
HV: 112


D
109
90
LmdV: 110
Q
121
102
HV: 113


S
110
91
LmdV: 111
R
122
103
HV: 114


R
111
92
LmdV: 112
I
123
104
HV: 115



111.1
92.1
LmdV: 113
Y
124
105
HV: 116



111.2
92.2
LmdV: 114
G
125
106
HV: 117



111.3
92.3
LmdV: 115
V
126
107
HV: 118



111.4
92.4
LmdV: 116
V
127
108
HV: 119



111.5
92.5
LmdV: 117

127.1
108.1
HV: 120



111.6
92.6
LmdV: 118

127.2
108.2
HV: 121



111.7
92.7
LmdV: 119

127.3
108.3
HV: 122



111.8
92.8
LmdV: 120

127.4
108.4
HV: 123



111.9
92.9
LmdV: 121

127.5
108.5
HV: 124



111.10
92.10
LmdV: 122

127.6
108.6
HV: 125



111.11
92.11
LmdV: 123
S
128
109
HV: 126



111.12
92.12
LmdV: 124
F
129
110
HV: 127



111.13
92.13
LmdV: 125
G
130
111
HV: 128



111.14
92.14
LmdV: 126
E
131
112
HV: 129



111.15
92.15
LmdV: 127
F
132
113
HV: 130



111.16
92.16
LmdV: 128
F
133
114
HV: 131



111.17
92.17
LmdV: 129
Y
134
115
HV: 132



111.18
92.18
LmdV: 130
Y
135
116
HV: 133



111.19
92.19
LmdV: 131
Y
136
117
HV: 134



111.20
92.20
LmdV: 132
S
137
118
HV: 135


S
112
93
LmdV: 133
M
138
119
HV: 136


G
113
94
LmdV: 134
D
139
120
HV: 137


F
114
95
LmdV: 135
V
140
121
HV: 138


S
115
96
LmdV: 136
W
141
122
HV: 139


W
116
97
LmdV: 137
G
142
123
HV: 140


S
117
98
LmdV: 138
K
143
124
HV: 141


F
118
99
LmdV: 139
G
144
125
HV: 142


G
119
100
LmdV: 140
T
145
126
HV: 143


G
120
101
LmdV: 141
T
146
127
HV: 144


A
121
102
LmdV: 142
V
147
128
HV: 145


T
122
103
LmdV: 143
T
148
129
HV: 146


R
123
104
LmdV: 144
V
149
130
HV: 147


L
124
105
LmdV: 145
S
150
131
HV: 148


T
125
106
LmdV: 146
S
151
132
HV: 149


V
126
107
LmdV: 147

151.1
132.1
HCnst-Ig: 1


L
127
108
LmdV: 148

151.2
132.2
HCnst-Ig: 2


G
128
109
LmdV: 149
A
152
133
HCnst-Ig: 3


Q
129
110
LmdCnst-Ig: 1
S
153
134
HCnst-Ig: 4


P
130
111
LmdCnst-Ig: 2
T
154
135
HCnst-Ig: 5


K
131
112
LmdCnst-Ig: 3
K
155
136
HCnst-Ig: 6


A
132
113
LmdCnst-Ig: 4
G
156
137
HCnst-Ig: 7


A
133
114
LmdCnst-Ig: 5
P
157
138
HCnst-Ig: 8


P
134
115
LmdCnst-Ig: 6
S
158
139
HCnst-Ig: 9


S
135
116
LmdCnst-Ig: 7
V
159
140
HCnst-Ig: 10


V
136
117
LmdCnst-Ig: 8
F
160
141
HCnst-Ig: 11


T
137
118
LmdCnst-Ig: 9
P
161
142
HCnst-Ig: 12


L
138
119
LmdCnst-Ig: 10
L
162
143
HCnst-Ig: 13


F
139
120
LmdCnst-Ig: 11
A
163
144
HCnst-Ig: 14


P
140
121
LmdCnst-Ig: 12
P
164
145
HCnst-Ig: 15


P
141
122
LmdCnst-Ig: 13

164.1
145.1
HCnst-Ig: 16


S
142
123
LmdCnst-Ig: 14
S
165
146
HCnst-Ig: 17


S
143
124
LmdCnst-Ig: 15

165.1
146.1
HCnst-Ig: 18


E
144
125
LmdCnst-Ig: 16
S
166
147
HCnst-Ig: 19



144.1
125.1
LmdCnst-Ig: 17
K
167
148
HCnst-Ig: 20



144.2
125.2
LmdCnst-Ig: 18
S
168
149
HCnst-Ig: 21


E
145
126
LmdCnst-Ig: 19
T
169
150
HCnst-Ig: 22


L
146
127
LmdCnst-Ig: 20
S
170
151
HCnst-Ig: 23



146.1
127.1
LmdCnst-Ig: 21
G
171
152
HCnst-Ig: 24



146.2
127.2
LmdCnst-Ig: 22
G
172
153
HCnst-Ig: 25


Q
147
128
LmdCnst-Ig: 23
T
173
154
HCnst-Ig: 26


A
148
129
LmdCnst-Ig: 24
A
174
155
HCnst-Ig: 27


N
149
130
LmdCnst-Ig: 25
A
175
156
HCnst-Ig: 28


K
150
131
LmdCnst-Ig: 26
L
176
157
HCnst-Ig: 29


A
151
132
LmdCnst-Ig: 27
G
177
158
HCnst-Ig: 30


T
152
133
LmdCnst-Ig: 28
C
178
159
HCnst-Ig: 31


L
153
134
LmdCnst-Ig: 29
L
179
160
HCnst-Ig: 32


V
154
135
LmdCnst-Ig: 30
V
180
161
HCnst-Ig: 33


C
155
136
LmdCnst-Ig: 31
K
181
162
HCnst-Ig: 34


L
156
137
LmdCnst-Ig: 32
D
182
163
HCnst-Ig: 35


I
157
138
LmdCnst-Ig: 33
Y
183
164
HCnst-Ig: 36


S
158
139
LmdCnst-Ig: 34
F
184
165
HCnst-Ig: 37


D
159
140
LmdCnst-Ig: 35
P
185
166
HCnst-Ig: 38


F
160
141
LmdCnst-Ig: 36

185.1
166.1
HCnst-Ig: 39


Y
161
142
LmdCnst-Ig: 37

185.2
166.2
HCnst-Ig: 40


P
162
143
LmdCnst-Ig: 38
E
186
167
HCnst-Ig: 41



162.1
143.1
LmdCnst-Ig: 39
P
187
168
HCnst-Ig: 42



162.2
143.2
LmdCnst-Ig: 40
V
188
169
HCnst-Ig: 43


G
163
144
LmdCnst-Ig: 41
T
189
170
HCnst-Ig: 44


A
164
145
LmdCnst-Ig: 42
V
190
171
HCnst-Ig: 45


V
165
146
LmdCnst-Ig: 43
S
191
172
HCnst-Ig: 46


T
166
147
LmdCnst-Ig: 44
W
192
173
HCnst-Ig: 47


V
167
148
LmdCnst-Ig: 45

192.1
173.1
HCnst-Ig: 48


A
168
149
LmdCnst-Ig: 46
N
193
174
HCnst-Ig: 49


W
169
150
LmdCnst-Ig: 47
S
194
175
HCnst-Ig: 50



169.1
150.1
LmdCnst-Ig: 48
G
195
176
HCnst-Ig: 51


K
170
151
LmdCnst-Ig: 49
A
196
177
HCnst-Ig: 52


A
171
152
LmdCnst-Ig: 50
L
197
178
HCnst-Ig: 53


D
172
153
LmdCnst-Ig: 51
T
198
179
HCnst-Ig: 54


S
173
154
LmdCnst-Ig: 52
S
199
180
HCnst-Ig: 55


S
174
155
LmdCnst-Ig: 53
G
200
181
HCnst-Ig: 56


P
175
156
LmdCnst-Ig: 54
V
201
182
HCnst-Ig: 57


V
176
157
LmdCnst-Ig: 55
H
202
183
HCnst-Ig: 58


K
177
158
LmdCnst-Ig: 56
T
203
184
HCnst-Ig: 59


A
178
159
LmdCnst-Ig: 57

203.1
184.1
HCnst-Ig: 60


G
179
160
LmdCnst-Ig: 58

203.2
184.2
HCnst-Ig: 61


V
180
161
LmdCnst-Ig: 59
F
204
185
HCnst-Ig: 62


E
181
162
LmdCnst-Ig: 60
P
205
186
HCnst-Ig: 63


T
182
163
LmdCnst-Ig: 61
A
206
187
HCnst-Ig: 64


T
183
164
LmdCnst-Ig: 62
V
207
188
HCnst-Ig: 65


T
184
165
LmdCnst-Ig: 63
L
208
189
HCnst-Ig: 66


P
185
166
LmdCnst-Ig: 64
Q
209
190
HCnst-Ig: 67


S
186
167
LmdCnst-Ig: 65

209.1
190.1
HCnst-Ig: 68


K
187
168
LmdCnst-Ig: 66

209.2
190.2
HCnst-Ig: 69


Q
188
169
LmdCnst-Ig: 67

209.3
190.3
HCnst-Ig: 70



188.1
169.1
LmdCnst-Ig: 68

209.4
190.4
HCnst-Ig: 71



188.2
169.2
LmdCnst-Ig: 69

209.5
190.5
HCnst-Ig: 72



188.3
169.3
LmdCnst-Ig: 70
S
210
191
HCnst-Ig: 73



188.4
169.4
LmdCnst-Ig: 71
S
211
192
HCnst-Ig: 74



188.5
169.5
LmdCnst-Ig: 72
G
212
193
HCnst-Ig: 75


S
189
170
LmdCnst-Ig: 73
L
213
194
HCnst-Ig: 76


N
190
171
LmdCnst-Ig: 74
Y
214
195
HCnst-Ig: 77


N
191
172
LmdCnst-Ig: 75
S
215
196
HCnst-Ig: 78


K
192
173
LmdCnst-Ig: 76
L
216
197
HCnst-Ig: 79


Y
193
174
LmdCnst-Ig: 77
S
217
198
HCnst-Ig: 80


A
194
175
LmdCnst-Ig: 78
S
218
199
HCnst-Ig: 81


A
195
176
LmdCnst-Ig: 79
V
219
200
HCnst-Ig: 82


S
196
177
LmdCnst-Ig: 80
V
220
201
HCnst-Ig: 83


S
197
178
LmdCnst-Ig: 81
T
221
202
HCnst-Ig: 84


Y
198
179
LmdCnst-Ig: 82
V
222
203
HCnst-Ig: 85


L
199
180
LmdCnst-Ig: 83
P
223
204
HCnst-Ig: 86


S
200
181
LmdCnst-Ig: 84
S
224
205
HCnst-Ig: 87


L
201
182
LmdCnst-Ig: 85
S
225
206
HCnst-Ig: 88


T
202
183
LmdCnst-Ig: 86
S
226
207
HCnst-Ig: 89


P
203
184
LmdCnst-Ig: 87
L
227
208
HCnst-Ig: 90


E
204
185
LmdCnst-Ig: 88

227.1
208.1
HCnst-Ig: 91


Q
205
186
LmdCnst-Ig: 89
G
228
209
HCnst-Ig: 92


W
206
187
LmdCnst-Ig: 90
T
229
210
HCnst-Ig: 93



206.1
187.1
LmdCnst-Ig: 91
Q
230
211
HCnst-Ig: 94


K
207
188
LmdCnst-Ig: 92
T
231
212
HCnst-Ig: 95


S
208
189
LmdCnst-Ig: 93

231.1
212.1
HCnst-Ig: 96


H
209
190
LmdCnst-Ig: 94

231.2
212.2
HCnst-Ig: 97


R
210
191
LmdCnst-Ig: 95

231.3
212.3
HCnst-Ig: 98


S
211
192
LmdCnst-Ig: 96
Y
232
213
HCnst-Ig: 99



211.1
192.1
LmdCnst-Ig: 97
I
233
214
HCnst-Ig: 100



211.2
192.2
LmdCnst-Ig: 98
C
234
215
HCnst-Ig: 101


Y
212
193
LmdCnst-Ig: 99
N
235
216
HCnst-Ig: 102


S
213
194
LmdCnst-Ig: 100
V
236
217
HCnst-Ig: 103


C
214
195
LmdCnst-Ig: 101
N
237
218
HCnst-Ig: 104


Q
215
196
LmdCnst-Ig: 102
H
238
219
HCnst-Ig: 105


V
216
197
LmdCnst-Ig: 103
K
239
220
HCnst-Ig: 106


T
217
198
LmdCnst-Ig: 104
P
240
221
HCnst-Ig: 107


H
218
199
LmdCnst-Ig: 105
S
241
222
HCnst-Ig: 108


E
219
200
LmdCnst-Ig: 106
N
242
223
HCnst-Ig: 109


G
220
201
LmdCnst-Ig: 107

242.1
223.1
HCnst-Ig: 110


S
221
202
LmdCnst-Ig: 108

242.2
223.2
HCnst-Ig: 111


T
222
203
LmdCnst-Ig: 109
T
243
224
HCnst-Ig: 112



222.1
203.1
LmdCnst-Ig: 110
K
244
225
HCnst-Ig: 113



222.2
203.2
LmdCnst-Ig: 111
V
245
226
HCnst-Ig: 114


V
223
204
LmdCnst-Ig: 112
D
246
227
HCnst-Ig: 115


E
224
205
LmdCnst-Ig: 113
K
247
228
HCnst-Ig: 116


K
225
206
LmdCnst-Ig: 114

247.1
228.1
HCnst-Ig: 117


T
226
207
LmdCnst-Ig: 115
K
248
229
HCnst-Ig: 118


V
227
208
LmdCnst-Ig: 116
V
249
230
HCnst-Ig: 119



227.1
208.1
LmdCnst-Ig: 117

249.1
230.1
HCnst-Ig: 120


A
228
209
LmdCnst-Ig: 118

249.2
230.2
HCnst-Ig: 121


P
229
210
LmdCnst-Ig: 119

249.3
230.3
HCnst-Ig: 122


T
230
211
LmdCnst-Ig: 120

249.4
230.4
HCnst-Ig: 123


E
231
212
LmdCnst-Ig: 121

249.5
230.5
Hinge: 1


C
232
213
LmdCnst-Ig: 122

249.6
230.6
Hinge: 2


S
233
214
LmdCnst-Ig: 123

249.7
230.7
Hinge: 3







249.8
230.8
Hinge: 4







249.9
230.9
Hinge: 5







249.10
230.10
Hinge: 6







249.11
230.11
Hinge: 7







249.12
230.12
Hinge: 8







249.13
230.13
Hinge: 9







249.14
230.14
Hinge: 10







249.15
230.15
Hinge: 11







249.16
230.16
Hinge: 12







249.17
230.17
Hinge: 13







249.18
230.18
Hinge: 14







249.19
230.19
Hinge: 15







249.20
230.20
Hinge: 16







249.21
230.21
Hinge: 17







249.22
230.22
Hinge: 18







249.23
230.23
Hinge: 19







249.24
230.24
Hinge: 20







249.25
230.25
Hinge: 21







249.26
230.26
Hinge: 22







249.27
230.27
Hinge: 23







249.28
230.28
Hinge: 24







249.29
230.29
Hinge: 25







249.29
230.29
Hinge: 25







249.30
230.30
Hinge: 26







249.31
230.31
Hinge: 27







249.32
230.32
Hinge: 28







249.33
230.33
Hinge: 29







249.34
230.34
Hinge: 30







249.35
230.35
Hinge: 31







249.36
230.36
Hinge: 32







249.37
230.37
Hinge: 33







249.38
230.38
Hinge: 34







249.39
230.39
Hinge: 35







249.40
230.40
Hinge: 36







249.41
230.41
Hinge: 37







249.42
230.42
Hinge: 38







249.43
230.43
Hinge: 39







249.44
230.44
Hinge: 40







249.45
230.45
Hinge: 41







249.46
230.46
Hinge: 42







249.47
230.47
Hinge: 43







249.48
230.48
Hinge: 44







249.49
230.49
Hinge: 45







249.50
230.50
Hinge: 46







249.51
230.51
Hinge: 47







249.52
230.52
Hinge: 48







249.53
230.53
Hinge: 49







249.54
230.54
Hinge: 50







249.55
230.55
Hinge: 51







249.56
230.56
Hinge: 52







249.57
230.57
Hinge: 53







249.58
230.58
Hinge: 54







249.59
230.59
Hinge: 55







249.60
230.60
Hinge: 56







249.61
230.61
Hinge: 57







249.62
230.62
Hinge: 58







249.63
230.63
Hinge: 59







249.64
230.64
Hinge: 60







249.65
230.65
Hinge: 61







249.66
230.66
Hinge: 62







249.67
230.67
Hinge: 63







249.68
230.68
Hinge: 64







249.69
230.69
Hinge: 65







249.70
230.70
Hinge: 66







249.71
230.71
Hinge: 67







249.72
230.72
Hinge: 68







249.73
230.73
Hinge: 69







249.74
230.74
Hinge: 70







249.75
230.75
Hinge: 71







249.76
230.76
Hinge: 72







249.77
230.77
Hinge: 73







249.78
230.78
Hinge: 74







249.79
230.79
Hinge: 75







249.80
230.80
Hinge: 76







249.81
230.81
Hinge: 77







249.82
230.82
Hinge: 78







249.83
230.83
Hinge: 79







249.84
230.84
Hinge: 80







249.85
230.85
Hinge: 81







249.86
230.86
Hinge: 82







249.87
230.87
Hinge: 83







249.88
230.88
Hinge: 84







249.89
230.89
Hinge: 85







249.90
230.90
Hinge: 86







249.91
230.91
Hinge: 87







249.92
230.92
Hinge: 88







249.93
230.93
Hinge: 89







249.94
230.94
Hinge: 90







249.95
230.95
Hinge: 91







249.96
230.96
Hinge: 92







249.97
230.97
Hinge: 93







249.98
230.98
Hinge: 94







249.99
230.99
Hinge: 95






E
250
231
Hinge: 96






P
251
232
Hinge: 97






K
252
233
Hinge: 98






S
253
234
Hinge: 99







253.1
234.1
Hinge: 100







253.2
234.2
Hinge: 101







253.3
234.3
Hinge: 102







253.4
234.4
Hinge: 103







253.5
234.5
Hinge: 104







253.6
234.6
Hinge: 105







253.7
234.7
Hinge: 106






C
254
235
Hinge: 107






D
255
236
Hinge: 108






K
256
237
Hinge: 109






T
257
238
Hinge: 110






H
258
239
Hinge: 111






T
259
240
Hinge: 112






C
260
241
Hinge: 113






P
261
242
Hinge: 114






P
262
243
Hinge: 115






C
263
244
Hinge: 116






P
264
245
Hinge: 117






A
265
246
Hinge: 118






P
266
247
Hinge: 119






E
267
248
Hinge: 120






L
268
249
Hinge: 121






L
269
250
Hinge: 122






G
270
251
Hinge: 123







270.1
251.1
Fc-N: 1







270.2
251.2
Fc-N: 2







270.3
251.3
Fc-N: 3







270.4
251.4
Fc-N: 4






G
271
252
Fc-N: 5






P
272
253
Fc-N: 6






S
273
254
Fc-N: 7






V
274
255
Fc-N: 8






F
275
256
Fc-N: 9






L
276
257
Fc-N: 10






F
277
258
Fc-N: 11






P
278
259
Fc-N: 12






P
279
260
Fc-N: 13







279.1
260.1
Fc-N: 14






K
280
261
Fc-N: 15






P
281
262
Fc-N: 16






K
282
263
Fc-N: 17







282.1
263.1
Fc-N: 18






D
283
264
Fc-N: 19






T
284
265
Fc-N: 20






L
285
266
Fc-N: 21






M
286
267
Fc-N: 22






I
287
268
Fc-N: 23






S
288
269
Fc-N: 24






R
289
270
Fc-N: 25






T
290
271
Fc-N: 26






P
291
272
Fc-N: 27






E
292
273
Fc-N: 28






V
293
274
Fc-N: 29






T
294
275
Fc-N: 30






C
295
276
Fc-N: 31






V
296
277
Fc-N: 32






V
297
278
Fc-N: 33






V
298
279
Fc-N: 34






D
299
280
Fc-N: 35






V
300
281
Fc-N: 36






S
301
282
Fc-N: 37






H
302
283
Fc-N: 38






E
303
284
Fc-N: 39






D
304
285
Fc-N: 40






P
305
286
Fc-N: 41






E
306
287
Fc-N: 42






V
307
288
Fc-N: 43






K
308
289
Fc-N: 44






F
309
290
Fc-N: 45






N
310
291
Fc-N: 46






W
311
292
Fc-N: 47







311.1
292.1
Fc-N: 48






Y
312
293
Fc-N: 49






V
313
294
Fc-N: 50






D
314
295
Fc-N: 51






G
315
296
Fc-N: 52






V
316
297
Fc-N: 53






E
317
298
Fc-N: 54







317.1
298.1
Fc-N: 55







317.2
298.2
Fc-N: 56






V
318
299
Fc-N: 57






H
319
300
Fc-N: 58






N
320
301
Fc-N: 59






A
321
302
Fc-N: 60






K
322
303
Fc-N: 61






T
323
304
Fc-N: 62






K
324
305
Fc-N: 63






P
325
306
Fc-N: 64






R
326
307
Fc-N: 65






E
327
308
Fc-N: 66






E
328
309
Fc-N: 67






Q
329
310
Fc-N: 68







329.1
310.1
Fc-N: 69







329.2
310.2
Fc-N: 70







329.3
310.3
Fc-N: 71







329.4
310.4
Fc-N: 72






Y
330
311
Fc-N: 73






N
331
312
Fc-N: 74






S
332
313
Fc-N: 75






T
333
314
Fc-N: 76






Y
334
315
Fc-N: 77






R
335
316
Fc-N: 78






V
336
317
Fc-N: 79






V
337
318
Fc-N: 80






S
338
319
Fc-N: 81






V
339
320
Fc-N: 82






L
340
321
Fc-N: 83






T
341
322
Fc-N: 84






V
342
323
Fc-N: 85






L
343
324
Fc-N: 86






H
344
325
Fc-N: 87






Q
345
326
Fc-N: 88






D
346
327
Fc-N: 89






W
347
328
Fc-N: 90







347.1
328.1
Fc-N: 91






L
348
329
Fc-N: 92






N
349
330
Fc-N: 93






G
350
331
Fc-N: 94






K
351
332
Fc-N: 95






E
352
333
Fc-N: 96







352.1
333.1
Fc-N: 97







352.2
333.2
Fc-N: 98






Y
353
334
Fc-N: 99






K
354
335
Fc-N: 100






C
355
336
Fc-N: 101






K
356
337
Fc-N: 102






V
357
338
Fc-N: 103






S
358
339
Fc-N: 104






N
359
340
Fc-N: 105






K
360
341
Fc-N: 106






A
361
342
Fc-N: 107






L
362
343
Fc-N: 108






P
363
344
Fc-N: 109







363.1
344.1
Fc-N: 110







363.2
344.2
Fc-N: 111






A
364
345
Fc-N: 112






P
365
346
Fc-N: 113






I
366
347
Fc-N: 114






E
367
348
Fc-N: 115






K
368
349
Fc-N: 116






T
369
350
Fc-N: 117






I
370
351
Fc-N: 118






S
371
352
Fc-N: 119






K
372
353
Fc-N: 120






A
373
354
Fc-N: 121






K
374
355
Fc-N: 122






G
375
356
Fc-N: 123







375.1
356.1
Fc-C: 1






Q
376
357
Fc-C: 2






P
377
358
Fc-C: 3






R
378
359
Fc-C: 4






E
379
360
Fc-C: 5






P
380
361
Fc-C: 6






Q
381
362
Fc-C: 7






V
382
363
Fc-C: 8






Y
383
364
Fc-C: 9






T
384
365
Fc-C: 10






L
385
366
Fc-C: 11






P
386
367
Fc-C: 12






P
387
368
Fc-C: 13







387.1
368.1
Fc-C: 14






S
388
369
Fc-C: 15






R
389
370
Fc-C: 16






D
390
371
Fc-C: 17







390.1
371.1
Fc-C: 18






E
391
372
Fc-C: 19






L
392
373
Fc-C: 20







392.1
373.1
Fc-C: 21







392.2
373.2
Fc-C: 22






T
393
374
Fc-C: 23






K
394
375
Fc-C: 24






N
395
376
Fc-C: 25






Q
396
377
Fc-C: 26






V
397
378
Fc-C: 27






S
398
379
Fc-C: 28






L
399
380
Fc-C: 29






T
400
381
Fc-C: 30






C
401
382
Fc-C: 31






L
402
383
Fc-C: 32






V
403
384
Fc-C: 33






K
404
385
Fc-C: 34






G
405
386
Fc-C: 35






F
406
387
Fc-C: 36






Y
407
388
Fc-C: 37






P
408
389
Fc-C: 38







408.1
389.1
Fc-C: 39







408.2
389.2
Fc-C: 40






S
409
390
Fc-C: 41






D
410
391
Fc-C: 42






I
411
392
Fc-C: 43






A
412
393
Fc-C: 44






V
413
394
Fc-C: 45






E
414
395
Fc-C: 46






W
415
396
Fc-C: 47







415.1
396.1
Fc-C: 48






E
416
397
Fc-C: 49






S
417
398
Fc-C: 50






N
418
399
Fc-C: 51






G
419
400
Fc-C: 52






Q
420
401
Fc-C: 53






P
421
402
Fc-C: 54







421.1
402.1
Fc-C: 55







421.2
402.2
Fc-C: 56






E
422
403
Fc-C: 57






N
423
404
Fc-C: 58






N
424
405
Fc-C: 59






Y
425
406
Fc-C: 60






K
426
407
Fc-C: 61






T
427
408
Fc-C: 62






T
428
409
Fc-C: 63






P
429
410
Fc-C: 64






P
430
411
Fc-C: 65






V
431
412
Fc-C: 66






L
432
413
Fc-C: 67






D
433
414
Fc-C: 68







433.1
414.1
Fc-C: 69







433.2
414.2
Fc-C: 70







433.3
414.3
Fc-C: 71







433.4
414.4
Fc-C: 72






S
434
415
Fc-C: 73






D
435
416
Fc-C: 74






G
436
417
Fc-C: 75






S
437
418
Fc-C: 76






F
438
419
Fc-C: 77






F
439
420
Fc-C: 78






L
440
421
Fc-C: 79






Y
441
422
Fc-C: 80






S
442
423
Fc-C: 81






K
443
424
Fc-C: 82






L
444
425
Fc-C: 83






T
445
426
Fc-C: 84






V
446
427
Fc-C: 85






D
447
428
Fc-C: 86






K
448
429
Fc-C: 87






S
449
430
Fc-C: 88






R
450
431
Fc-C: 89






W
451
432
Fc-C: 90







451.1
432.1
Fc-C: 91






Q
452
433
Fc-C: 92






Q
453
434
Fc-C: 93






G
454
435
Fc-C: 94






N
455
436
Fc-C: 95






V
456
437
Fc-C: 96







456.1
437.1
Fc-C: 97







456.2
437.2
Fc-C: 98






F
457
438
Fc-C: 99






S
458
439
Fc-C: 100






C
459
440
Fc-C: 101






S
460
441
Fc-C: 102






V
461
442
Fc-C: 103






L
462
443
Fc-C: 104






H
463
444
Fc-C: 105






E
464
445
Fc-C: 106






A
465
446
Fc-C: 107






L
466
447
Fc-C: 108






H
467
448
Fc-C: 109







467.1
448.1
Fc-C: 110







467.2
448.2
Fc-C: 111






S
468
449
Fc-C: 112






H
469
450
Fc-C: 113






Y
470
451
Fc-C: 114






T
471
452
Fc-C: 115







471.1
452.1
Fc-C: 116






Q
472
453
Fc-C: 117






K
473
454
Fc-C: 118






S
474
455
Fc-C: 119






L
475
456
Fc-C: 120






S
476
457
Fc-C: 121






L
477
458
Fc-C: 122






S
478
459
Fc-C: 123






P
479
460
HCnst-Po: 1






G
480
461
HCnst-Po: 2






K
481
462
HCnst-Po: 3







481.1
462.1
HCnst-Po: 4







481.2
462.2
HCnst-Po: 5







481.3
462.3
HCnst-Po: 6







481.4
462.4
HCnst-Po: 7







481.5
462.5
HCnst-Po: 8







481.6
462.6
HCnst-Po: 9







481.7
462.7
HCnst-Po: 10







481.8
462.8
HCnst-Po: 11







481.9
462.9
HCnst-Po: 12







481.10
462.10
HCnst-Po: 13







481.11
462.11
HCnst-Po: 14







481.12
462.12
HCnst-Po: 15







481.13
462.13
HCnst-Po: 16







481.14
462.14
HCnst-Po: 17







481.15
462.15
HCnst-Po: 18







481.16
462.16
HCnst-Po: 19







481.17
462.17
HCnst-Po: 20







481.18
462.18
HCnst-Po: 21







481.19
462.19
HCnst-Po: 22







481.20
462.20
HCnst-Po: 23







481.21
462.21
HCnst-Po: 24







481.22
462.22
HCnst-Po: 25







481.23
462.23
HCnst-Po: 26







481.24
462.24
HCnst-Po: 27







481.25
462.25
HCnst-Po: 28







481.26
462.26
HCnst-Po: 29







481.27
462.27
HCnst-Po: 30







481.28
462.28
HCnst-Po: 31







481.29
462.29
HCnst-Po: 32







481.30
462.30
HCnst-Po: 33







481.31
462.31
HCnst-Po: 34







481.32
462.32
HCnst-Po: 35







481.33
462.33
HCnst-Po: 36







481.34
462.34
HCnst-Po: 37







481.35
462.35
HCnst-Po: 38







481.36
462.36
HCnst-Po: 39







481.37
462.37
HCnst-Po: 40







481.38
462.38
HCnst-Po: 41







481.39
462.39
HCnst-Po: 42







481.40
462.40
HCnst-Po: 43







481.41
462.41
HCnst-Po: 44







481.42
462.42
HCnst-Po: 45







481.43
462.43
HCnst-Po: 46







481.44
462.44
HCnst-Po: 47







481.45
462.45
HCnst-Po: 48







481.46
462.46
HCnst-Po: 49







481.47
462.47
HCnst-Po: 50







481.48
462.48
HCnst-Po: 51







481.49
462.49
HCnst-Po: 52







481.50
462.50
HCnst-Po: 53







481.51
462.51
HCnst-Po: 54







481.52
462.52
HCnst-Po: 55







481.53
462.53
HCnst-Po: 56







481.54
462.54
HCnst-Po: 57







481.55
462.55
HCnst-Po: 58







481.56
462.56
HCnst-Po: 59







481.57
462.57
HCnst-Po: 60







481.58
462.58
HCnst-Po: 61







481.59
462.59
HCnst-Po: 62







481.60
462.60
HCnst-Po: 63







481.61
462.61
HCnst-Po: 64







481.62
462.62
HCnst-Po: 65







481.63
462.63
HCnst-Po: 66







481.64
462.64
HCnst-Po: 67







481.65
462.65
HCnst-Po: 68







481.66
462.66
HCnst-Po: 69







481.67
462.67
HCnst-Po: 70







481.68
462.68
HCnst-Po: 71







481.69
462.69
HCnst-Po: 72







481.70
462.70
HCnst-Po: 73







481.71
462.71
HCnst-Po: 74







481.72
462.72
HCnst-Po: 75







481.73
462.73
HCnst-Po: 76







481.74
462.74
HCnst-Po: 77







481.75
462.75
HCnst-Po: 78







481.76
462.76
HCnst-Po: 79







481.77
462.77
HCnst-Po: 80







481.78
462.78
HCnst-Po: 81







481.79
462.79
HCnst-Po: 82







481.80
462.80
HCnst-Po: 83







481.81
462.81
HCnst-Po: 84







481.82
462.82
HCnst-Po: 85







481.83
462.83
HCnst-Po: 86







481.84
462.84
HCnst-Po: 87







481.85
462.85
HCnst-Po: 88







481.86
462.86
HCnst-Po: 89







481.87
462.87
HCnst-Po: 90







481.88
462.88
HCnst-Po: 91







481.89
462.89
HCnst-Po: 92







481.90
462.90
HCnst-Po: 93







481.91
462.91
HCnst-Po: 94







481.92
462.92
HCnst-Po: 95







481.93
462.93
HCnst-Po: 96







481.94
462.94
HCnst-Po: 97







481.95
462.95
HCnst-Po: 98







481.96
462.96
HCnst-Po: 99







481.97
462.97
HCnst-Po: 100







481.98
462.98
HCnst-Po: 101







481.99
462.99
HCnst-Po: 102







481.100
462.100
HCnst-Po: 103







481.101
462.101
HCnst-Po: 104







481.102
462.102
HCnst-Po: 105







481.103
462.103
HCnst-Po: 106







481.104
462.104
HCnst-Po: 107







481.105
462.105
HCnst-Po: 108







481.106
462.106
HCnst-Po: 109







481.107
462.107
HCnst-Po: 110







481.108
462.108
HCnst-Po: 111







481.109
462.109
HCnst-Po: 112







481.110
462.110
HCnst-Po: 113







481.111
462.111
HCnst-Po: 114







481.112
462.112
HCnst-Po: 115







481.113
462.113
HCnst-Po: 116







481.114
462.114
HCnst-Po: 117







481.115
462.115
HCnst-Po: 118







481.116
462.116
HCnst-Po: 119







481.117
462.117
HCnst-Po: 120







481.118
462.118
HCnst-Po: 121







481.119
462.119
HCnst-Po: 122







481.120
462.120
HCnst-Po: 123
















TABLE 2







Amino acid sequences of light chain variable


regions (hightlighted in bold) of the


10-1074 antibody variants









SEQ ID

OTHER


NO.
SEQUENCE
INFORMATION 





SEQ ID
MGWSCIILFLVATATGVHSS
MS-193_LC


NO: 1
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-194_LC


NO: 2
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-203_LC


NO: 3
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-204_LC


NO: 4
YVPPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-205_LC


NO: 5
YVRSLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-206_LC


NO: 6
YVRPLSVALGQTARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-207_LC


NO: 7
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQQRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-208_LC


NO: 8
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTN





DINEGTRATLTISGVEAGDE





ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-209_LC


NO: 9
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DSNEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-210_LC


NO: 10
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DIGEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-211_LC


NO: 11
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTTATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-212_LC


NO: 12
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWESRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-213_LC


NO: 13
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





GTRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-214_LC


NO: 14
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-215_LC


NO: 15
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-216_LC


NO: 16
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-217_LC


NO: 17
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-218_LC


NO: 18
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-219_LC



YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV



NO: 19
ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-220_LC


NO: 20
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-224_LC


NO: 21
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-200_LC


NO: 22
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-201_LC


NO: 23
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIY






NNQDRPSGIPERFSGTPDIN






FGTRATLTISGVEAGDEADY






YCHMWDSRSGFSWSFGGATR





LTVLGQPKAAPSVTLFPPSS




EELQANKATLVCLISDFYPG




AVTVAWKADSSPVKAGVETT




TPSKQSNNKYAASSYLSLTP




EQWKSHRSYSCQVTHEGSTV




EKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-202_LC


NO: 24
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-225_LC


NO: 25
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-226_LC


NO: 26
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-227_LC


NO: 27
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-228_LC


NO: 28
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-229_LC


NO: 29
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-230_LC


NO: 30
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-231_LC


NO: 31
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-232_LC


NO: 32
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-233_LC


NO: 33
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-234_LC


NO: 34
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-235_LC


NO: 35
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-236_LC


NO: 36
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-237_LC


NO: 37
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-238_LC


NO: 38
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-239_LC


NO: 39
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINEGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-240_LC


NO: 40
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-241_LC


NO: 41
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-242_LC


NO: 42
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-243_LC


NO: 43
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-244_LC


NO: 44
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-245_LC


NO: 45
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-246_LC


NO: 46
YVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS






SEQ ID
MGWSCIILFLVATATGVHSS
MS-247_LC


NO: 47
PVRPLSVALGETARISCGRQ





ALGSRAVQWYQHRPGQAPIL






LIYNNQDRPSGIPERFSGTP






DINFGTRATLTISGVEAGDE






ADYYCHMWDSRSGFSWSFGG





ATRLTVLGQPKAAPSVTLFP




PSSEELQANKATLVCLISDF




YPGAVTVAWKADSSPVKAGV




ETTTPSKQSNNKYAASSYLS




LTPEQWKSHRSYSCQVTHEG




STVEKTVAPTECS
















TABLE 3







Amino acid sequences of heavy chain variable


regions (highlighted in bold) of the 10-1074


antibody variants











SEQ





ID

OTHER



NO.
SEQUENCE
INFORMATION 






SEQ ID
MGWSCIILFLVATAT
MS-193_HC



NO: 48
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVMHEA





LHNHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-194_HC



NO: 49
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-203_HC



NO: 50
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-204_HC



NO: 51
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-205_HC



NO: 52
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-206_HC



NO: 53
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-207_HC



NO: 54
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-208_HC



NO: 55
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-209_HC



NO: 56
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-210_HC



NO: 57
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-211_HC



NO: 58
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-212_HC



NO: 59
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-213_HC



NO: 60
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-214_HC



NO: 61
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





GSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-215_HC



NO: 62
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQPP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-216_HC



NO: 63
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-217_HC



NO: 64
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISV







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-218_HC



NO: 65
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQFSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-219_HC



NO: 66
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-220_HC



NO: 67
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGQGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-224_HC



NO: 68
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLQSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-200_HC



NO: 69
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISV







DTSKNQLSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-201_HC



NO: 70
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISR







DTSKNQFSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-202_HC



NO: 71
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISR







DTSKNQFSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-225_HC



NO: 72
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISR







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-226_HC



NO: 73
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISV







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-227_HC



NO: 74
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQFSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-228_HC



NO: 75
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQLSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-229_HC



NO: 76
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISV







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-230_HC



NO: 77
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISR







DTSKNQFSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-231_HC



NO: 78
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISR







DTSKNQLSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-232_HC



NO: 79
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISV







DTSKNQFSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-233_HC



NO: 80
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISV







DTSKNQLSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-234_HC



NO: 81
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQFSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-235_HC



NO: 82
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISV







DTSKNQLSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-236_HC



NO: 83
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISR







DTSKNQFSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-237_HC



NO: 84
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISR







DTSKNQLSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-238_HC



NO: 85
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISV







DTSKNQFSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-239_HC



NO: 86
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISR







DTSKNQFSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-240_HC



NO: 87
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISV







DTSKNQFSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-241_HC



NO: 88
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISV







DTSKNQLSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-242_HC



NO: 89
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISV







DTSKNQFSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-243_HC



NO: 90
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISV







DTSKNQFSLKLNSVT







PADTAVYYCATARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-244_HC



NO: 91
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISV







DTSKNQLSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-245_HC



NO: 92
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVVISV







DTSKNQFSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-246_HC



NO: 93
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISV







DTSKNQFSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K







SEQ ID
MGWSCIILFLVATAT
MS-247_HC



NO: 94
GVHSQVQLQESGPGL





VKPSETLSVTCSVSG





DSMNNYYWTWIRQSP






GKGLEWIGYISDRES







ATYNPSLNSRVTISV







DTSKNQFSLKLNSVT







PADTAVYYCARARRG







QRIYGVVSFGEFFYY







YSMDVWGKGTTVTVS






SASTKGPSVFPLAPS





SKSTSGGTAALGCLV





KDYFPEPVTVSWNSG





ALTSGVHTFPAVLQS





SGLYSLSSVVTVPSS





SLGTQTYICNVNHKP





SNTKVDKKVEPKSCD





KTHTCPPCPAPELLG





GPSVFLFPPKPKDTL





MISRTPEVTCVVVDV





SHEDPEVKFNWYVDG





VEVHNAKTKPREEQY





NSTYRVVSVLTVLHQ





DWLNGKEYKCKVSNK





ALPAPIEKTISKAKG





QPREPQVYTLPPSRD





ELTKNQVSLTCLVKG





FYPSDIAVEWESNGQ





PENNYKTTPPVLDSD





GSFFLYSKLTVDKSR





WQQGNVFSCSVLHEA





LHSHYTQKSLSLSPG





K
















TABLE 4







Amino acid sequences of CDR regions of


the 10-1074 antibody variants











OTHER


SEQ ID NO.
SEQUENCE
INFORMATION





SEQ ID NO: 95
GRQALGSRAVQ
MS-193_LC CDR1





SEQ ID NO: 96
NNQDRPS
MS-193_LC CDR2





SEQ ID NO: 97
HMWDSRSGFSWS
MS-193_LC CDR3





SEQ ID NO: 98
NNYYWT
MS-193_HC CDR1





SEQ ID NO: 99
YISDRESATYNPSLNS
MS-193_HC CDR2





SEQ ID NO: 100
ARRGQRIYGVVSFGEF
MS-193_HC CDR3



FYYYSMDV






SEQ ID NO: 101
GRQALGSRAVQ
MS-194_LC CDR1





SEQ ID NO: 102
NNQDRPS
MS-194_LC CDR2





SEQ ID NO: 103
HMWDSRSGFSWS
MS-194_LC CDR3





SEQ ID NO: 104
NNYYWT
MS-194_HC CDR1





SEQ ID NO: 105
YISDRESATYNPSLNS
MS-194_HC CDR2





SEQ ID NO: 106
ARRGQRIYGVVSFGEF
MS-194_HC CDR3



FYYYSMDV






SEQ ID NO: 107
GRQALGSRAVQ
MS-203_LC CDR1





SEQ ID NO: 108
NNQDRPS
MS-203_LC CDR2





SEQ ID NO: 109
HMWDSRSGFSWS
MS-203_LC CDR3





SEQ ID NO: 110
NNYYWT
MS-203_HC CDR1





SEQ ID NO: 111
YISDRESATYNPSLNS
MS-203_HC CDR2





SEQ ID NO: 112
ARRGQRIYGVVSFGEF
MS-203_HC CDR3



FYYYSMDV






SEQ ID NO: 113
GRQALGSRAVQ
MS-204_LC CDR1





SEQ ID NO: 114
NNQDRPS
MS-204_LC CDR2





SEQ ID NO: 115
HMWDSRSGFSWS
MS-204_LC CDR3





SEQ ID NO: 116
NNYYWT
MS-204_HC CDR1





SEQ ID NO: 117
YISDRESATYNPSLNS
MS-204_HC CDR2





SEQ ID NO: 118
ARRGQRIYGVVSFGEF
MS-204_HC CDR3



FYYYSMDV






SEQ ID NO: 119
GRQALGSRAVQ
MS-205_LC CDR1





SEQ ID NO: 120
NNQDRPS
MS-205_LC CDR2





SEQ ID NO: 121
HMWDSRSGFSWS
MS-205_LC CDR3





SEQ ID NO: 122
NNYYWT
MS-205_HC CDR1





SEQ ID NO: 123
YISDRESATYNPSLNS
MS-205_HC CDR2





SEQ ID NO: 124
ARRGQRIYGVVSFGEF
MS-205_HC CDR3



FYYYSMDV






SEQ ID NO: 125
GRQALGSRAVQ
MS-206_LC CDR1





SEQ ID NO: 126
NNQDRPS
MS-206_LC CDR2





SEQ ID NO: 127
HMWDSRSGFSWS
MS-206_LC CDR3





SEQ ID NO: 128
NNYYWT
MS-206_HC CDR1





SEQ ID NO: 129
YISDRESATYNPSLNS
MS-206_HC CDR2





SEQ ID NO: 130
ARRGQRIYGVVSFGEF
MS-206_HC CDR3



FYYYSMDV






SEQ ID NO: 131
GRQALGSRAVQ
MS-207_LC CDR1





SEQ ID NO: 132
NNQDRPS
MS-207_LC CDR2





SEQ ID NO: 133
HMWDSRSGFSWS
MS-207_LC CDR3





SEQ ID NO: 134
NNYYWT
MS-207_HC CDR1





SEQ ID NO: 135
YISDRESATYNPSLNS
MS-207_HC CDR2





SEQ ID NO: 136
ARRGQRIYGVVSFGEF
MS-207_HC CDR3



FYYYSMDV






SEQ ID NO: 137
GRQALGSRAVQ
MS-208_LC CDR1





SEQ ID NO: 138
NNQDRPS
MS-208_LC CDR2





SEQ ID NO: 139
HMWDSRSGFSWS
MS-208_LC CDR3





SEQ ID NO: 140
NNYYWT
MS-208_HC CDR1





SEQ ID NO: 141
YISDRESATYNPSLNS
MS-208_HC CDR2





SEQ ID NO: 142
ARRGQRIYGVVSFGEF
MS-208_HC CDR3



FYYYSMDV






SEQ ID NO: 143
GRQALGSRAVQ
MS-209_LC CDR1





SEQ ID NO: 144
NNQDRPS
MS-209_LC CDR2





SEQ ID NO: 145
HMWDSRSGFSWS
MS-209_LC CDR3





SEQ ID NO: 146
NNYYWT
MS-209_HC CDR1





SEQ ID NO: 147
YISDRESATYNPSLNS
MS-209_HC CDR2





SEQ ID NO: 148
ARRGQRIYGVVSFGEF
MS-209_HC CDR3



FYYYSMDV






SEQ ID NO: 149
GRQALGSRAVQ
MS-210_LC CDR1





SEQ ID NO: 150
NNQDRPS
MS-210_LC CDR2





SEQ ID NO: 151
HMWDSRSGFSWS
MS-210_LC CDR3





SEQ ID NO: 152
NNYYWT
MS-210_HC CDR1





SEQ ID NO: 153
YISDRESATYNPSLNS
MS-210_HC CDR2





SEQ ID NO: 154
ARRGQRIYGVVSFGEF
MS-210_HC CDR3



FYYYSMDV






SEQ ID NO: 155
GRQALGSRAVQ
MS-211_LC CDR1





SEQ ID NO: 156
NNQDRPS
MS-211_LC CDR2





SEQ ID NO: 157
HMWDSRSGFSWS
MS-211_LC CDR3





SEQ ID NO: 158
NNYYWT
MS-211_HC CDR1





SEQ ID NO: 159
YISDRESATYNPSLNS
MS-211_HC CDR2





SEQ ID NO: 160
ARRGQRIYGVVSFGEF
MS-211_HC CDR3



FYYYSMDV






SEQ ID NO: 161
GRQALGSRAVQ
MS-212_LC CDR1





SEQ ID NO: 162
NNQDRPS
MS-212_LC CDR2





SEQ ID NO: 163
HMWESRSGFSWS
MS-212_LC CDR3





SEQ ID NO: 164
NNYYWT
MS-212_HC CDR1





SEQ ID NO: 165
YISDRESATYNPSLNS
MS-212_HC CDR2





SEQ ID NO: 166
ARRGQRIYGVVSFGEF
MS-212_HC CDR3



FYYYSMDV






SEQ ID NO: 167
GRQALGSRAVQ
MS-213_LC CDR1





SEQ ID NO: 168
NNQDRPS
MS-213_LC CDR2





SEQ ID NO: 169
HMWDSRSGFSWS
MS-213_LC CDR3





SEQ ID NO: 170
NNYYWT
MS-213_HC CDR1





SEQ ID NO: 171
YISDRESATYNPSLNS
MS-213_HC CDR2





SEQ ID NO: 172
ARRGQRIYGVVSFGEF
MS-213_HC CDR3



FYYYSMDV






SEQ ID NO: 173
GRQALGSRAVQ
MS-214_LC CDR1





SEQ ID NO: 174
NNQDRPS
MS-214_LC CDR2





SEQ ID NO: 175
HMWDSRSGFSWS
MS-214_LC CDR3





SEQ ID NO: 176
NNYYWT
MS-214_HC CDR1





SEQ ID NO: 177
YISDRESATYNPSLNS
MS-214_HC CDR2





SEQ ID NO: 178
ARRGQRIYGVVSFGEF
MS-214_HC CDR3



FYYYSMDV






SEQ ID NO: 179
GRQALGSRAVQ
MS-215_LC CDR1





SEQ ID NO: 180
NNQDRPS
MS-215_LC CDR2





SEQ ID NO: 181
HMWDSRSGFSWS
MS-215_LC CDR3





SEQ ID NO: 182
NNYYWT
MS-215_HC CDR1





SEQ ID NO: 183
YISDRESATYNPSLNS
MS-215_HC CDR2





SEQ ID NO: 184
ARRGQRIYGVVSFGEF
MS-215_HC CDR3



FYYYSMDV






SEQ ID NO: 185
GRQALGSRAVQ
MS-216_LC CDR1





SEQ ID NO: 186
NNQDRPS
MS-216_LC CDR2





SEQ ID NO: 187
HMWDSRSGFSWS
MS-216_LC CDR3





SEQ ID NO: 188
NNYYWT
MS-216_HC CDR1





SEQ ID NO: 189
YISDRESATYNPSLNS
MS-216_HC CDR2





SEQ ID NO: 190
ARRGQRIYGVVSFGEF
MS-216_HC CDR3



FYYYSMDV






SEQ ID NO: 191
GRQALGSRAVQ
MS-217_LC CDR1





SEQ ID NO: 192
NNQDRPS
MS-217_LC CDR2





SEQ ID NO: 193
HMWDSRSGFSWS
MS-217_LC CDR3





SEQ ID NO: 194
NNYYWT
MS-217_HC CDR1





SEQ ID NO: 195
YISDRESATYNPSLNS
MS-217_HC CDR2





SEQ ID NO: 196
ARRGQRIYGVVSFGEF
MS-217_HC CDR3



FYYYSMDV






SEQ ID NO: 197
GRQALGSRAVQ
MS-218_LC CDR1





SEQ ID NO: 198
NNQDRPS
MS-218_LC CDR2





SEQ ID NO: 199
HMWDSRSGFSWS
MS-218_LC CDR3





SEQ ID NO: 200
NNYYWT
MS-218_HC CDR1





SEQ ID NO: 201
YISDRESATYNPSLNS
MS-218_HC CDR2





SEQ ID NO: 202
ARRGQRIYGVVSFGEF
MS-218_HC CDR3



FYYYSMDV






SEQ ID NO: 203
GRQALGSRAVQ
MS-219_LC CDR1





SEQ ID NO: 204
NNQDRPS
MS-219_LC CDR2





SEQ ID NO: 205
HMWDSRSGFSWS
MS-219_LC CDR3





SEQ ID NO: 206
NNYYWT
MS-219_HC CDR1





SEQ ID NO: 207
YISDRESATYNPSLNS
MS-219_HC CDR2





SEQ ID NO: 208
ARRGQRIYGVVSFGEF
MS-219_HC CDR3



FYYYSMDV






SEQ ID NO: 209
GRQALGSRAVQ
MS-220_LC CDR1





SEQ ID NO: 210
NNQDRPS
MS-220_LC CDR2





SEQ ID NO: 211
HMWDSRSGFSWS
MS-220_LC CDR3





SEQ ID NO: 212
NNYYWT
MS-220_HC CDR1





SEQ ID NO: 213
YISDRESATYNPSLNS
MS-220_HC CDR2





SEQ ID NO: 214
ARRGQRIYGVVSFGEF
MS-220_HC CDR3



FYYYSMDV






SEQ ID NO: 215
GRQALGSRAVQ
MS-224_LC CDR1





SEQ ID NO: 216
NNQDRPS
MS-224_LC CDR2





SEQ ID NO: 217
HMWDSRSGFSWS
MS-224_LC CDR3





SEQ ID NO: 218
NNYYWT
MS-224_HC CDR1





SEQ ID NO: 219
YISDRESATYNPSLQS
MS-224_HC CDR2





SEQ ID NO: 220
ARRGQRIYGVVSFGEF
MS-224_HC CDR3



FYYYSMDV






SEQ ID NO: 221
GRQALGSRAVQ
MS-200_LC CDR1





SEQ ID NO: 222
NNQDRPS
MS-200_LC CDR2





SEQ ID NO: 223
HMWDSRSGFSWS
MS-200_LC CDR3





SEQ ID NO: 224
NNYYWT
MS-200_HC CDR1





SEQ ID NO: 225
YISDRESATYNPSLNS
MS-200_HC CDR2





SEQ ID NO: 226
ARRGQRIYGVVSFGEF
MS-200_HC CDR3



FYYYSMDV






SEQ ID NO: 227
GRQALGSRAVQ
MS-201_LC CDR1





SEQ ID NO: 228
NNQDRPS
MS-201_LC CDR2





SEQ ID NO: 229
HMWDSRSGFSWS
MS-201_LC CDR3





SEQ ID NO: 230
NNYYWT
MS-201_HC CDR1





SEQ ID NO: 231
YISDRESATYNPSLNS
MS-201_HC CDR2





SEQ ID NO: 232
ARRGQRIYGVVSFGEF
MS-201_HC CDR3



FYYYSMDV






SEQ ID NO: 233
GRQALGSRAVQ
MS-202_LC CDR1





SEQ ID NO: 234
NNQDRPS
MS-202_LC CDR2





SEQ ID NO: 235
HMWDSRSGFSWS
MS-202_LC CDR3





SEQ ID NO: 236
NNYYWT
MS-202_HC CDR1





SEQ ID NO: 237
YISDRESATYNPSLNS
MS-202_HC CDR2





SEQ ID NO: 238
ARRGQRIYGVVSFGEF
MS-202_HC CDR3



FYYYSMDV






SEQ ID NO: 239
GRQALGSRAVQ
MS-225_LC CDR1





SEQ ID NO: 240
NNQDRPS
MS-225_LC CDR2





SEQ ID NO: 241
HMWDSRSGFSWS
MS-225_LC CDR3





SEQ ID NO: 242
NNYYWT
MS-225_HC CDR1





SEQ ID NO: 243
YISDRESATYNPSLNS
MS-225_HC CDR2





SEQ ID NO: 244
ARRGQRIYGVVSFGEF
MS-225_HC CDR3



FYYYSMDV






SEQ ID NO: 245
GRQALGSRAVQ
MS-226_LC CDR1





SEQ ID NO: 246
NNQDRPS
MS-226_LC CDR2





SEQ ID NO: 247
HMWDSRSGFSWS
MS-226_LC CDR3





SEQ ID NO: 248
NNYYWT
MS-226_HC CDR1





SEQ ID NO: 249
YISDRESATYNPSLNS
MS-226_HC CDR2





SEQ ID NO: 250
ARRGQRIYGVVSFGEF
MS-226_HC CDR3



FYYYSMDV






SEQ ID NO: 251
GRQALGSRAVQ
MS-227_LC CDR1





SEQ ID NO: 252
NNQDRPS
MS-227_LC CDR2





SEQ ID NO: 253
HMWDSRSGFSWS
MS-227_LC CDR3





SEQ ID NO: 254
NNYYWT
MS-227_HC CDR1





SEQ ID NO: 255
YISDRESATYNPSLNS
MS-227_HC CDR2





SEQ ID NO: 256
ARRGQRIYGVVSFGEF
MS-227_HC CDR3



FYYYSMDV






SEQ ID NO: 257
GRQALGSRAVQ
MS-228_LC CDR1





SEQ ID NO: 258
NNQDRPS
MS-228_LC CDR2





SEQ ID NO: 259
HMWDSRSGFSWS
MS-228_LC CDR3





SEQ ID NO: 260
NNYYWT
MS-228_HC CDR1





SEQ ID NO: 261
YISDRESATYNPSLNS
MS-228_HC CDR2





SEQ ID NO: 262
ARRGQRIYGVVSFGEF
MS-228_HC CDR3



FYYYSMDV






SEQ ID NO: 263
GRQALGSRAVQ
MS-229_LC CDR1





SEQ ID NO: 264
NNQDRPS
MS-229_LC CDR2





SEQ ID NO: 265
HMWDSRSGFSWS
MS-229_LC CDR3





SEQ ID NO: 266
NNYYWT
MS-229_HC CDR1





SEQ ID NO: 267
YISDRESATYNPSLNS
MS-229_HC CDR2





SEQ ID NO: 268
ARRGQRIYGVVSFGEF
MS-229_HC CDR3



FYYYSMDV






SEQ ID NO: 269
GRQALGSRAVQ
MS-230_LC CDR1





SEQ ID NO: 270
NNQDRPS
MS-230_LC CDR2





SEQ ID NO: 271
HMWDSRSGFSWS
MS-230_LC CDR3





SEQ ID NO: 272
NNYYWT
MS-230_HC CDR1





SEQ ID NO: 273
YISDRESATYNPSLNS
MS-230_HC CDR2





SEQ ID NO: 274
ARRGQRIYGVVSFGEF
MS-230_HC CDR3



FYYYSMDV






SEQ ID NO: 275
GRQALGSRAVQ
MS-231_LC CDR1





SEQ ID NO: 276
NNQDRPS
MS-231_LC CDR2





SEQ ID NO: 277
HMWDSRSGFSWS
MS-231_LC CDR3





SEQ ID NO: 278
NNYYWT
MS-231_HC CDR1





SEQ ID NO: 279
YISDRESATYNPSLNS
MS-231_HC CDR2





SEQ ID NO: 280
ARRGQRIYGVVSFGEF
MS-231_HC CDR3



FYYYSMDV






SEQ ID NO: 281
GRQALGSRAVQ
MS-232_LC CDR1





SEQ ID NO: 282
NNQDRPS
MS-232_LC CDR2





SEQ ID NO: 283
HMWDSRSGFSWS
MS-232_LC CDR3





SEQ ID NO: 284
NNYYWT
MS-232_HC CDR1





SEQ ID NO: 285
YISDRESATYNPSLNS
MS-232_HC CDR2





SEQ ID NO: 286
ARRGQRIYGVVSFGEF
MS-232_HC CDR3



FYYYSMDV






SEQ ID NO: 287
GRQALGSRAVQ
MS-233_LC CDR1





SEQ ID NO: 288
NNQDRPS
MS-233_LC CDR2





SEQ ID NO: 289
HMWDSRSGFSWS
MS-233_LC CDR3





SEQ ID NO: 290
NNYYWT
MS-233_HC CDR1





SEQ ID NO: 291
YISDRESATYNPSLNS
MS-233_HC CDR2





SEQ ID NO: 292
ARRGQRIYGVVSFGEF
MS-233_HC CDR3



FYYYSMDV






SEQ ID NO: 293
GRQALGSRAVQ
MS-234_LC CDR1





SEQ ID NO: 294
NNQDRPS
MS-234_LC CDR2





SEQ ID NO: 295
HMWDSRSGFSWS
MS-234_LC CDR3





SEQ ID NO: 296
NNYYWT
MS-234_HC CDR1





SEQ ID NO: 297
YISDRESATYNPSLNS
MS-234_HC CDR2





SEQ ID NO: 298
ARRGQRIYGVVSFGEF
MS-234_HC CDR3



FYYYSMDV






SEQ ID NO: 299
GRQALGSRAVQ
MS-235_LC CDR1





SEQ ID NO: 300
NNQDRPS
MS-235_LC CDR2





SEQ ID NO: 301
HMWDSRSGFSWS
MS-235_LC CDR3





SEQ ID NO: 302
NNYYWT
MS-235_HC CDR1





SEQ ID NO: 303
YISDRESATYNPSLNS
MS-235_HC CDR2





SEQ ID NO: 304
ARRGQRIYGVVSFGEF
MS-235_HC CDR3



FYYYSMDV






SEQ ID NO: 305
GRQALGSRAVQ
MS-236_LC CDR1





SEQ ID NO: 306
NNQDRPS
MS-236_LC CDR2





SEQ ID NO: 307
HMWDSRSGFSWS
MS-236_LC CDR3





SEQ ID NO: 308
NNYYWT
MS-236_HC CDR1





SEQ ID NO: 309
YISDRESATYNPSLNS
MS-236_HC CDR2





SEQ ID NO: 310
ARRGQRIYGVVSFGEF
MS-236_HC CDR3



FYYYSMDV






SEQ ID NO: 311
GRQALGSRAVQ
MS-237_LC CDR1





SEQ ID NO: 312
NNQDRPS
MS-237_LC CDR2





SEQ ID NO: 313
HMWDSRSGFSWS
MS-237_LC CDR3





SEQ ID NO: 314
NNYYWT
MS-237_HC CDR1





SEQ ID NO: 315
YISDRESATYNPSLNS
MS-237_HC CDR2





SEQ ID NO: 316
ARRGQRIYGVVSFGEF
MS-237_HC CDR3



FYYYSMDV






SEQ ID NO: 317
GRQALGSRAVQ
MS-238_LC CDR1





SEQ ID NO: 318
NNQDRPS
MS-238_LC CDR2





SEQ ID NO: 319
HMWDSRSGFSWS
MS-238_LC CDR3





SEQ ID NO: 320
NNYYWT
MS-238_HC CDR1





SEQ ID NO: 321
YISDRESATYNPSLNS
MS-238_HC CDR2





SEQ ID NO: 322
ARRGQRIYGVVSFGEF
MS-238_HC CDR3



FYYYSMDV






SEQ ID NO: 323
GRQALGSRAVQ
MS-239_LC CDR1





SEQ ID NO: 324
NNQDRPS
MS-239_LC CDR2





SEQ ID NO: 325
HMWDSRSGFSWS
MS-239_LC CDR3





SEQ ID NO: 326
NNYYWT
MS-239_HC CDR1





SEQ ID NO: 327
YISDRESATYNPSLNS
MS-239_HC CDR2





SEQ ID NO: 328
ARRGQRIYGVVSFGEF
MS-239_HC CDR3



FYYYSMDV






SEQ ID NO: 329
GRQALGSRAVQ
MS-240_LC CDR1





SEQ ID NO: 330
NNQDRPS
MS-240_LC CDR2





SEQ ID NO: 331
HMWDSRSGFSWS
MS-240_LC CDR3





SEQ ID NO: 332
NNYYWT
MS-240_HC CDR1





SEQ ID NO: 333
YISDRESATYNPSLNS
MS-240_HC CDR2





SEQ ID NO: 334
ARRGQRIYGVVSFGEF
MS-240_HC CDR3



FYYYSMDV






SEQ ID NO: 335
GRQALGSRAVQ
MS-241_LC CDR1





SEQ ID NO: 336
NNQDRPS
MS-241_LC CDR2





SEQ ID NO: 337
HMWDSRSGFSWS
MS-241_LC CDR3





SEQ ID NO: 338
NNYYWT
MS-241_HC CDR1





SEQ ID NO: 339
YISDRESATYNPSLNS
MS-241_HC CDR2





SEQ ID NO: 340
ARRGQRIYGVVSFGEF
MS-241_HC CDR3



FYYYSMDV






SEQ ID NO: 341
GRQALGSRAVQ
MS-242_LC CDR1





SEQ ID NO: 342
NNQDRPS
MS-242_LC CDR2





SEQ ID NO: 343
HMWDSRSGFSWS
MS-242_LC CDR3





SEQ ID NO: 344
NNYYWT
MS-242_HC CDR1





SEQ ID NO: 345
YISDRESATYNPSLNS
MS-242_HC CDR2





SEQ ID NO: 346
ARRGQRIYGVVSFGEF
MS-242_HC CDR3



FYYYSMDV






SEQ ID NO: 347
GRQALGSRAVQ
MS-243_LC CDR1





SEQ ID NO: 348
NNQDRPS
MS-243_LC CDR2





SEQ ID NO: 349
HMWDSRSGFSWS
MS-243_LC CDR3





SEQ ID NO: 350
NNYYWT
MS-243_HC CDR1





SEQ ID NO: 351
YISDRESATYNPSLNS
MS-243_HC CDR2





SEQ ID NO: 352
ARRGQRIYGVVSFGEF
MS-243_HC CDR3



FYYYSMDV






SEQ ID NO: 353
GRQALGSRAVQ
MS-244_LC CDR1





SEQ ID NO: 354
NNQDRPS
MS-244_LC CDR2





SEQ ID NO: 355
HMWDSRSGFSWS
MS-244_LC CDR3





SEQ ID NO: 356
NNYYWT
MS-244_HC CDR1





SEQ ID NO: 357
YISDRESATYNPSLNS
MS-244_HC CDR2





SEQ ID NO: 358
ARRGQRIYGVVSFGEF
MS-244_HC CDR3



FYYYSMDV






SEQ ID NO: 359
GRQALGSRAVQ
MS-245_LC CDR1





SEQ ID NO: 360
NNQDRPS
MS-245_LC CDR2





SEQ ID NO: 361
HMWDSRSGFSWS
MS-245_LC CDR3





SEQ ID NO: 362
NNYYWT
MS-245_HC CDR1





SEQ ID NO: 363
YISDRESATYNPSLNS
MS-245_HC CDR2





SEQ ID NO: 364
ARRGQRIYGVVSFGEF
MS-245_HC CDR3



FYYYSMDV






SEQ ID NO: 365
GRQALGSRAVQ
MS-246_LC CDR1





SEQ ID NO: 366
NNQDRPS
MS-246_LC CDR2





SEQ ID NO: 367
HMWDSRSGFSWS
MS-246_LC CDR3





SEQ ID NO: 368
NNYYWT
MS-246_HC CDR1





SEQ ID NO: 369
YISDRESATYNPSLNS
MS-246_HC CDR2





SEQ ID NO: 370
ARRGQRIYGVVSFGEF
MS-246_HC CDR3



FYYYSMDV






SEQ ID NO: 371
GRQALGSRAVQ
MS-247_LC CDR1





SEQ ID NO: 372
NNQDRPS
MS-247_LC CDR2





SEQ ID NO: 373
HMWDSRSGFSWS
MS-247_LC CDR3





SEQ ID NO: 374
NNYYWT
MS-247_HC CDR1





SEQ ID NO: 375
YISDRESATYNPSLNS
MS-247_HC CDR2





SEQ ID NO: 376
ARRGQRIYGVVSFGEF
MS-247_HC CDR3



FYYYSMDV
















TABLE 5







Nucleic acid sequences of light chain variable regions of


the 10-1074 antibody variants









SEQ ID

OTHER


NO.
SEQUENCE
INFORMATION





SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-193_LC


NO: 377
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-194_LC


NO: 378
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-203_LC


NO: 379
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-204_LC


NO: 380
GTGCCACCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-205_LC


NO: 381
GTGCGCAGCCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-206_LC


NO: 382
GTGCGCCCGCTGTCAGTGGCCCTGGGGCAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-207_LC


NO: 383
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACAGAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-208_LC


NO: 384
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCAATGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-209_LC


NO: 385
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATTCCAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-210_LC


NO: 386
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTGGCTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-211_LC


NO: 387
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCACCGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-212_LC


NO: 388
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGAGAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-213_LC


NO: 389
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGGAACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-214_LC


NO: 390
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-215_LC


NO: 391
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-216_LC


NO: 392
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-217_LC


NO: 393
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-218_LC


NO: 394
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-219_LC


NO: 395
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC




CCTACAGAATGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-220_LC


NO: 396
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-224_LC


NO: 397
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC




CCTACAGAATGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-200_LC


NO: 398
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC




CCTACAGAATGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-201_LC


NO: 399
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-202_LC


NO: 400
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-225_LC


NO: 401
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC




CCTACAGAATGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-226_LC


NO: 402
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-227_LC


NO: 403
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-228_LC


NO: 404
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-229_LC


NO: 405
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-230_LC


NO: 406
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-231_LC


NO: 407
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-232_LC


NO: 408
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC




CCTACAGAATGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-233_LC


NO: 409
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-234_LC


NO: 410
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-235_LC


NO: 411
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-236_LC


NO: 412
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-237_LC


NO: 413
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-238_LC


NO: 414
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-239_LC


NO: 415
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-240_LC


NO: 416
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-241_LC


NO: 417
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-242_LC


NO: 418
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-243_LC


NO: 419
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-244_LC


NO: 420
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-245_LC


NO: 421
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCTAT
MS-246_LC


NO: 422
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA






SEQ ID
ATGGGATGGAGCTGTATCATCCTGTTCCTCGTGGCCACAGCAACCGGTGTACATTCTTCCCCT
MS-247_LC


NO: 423
GTGCGCCCGCTGTCAGTGGCCCTGGGGGAGACGGCCAGGATTTCCTGTGGACGACAGGCCCTT




GGAAGTAGAGCTGTTCAGTGGTATCAACATAGGCCAGGCCAGGCCCCTATATTGCTCATTTAT




AATAATCAAGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCACCCCTGATATTAATTTT




GGGACCAGGGCCACCCTGACCATCAGCGGGGTCGAAGCCGGGGATGAAGCCGACTATTACTGT




CACATGTGGGATAGTAGAAGTGGCTTCAGTTGGTCTTTCGGCGGGGCGACCAGGCTGACCGTC




CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAA




GCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCC




TGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC




AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGA




AGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAA




TGTTCA
















TABLE 6







Nucleic acid sequences of heavy chain variable regions of the 10-1074 antibody variants









SEQ ID

OTHER


NO.
SEQUENCE
INFORMATION





SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-193_HC


NO: 424
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT




GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-194_HC


NO: 425
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-203_HC


NO: 426
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-204_HC


NO: 427
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-205_HC


NO: 428
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-206_HC


NO: 429
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-207_HC


NO: 430
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-208_HC


NO: 431
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-209_HC


NO: 432
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-210_HC


NO: 433
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-211_HC


NO: 434
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-212_HC


NO: 435
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-213_HC


NO: 436
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-214_HC


NO: 437
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGGTTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-215_HC


NO: 438
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGCCACCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-216_HC


NO: 439
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-217_HC


NO: 440
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCAGTTGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-218_HC


NO: 441
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-219_HC


NO: 442
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-220_HC


NO: 443
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCCAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-224_HC


NO: 444
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCCAAAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-200_HC


NO: 445
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCAGTTGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-201_HC


NO: 446
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCACGAGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-202_HC


NO: 447
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCACGAGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-225_HC


NO: 448
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-226_HC


NO: 449
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCAGTTGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-227_HC


NO: 450
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-228_HC


NO: 451
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-229_HC


NO: 452
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCAGTTGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-230_HC


NO: 453
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCACGAGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-231_HC


NO: 454
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-232_HC


NO: 455
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCAGTTGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-233_HC


NO: 456
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCAGTTGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-234_HC


NO: 457
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-235_HC


NO: 458
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCAGTTGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-236_HC


NO: 459
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCACGAGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-237_HC


NO: 460
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCACGAGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-238_HC


NO: 461
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCAGTTGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-239_HC


NO: 462
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCACGAGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-240_HC


NO: 463
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCAGTTGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-241_HC


NO: 464
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCAGTTGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-242_HC


NO: 465
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCAGTTGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-243_HC


NO: 466
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCAGTTGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGACAGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-244_HC


NO: 467
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCAGTTGACACGTCGAAAAACCAATTGTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-245_HC


NO: 468
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCGTCATATCAGTTGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-246_HC


NO: 469
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCAGTTGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA






SEQ ID
ATGGGATGGTCATGTATCATCCTTTTTCTAGTAGCAACTGCAACCGGTGTACACTCGCAGGTGC
MS-247_HC


NO: 470
AGCTGCAGGAGTCGGGCCCAGGACTGGTGAAACCTTCGGAGACCCTGTCCGTCACCTGCAGTG




TCTCTGGAGATTCCATGAATAATTACTACTGGACTTGGATCCGGCAGTCCCCCGGAAAGGGAC




TGGAGTGGATAGGCTATATCTCTGACAGAGAATCAGCGACTTACAACCCCTCCCTCAATAGTC




GAGTCACCATATCAGTTGACACGTCGAAAAACCAATTTTCCCTAAAATTAAACTCCGTCACCC




CTGCGGACACGGCCGTCTATTACTGTGCGCGCGCGCGCCGAGGACAGAGGATTTATGGAGTGG




TTTCCTTTGGAGAGTTCTTCTACTACTACTCCATGGACGTCTGGGGCAAGGGGACCACGGTCAC




CGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC




TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAGCCGGTGACGGTG




TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA




GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC




ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC




TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGT




CTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC




GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT




GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG




TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT




CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA




GAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG




ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG




CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC




AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCTG




CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
















TABLE 7







Nucleic acid sequences of CDR regions


of the 10-1074 antibody variants











SEQ ID

OTHER



NO.
SEQUENCE
INFORMATION






SEQ ID
ATGGGATGGAGCTGT
MS-193_LC



NO: 471
ATCATCCTGTTCCTC





GTGGCCACAGCAACC





GGTGTACATTCTTCC





TATGTGCGCCCGCTG





TCAGTGGCCCTGGGG





GAGACGGCCAGGATT





TCCTGTGGACGACAG





GCCCTTGGAAGTAGA





GCTGTTCAGTGGTAT





CAACATAGGCCAGGC





CAGGCCCCTATATTG





CTCATTTATAATAAT





CAAGACCGGCCCTCA





GGGATCCCTGAGCGA





TTCTCTGGCACCCCT





GATATTAATTTTGGG





ACCAGGGCCACCCTG





ACCATCAGCGGGGTC





GAAGCCGGGGATGAA





GCCGACTATTACTGT





CACATGTGGGATAGT





AGAAGTGGCTTCAGT





TGGTCTTTCGGCGGG





GCGACCAGGCTGACC





GTCCTAGGTCAGCCC





AAGGCTGCCCCCTCG





GTCACTCTGTTCCCG





CCCTCCTCTGAGGAG





CTTCAAGCCAACAAG





GCCACACTGGTGTGT





CTCATAAGTGACTTC





TACCCGGGAGCCGTG





ACAGTGGCCTGGAAG





GCAGATAGCAGCCCC





GTCAAGGCGGGAGTG





GAGACCACCACACCC





TCCAAACAAAGCAAC





AACAAGTACGCGGCC





AGCAGCTATCTGAGC





CTGACGCCTGAGCAG





TGGAAGTCCCACAGA





AGCTACAGCTGCCAG





GTCACGCATGAAGGG





AGCACCGTGGAGAAG





ACAGTGGCCCCTACA





GAATGTTCA







SEQ ID
GGACGACAGGCCCTT
MS-193_LC CDR1



NO: 472
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-193_LC CDR2



NO: 473
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-193_LC CDR3



NO: 474
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-193_HC CDR1



NO: 475
ACT







SEQ ID
TATATCTCTGACAGA
MS-193_HC CDR2



NO: 476
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-193_HC CDR3



NO: 477
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-194_LC CDR1



NO: 478
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-194_LC CDR2



NO: 479
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-194_LC CDR3



NO: 480
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-194_HC CDR1



NO: 481
ACT







SEQ ID
TATATCTCTGACAGA
MS-194_HC CDR2



NO: 482
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-194_HC CDR3



NO: 483
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-203_LC CDR1



NO: 484
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-203_LC CDR2



NO: 485
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-203_LC CDR3



NO: 486
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-203_HC CDR1



NO: 487
ACT







SEQ ID
TATATCTCTGACAGA
MS-203_HC CDR2



NO: 488
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-203_HC CDR3



NO: 489
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-204_LC CDR1



NO: 490
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-204_LC CDR2



NO: 491
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-204_LC CDR3



NO: 492
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-204_HC CDR1



NO: 493
ACT







SEQ ID
TATATCTCTGACAGA
MS-204_HC CDR2



NO: 494
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-204_HC CDR3



NO: 495
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-205_LC CDR1



NO: 496
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-205_LC CDR2



NO: 497
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-205_LC CDR3



NO: 498
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-205_HC CDR1



NO: 499
ACT







SEQ ID
TATATCTCTGACAGA
MS-205_HC CDR2



NO: 500
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-205_HC CDR3



NO: 501
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-206_LC CDR1



NO: 502
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-206_LC CDR2



NO: 503
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-206_LC CDR3



NO: 504
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-206_HC CDR1



NO: 505
ACT







SEQ ID
TATATCTCTGACAGA
MS-206_HC CDR2



NO: 506
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-206_HC CDR3



NO: 507
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-207_LC CDR1



NO: 508
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-207_LC CDR2



NO: 509
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-207_LC CDR3



NO: 510
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-207_HC CDR1



NO: 511
ACT







SEQ ID
TATATCTCTGACAGA
MS-207_HC CDR2



NO: 512
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-207_HC CDR3



NO: 513
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-208_LC CDR1



NO: 514
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-208_LC CDR2



NO: 515
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-208_LC CDR3



NO: 516
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-208_HC CDR1



NO: 517
ACT







SEQ ID
TATATCTCTGACAGA
MS-208_HC CDR2



NO: 518
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-208_HC CDR3



NO: 519
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-209_LC CDR1



NO: 520
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-209_LC CDR2



NO: 521
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-209_LC CDR3



NO: 522
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-209_HC CDR1



NO: 523
ACT







SEQ ID
TATATCTCTGACAGA
MS-209_HC CDR2



NO: 524
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-209_HC CDR3



NO: 525
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-210_LC CDR1



NO: 526
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-210_LC CDR2



NO: 527
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-210_LC CDR3



NO: 528
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-210_HC CDR1



NO: 529
ACT







SEQ ID
TATATCTCTGACAGA
MS-210_HC CDR2



NO: 530
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-210_HC CDR3



NO: 531
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-211_LC CDR1



NO: 532
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-211_LC CDR2



NO: 533
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-211_LC CDR3



NO: 534
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-211_HC CDR1



NO: 535
ACT







SEQ ID
TATATCTCTGACAGA
MS-211_HC CDR2



NO: 536
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-211_HC CDR3



NO: 537
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-212_LC CDR1



NO: 538
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-212_LC CDR2



NO: 539
CCCTCA







SEQ ID
CACATGTGGGAGAGT
MS-212_LC CDR3



NO: 540
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-212_HC CDR1



NO: 541
ACT







SEQ ID
TATATCTCTGACAGA
MS-212_HC CDR2



NO: 542
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-212_HC CDR3



NO: 543
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-213_LC CDR1



NO: 544
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-213_LC CDR2



NO: 545
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-213_LC CDR3



NO: 546
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-213_HC CDR1



NO: 547
ACT







SEQ ID
TATATCTCTGACAGA
MS-213_HC CDR2



NO: 548
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-213_HC CDR3



NO: 549
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-214_LC CDR1



NO: 550
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-214_LC CDR2



NO: 551
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-214_LC CDR3



NO: 552
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-214_HC CDR1



NO: 553
ACT







SEQ ID
TATATCTCTGACAGA
MS-214_HC CDR2



NO: 554
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-214_HC CDR3



NO: 555
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-215_LC CDR1



NO: 556
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-215_LC CDR2



NO: 557
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-215_LC CDR3



NO: 558
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-215_HC CDR1



NO: 559
ACT







SEQ ID
TATATCTCTGACAGA
MS-215_HC CDR2



NO: 560
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-215_HC CDR3



NO: 561
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-216_LC CDR1



NO: 562
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-216_LC CDR2



NO: 563
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-216_LC CDR3



NO: 564
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-216_HC CDR1



NO: 565
ACT







SEQ ID
TATATCTCTGACAGA
MS-216_HC CDR2



NO: 566
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-216_HC CDR3



NO: 567
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-217_LC CDR1



NO: 568
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-217_LC CDR2



NO: 569
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-217_LC CDR3



NO: 570
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-217_HC CDR1



NO: 571
ACT







SEQ ID
TATATCTCTGACAGA
MS-217_HC CDR2



NO: 572
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-217_HC CDR3



NO: 573
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-218_LC CDR1



NO: 574
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-218_LC CDR2



NO: 575
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-218_LC CDR3



NO: 576
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-218_HC CDR1



NO: 577
ACT







SEQ ID
TATATCTCTGACAGA
MS-218_HC CDR2



NO: 578
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-218_HC CDR3



NO: 579
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-219_LC CDR1



NO: 580
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-219_LC CDR2



NO: 581
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-219_LC CDR3



NO: 582
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-219_HC CDR1



NO: 583
ACT







SEQ ID
TATATCTCTGACAGA
MS-219_HC CDR2



NO: 584
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-219_HC CDR3



NO: 585
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-220_LC CDR1



NO: 586
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-220_LC CDR2



NO: 587
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-220_LC CDR3



NO: 588
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-220_HC CDR1



NO: 589
ACT







SEQ ID
TATATCTCTGACAGA
MS-220_HC CDR2



NO: 590
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-220_HC CDR3



NO: 591
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-224_LC CDR1



NO: 592
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-224_LC CDR2



NO: 593
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-224_LC CDR3



NO: 594
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-224_HC CDR1



NO: 595
ACT







SEQ ID
TATATCTCTGACAGA
MS-224_HC CDR2



NO: 596
GAATCAGCGACTTAC





AACC





CCTCCCTCCAAAGT







SEQ ID
GCGCGCCGAGGACAG
MS-224_HC CDR3



NO: 597
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-200_LC CDR1



NO: 598
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-200_LC CDR2



NO: 599
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-200_LC CDR3



NO: 600
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-200_HC CDR1



NO: 601
ACT







SEQ ID
TATATCTCTGACAGA
MS-200_HC CDR2



NO: 602
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-200_HC CDR3



NO: 603
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-201_LC CDR1



NO: 604
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-201_LC CDR2



NO: 605
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-201_LC CDR3



NO: 606
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-201_HC CDR1



NO: 607
ACT







SEQ ID
TATATCTCTGACAGA
MS-201_HC CDR2



NO: 608
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-201_HC CDR3



NO: 609
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-202_LC CDR1



NO: 610
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-202_LC CDR2



NO: 611
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-202_LC CDR3



NO: 612
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-202_HC CDR1



NO: 613
ACT







SEQ ID
TATATCTCTGACAGA
MS-202_HC CDR2



NO: 614
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-202_HC CDR3



NO: 615
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-225_LC CDR1



NO: 616
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-225_LC CDR2



NO: 617
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-225_LC CDR3



NO: 618
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-225_HC CDR1



NO: 619
ACT







SEQ ID
TATATCTCTGACAGA
MS-225_HC CDR2



NO: 620
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-225_HC CDR3



NO: 621
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-226_LC CDR1



NO: 622
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-226_LC CDR2



NO: 623
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-226_LC CDR3



NO: 624
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-226_HC CDR1



NO: 625
ACT







SEQ ID
TATATCTCTGACAGA
MS-226_HC CDR2



NO: 626
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-226_HC CDR3



NO: 627
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-227_LC CDR1



NO: 628
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-227_LC CDR2



NO: 629
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-227_LC CDR3



NO: 630
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-227_HC CDR1



NO: 631
ACT







SEQ ID
TATATCTCTGACAGA
MS-227_HC CDR2



NO: 632
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-227_HC CDR3



NO: 633
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-228_LC CDR1



NO: 634
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-228_LC CDR2



NO: 635
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-228_LC CDR3



NO: 636
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-228_HC CDR1



NO: 637
ACT







SEQ ID
TATATCTCTGACAGA
MS-228_HC CDR2



NO: 638
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-228_HC CDR3



NO: 639
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-229_LC CDR1



NO: 640
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-229_LC CDR2



NO: 641
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-229_LC CDR3



NO: 642
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-229_HC CDR1



NO: 643
ACT







SEQ ID
TATATCTCTGACAGA
MS-229_HC CDR2



NO: 644
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-229_HC CDR3



NO: 645
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-230_LC CDR1



NO: 646
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-230_LC CDR2



NO: 647
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-230_LC CDR3



NO: 648
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-230_HC CDR1



NO: 649
ACT







SEQ ID
TATATCTCTGACAGA
MS-230_HC CDR2



NO: 650
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-230_HC CDR3



NO: 651
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-231_LC CDR1



NO: 652
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-231_LC CDR2



NO: 653
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-231_LC CDR3



NO: 654
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-231_HC CDR1



NO: 655
ACT







SEQ ID
TATATCTCTGACAGA
MS-231_HC CDR2



NO: 656
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-231_HC CDR3



NO: 657
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-232_LC CDR1



NO: 658
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-232_LC CDR2



NO: 659
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-232_LC CDR3



NO: 660
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-232_HC CDR1



NO: 661
ACT







SEQ ID
TATATCTCTGACAGA
MS-232_HC CDR2



NO: 662
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-232_HC CDR3



NO: 663
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-233_LC CDR1



NO: 664
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-233_LC CDR2



NO: 665
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-233_LC CDR3



NO: 666
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-233_HC CDR1



NO: 667
ACT







SEQ ID
TATATCTCTGACAGA
MS-233_HC CDR2



NO: 668
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-233_HC CDR3



NO: 669
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-234_LC CDR1



NO: 670
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-234_LC CDR2



NO: 671
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-234_LC CDR3



NO: 672
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-234_HC CDR1



NO: 673
ACT







SEQ ID
TATATCTCTGACAGA
MS-234_HC CDR2



NO: 674
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-234_HC CDR3



NO: 675
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-235_LC CDR1



NO: 676
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-235_LC CDR2



NO: 677
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-235_LC CDR3



NO: 678
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-235_HC CDR1



NO: 679
ACT







SEQ ID
TATATCTCTGACAGA
MS-235_HC CDR2



NO: 680
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-235_HC CDR3



NO: 681
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-236_LC CDR1



NO: 682
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-236_LC CDR2



NO: 683
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-236_LC CDR3



NO: 684
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-236_HC CDR1



NO: 685
ACT







SEQ ID
TATATCTCTGACAGA
MS-236_HC CDR2



NO: 686
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-236_HC CDR3



NO: 687
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-237_LC CDR1



NO: 688
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-237_LC CDR2



NO: 689
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-237_LC CDR3



NO: 690
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-237_HC CDR1



NO: 691
ACT







SEQ ID
TATATCTCTGACAGA
MS-237_HC CDR2



NO: 692
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-237_HC CDR3




AGGATTTATGGAGTG





GTTT




NO: 693
CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-238_LC CDR1



NO: 694
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-238_LC CDR2



NO: 695
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-238_LC CDR3



NO: 696
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-238_HC CDR1



NO: 697
ACT







SEQ ID
TATATCTCTGACAGA
MS-238_HC CDR2



NO: 698
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-238_HC CDR3



NO: 699
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-239_LC CDR1



NO: 700
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-239_LC CDR2



NO: 701
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-239_LC CDR3



NO: 702
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-239_HC CDR1



NO: 703
ACT







SEQ ID
TATATCTCTGACAGA
MS-239_HC CDR2



NO: 704
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-239_HC CDR3



NO: 705
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-240_LC CDR1



NO: 706
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-240_LC CDR2



NO: 707
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-240_LC CDR3



NO: 708
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-240_HC CDR1



NO: 709
ACT







SEQ ID
TATATCTCTGACAGA
MS-240_HC CDR2



NO: 710
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-240_HC CDR3



NO: 711
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-241_LC CDR1



NO: 712
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-241_LC CDR2



NO: 713
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-241_LC CDR3



NO: 714
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-241_HC CDR1



NO: 715
ACT







SEQ ID
TATATCTCTGACAGA
MS-241_HC CDR2



NO: 716
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-241_HC CDR3



NO: 717
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-242_LC CDR1



NO: 718
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-242_LC CDR2



NO: 719
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-242_LC CDR3



NO: 720
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-242_HC CDR1



NO: 721
ACT







SEQ ID
TATATCTCTGACAGA
MS-242_HC CDR2



NO: 722
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-242_HC CDR3



NO: 723
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-243_LC CDR1



NO: 724
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-243_LC CDR2



NO: 725
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-243_LC CDR3



NO: 726
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-243_HC CDR1



NO: 727
ACT







SEQ ID
TATATCTCTGACAGA
MS-243_HC CDR2



NO: 728
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-243_HC CDR3



NO: 729
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-244_LC CDR1



NO: 730
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-244_LC CDR2



NO: 731
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-244_LC CDR3



NO: 732
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-244_HC CDR1



NO: 733
ACT







SEQ ID
TATATCTCTGACAGA
MS-244_HC CDR2



NO: 734
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-244_HC CDR3



NO: 735
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-245_LC CDR1



NO: 736
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-245_LC CDR2



NO: 737
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-245_LC CDR3



NO: 738
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-245_HC CDR1



NO: 739
ACT







SEQ ID
TATATCTCTGACAGA
MS-245_HC CDR2



NO: 740
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-245_HC CDR3



NO: 741
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-246_LC CDR1



NO: 742
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-246_LC CDR2



NO: 743
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-246_LC CDR3



NO: 744
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-246_HC CDR1



NO: 745
ACT







SEQ ID
TATATCTCTGACAGA
MS-246_HC CDR2



NO: 746
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-246_HC CDR3



NO: 747
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC







SEQ ID
GGACGACAGGCCCTT
MS-247_LC CDR1



NO: 748
GGAAGTAGAGCTGTT





CAG







SEQ ID
AATAATCAAGACCGG
MS-247_LC CDR2



NO: 749
CCCTCA







SEQ ID
CACATGTGGGATAGT
MS-247_LC CDR3



NO: 750
AGAAGTGGCTTCAGT





TGGT





CT







SEQ ID
AATAATTACTACTGG
MS-247_HC CDR1



NO: 751
ACT







SEQ ID
TATATCTCTGACAGA
MS-247_HC CDR2



NO: 752
GAATCAGCGACTTAC





AACC





CCTCCCTCAATAGT







SEQ ID
GCGCGCCGAGGACAG
MS-247_HC CDR3



NO: 753
AGGATTTATGGAGTG





GTTT





CCTTTGGAGAGTTCT





TCTACTACTACTCCA





TGGAC





GTC
















TABLE 8







Methods for characterizing anti-HIV antibody 10-1074 variants









Method Name
Discard limits
Priority molecules





Titer (with caveat that
Discard molecules with
Variants with significant


transient titer is not
significant reduction in titer
increase in titer over


correlative with stable titer)

parental


Purification Yield
Discard molecules with a
Variants with yield close



significant decrease in yield as
to 100% based on the



compared to the titer
titer


Neutralization
Discard molecules with greater
Variants with no decrease



than 3-fold reduction in
in potency



neutralization potency for any



given virus


Size Exclusion
Dimer and higher order
Molecules with less than


Chromatography (SEC)
aggregates less than 10%.
5% dimer and higher



Priority for molecules with
order aggregates



lower values.


Differential Scanning
Discard molecules with loss of
Molecules with increased


Fluorimetry (DSF)
Tm2
or additional Tm


Chemical Unfolding by
Discard molecules with
Molecules with inflection


Guanidine-HCl
inflection point of unfolding
point of unfolding greater



less than parental molecule
than parental molecule


Relative Solubility Analysis
Discard molecules with
Molecules with increased


(RSA)
decreased solubility
relative solubility given




priority


Low pH Stability
Discard molecules with greater
No change in aggregation



than 5% increase in aggregation
level following low pH



following low pH incubation
incubation
















TABLE 9







Molecule sets and biophysical analysis of 10-1074 antibody variants (Round 1)



















Amount


DSF Tm1,
DSF Tm2,
DSF Tm1,
DSF Tm2,


Molecule


Purified
SEC
SEC
° C.
° C.
° C.
° C.


Set
LC
IgG1 HC
(mg)
(% Monomer)
(% HMW)
(rep 1)
(rep 1)
(rep 2)
(rep 2)



















MS-194


1.20
91.52
8.48
69.8

70.0



MS-203
LmdV: Y2P

0.60
95.24
4.76
69.3
81.6
69.3
81.1


MS-204
LmdV: R7P

0.87
65.98
34.02
69.9

70.1


MS-205
LmdV: P9S

1.25
71.66
28.34
70.1

70.2


MS-206
LmdV: E17Q

1.25
91.35
8.65
70.0

70.0


MS-207
LmdV: H46Q

0.87
65.30
34.70
69.8
80.8
69.9


MS-208
LmdV: P81.1N

0.24
88.68
11.32
68.8
81.3
69.0


MS-209
LmdV: I81.3S

1.27
60.79
39.21
70.0
81.3
70.1
80.1


MS-210
LmdV: N82G

0.28
88.24
11.76
70.1
81.7
70.3
81.3


MS-211
LmdV: R88T

0.22
83.11
16.89
66.9

67.1


MS-212
LmdV: D110E

0.25
82.78
17.22
68.5

68.6


MS-213
LmdV: A142G

0.44
90.48
9.52
68.1

68.2


MS-214

HV: D29G
2.01
94.00
6.00
69.9

69.9


MS-215

HV: S47P
2.68
92.88
7.12
70.0

70.1


MS-216

HV: V79T
1.48
94.67
5.33
69.8
81.8
69.9
80.1


MS-217

HV: R82V
1.31
94.21
5.79
69.8
80.9
69.9
80.1


MS-218

HV: L89F
0.68
96.33
3.67
70.0
80.9
70.1
81.3


MS-219

HV: T108R
2.24
91.93
8.07
70.3
75.4
70.3
76.0


MS-220

HV: K141Q
2.87
94.56
5.44
69.9

69.9


MS-224

HV: N75Q
0.05


70.2

69.9
80.8
















TABLE 10







Molecule sets and neutralization analysis against 10-


1074 sensitive virus panel in TZM.bl cells (Round 1)













Molecule
Du156.12
WITO4160.33
CNE17
CNE30
CAAN5342.A2
Du172.17



















Set
IC50
IC80
IC50
IC80
IC50
IC80
IC50
IC80
IC50
IC80
IC50
IC80






















Control
0.010
0.030
0.168
1.173
1.201
6.067
0.164
0.605
0.009
0.029
0.110
0.391


MS-203
0.008
0.025
0.205
0.979
1.291
4.519
0.193
0.546
0.009
0.024
0.084
0.295


MS-204
0.014
0.040
0.236
1.664
1.211
5.895
0.270
0.902
0.017
0.048
0.092
0.334


MS-205
0.012
0.035
0.162
0.922
1.237
4.411
0.249
0.824
0.011
0.029
0.098
0.329


MS-206
0.010
0.035
0.161
1.142
0.986
3.484
0.225
0.614
0.009
0.024
0.095
0.272


MS-207
0.010
0.036
0.252
0.840
1.285
5.873
0.240
0.836
0.026
0.115
0.211
0.875


MS-208
0.007
0.036
0.699
5.174
3.569
17.98
0.206
1.018
0.016
0.047
0.231
0.816


MS-209
0.007
0.025
0.276
1.833
1.155
5.751
0.174
0.618
0.009
0.029
0.088
0.303


MS-210
0.005
0.013
0.091
0.594
0.598
2.834
0.097
0.340
0.003
0.013
0.044
0.156


MS-211
0.008
0.028
0.237
1.514
1.151
4.240
0.205
0.744
0.010
0.025
0.092
0.309


MS-212
0.009
0.041
0.304
1.938
1.395
6.928
0.242
1.130
0.007
0.031
0.113
0.399


MS-213
0.007
0.028
0.183
1.271
0.955
5.049
0.141
0.689
0.011
0.033
0.119
0.315


MS-214
0.005
0.018
0.221
1.553
0.987
4.567
0.185
0.630
0.009
0.024
0.090
0.238


MS-215
0.007
0.023
0.157
1.118
1.174
5.438
0.224
0.760
0.011
0.031
0.095
0.305


MS-216
0.007
0.020
0.132
0.887
1.116
4.999
0.194
0.517
0.009
0.032
0.084
0.277


MS-217
0.010
0.037
0.260
1.678
1.159
5.397
0.216
0.743
0.010
0.038
0.075
0.275


MS-218
0.005
0.018
0.142
1.016
0.815
4.195
0.156
0.557
0.010
0.027
0.091
0.312


MS-219
0.006
0.020
0.308
1.349
0.966
3.559
0.176
0.609
0.007
0.022
0.104
0.278


MS-220
0.009
0.027
0.215
1.023
1.242
4.415
0.193
0.528
0.009
0.027
0.099
0.335


MS-224
0.005
0.022
0.269
1.219
1.147
4.026
0.162
0.564
0.009
0.032
0.096
0.329
















TABLE 11







Reasons for including or excluding variants based on neutralization


activity and biophysical analysis (Round1)








Molecule Set
Reason for inclusion/exclusion in Round 2





MS-203
Include: presence of Tm2 by DSF, HMW <10%


MS-204
Exclude: Lack of Tm2


MS-205
Exclude: Lack of Tm2


MS-206
Exclude: Lack of Tm2


MS-207
Exclude: Lack of Tm2


MS-208
Exclude: Lack of Tm2; Reduced neutralization activity


MS-209
Exclude: SEC shows HMW of 39.2%


MS-210
Exclude: Low production titer


MS-211
Exclude: Lack of Tm2


MS-212
Exclude: Lack of Tm2


MS-213
Exclude: Lack of Tm2


MS-214
Exclude: Lack of Tm2


MS-215
Exclude: Lack of Tm2


MS-216
Include: presence of Tm2 by DSF, HMW <10%


MS-217
Include: presence of Tm2 by DSF, HMW <10%


MS-218
Include: presence of Tm2 by DSF, HMW <10%


MS-219
Include: presence of Tm2 by DSF, HMW <10%


MS-220
Exclude: Lack of Tm2


MS-224
Exclude: Low production titer
















TABLE 12







Molecule sets of anti-HIV antibody 10-1074 variants (Round 2)









Molecule




Set
LC
IgG1 HC





MS-194




MS-225
LmdV: Y2P
HV: V79T


MS-226
LmdV: Y2P
HV: R82V


MS-227
LmdV: Y2P
HV: L89F


MS-228
LmdV: Y2P
HV: T108R


MS-229

HV: V79T, HV: R82V


MS-230

HV: V79T, HV: L89F


MS-231

HV: V79T, HV: T108R


MS-232

HV: R82V, HV: L89F


MS-233

HV: R82V, HV: T108R


MS-234

HV: L89F, HV: T108R


MS-235
LmdV: Y2P
HV: V79T, HV: R82V


MS-236
LmdV: Y2P
HV: V79T, HV: L89F


MS-237
LmdV: Y2P
HV: V79T, HV: T108R


MS-238
LmdV: Y2P
HV: R82V, HV: L89F


MS-200
LmdV: Y2P
HV: R82V, HV: T108R


MS-239
LmdV: Y2P
HV: L89F, HV: T108R


MS-240

HV: V79T, HV: R82V, HV: L89F


MS-241

HV: V79T, HV: R82V, HV: T108R


MS-201

HV: V79T, HV: L89F, HV: T108R


MS-242

HV: R82V, HV: L89F, HV: T108R


MS-243
LmdV: Y2P
HV: V79T, HV: R82V, HV: L89F


MS-244
LmdV: Y2P
HV: V79T, HV: R82V, HV: T108R


MS-202
LmdV: Y7P
HV: V79T, HV: L89F, HV: T108R


MS-245
LmdV: Y2P
HV: R82V, HV: L89F, HV: T108R


MS-246

HV: V79T, HV: R82V, HV: L89F, HV: T108R


MS-247
LmdV: Y2P
HV: V79T, HV: R82V, HV: L89F, HV: T108R
















TABLE 13







Molecule sets and biophysical analysis of 10-1074 antibody variants (Round 2)


















DSF Tm1

DSF Tm2



Molecule
SEC
SEC
SEC
° C.
DSF Tm1
° C.
DSF Tm2


Set
(% monomer)
(% dimer)
(% Oligomer)
(Avg. n = 2)
(Std Dev)
(Avg. n = 2)
(Std Dev)

















MS-194
92.40
3.72
3.89
70.00
0.01




MS-225
89.07
3.12
7.81
69.44
0.05


MS-226
93.49
3.51
3.00
69.52
0.03


MS-227
90.18
3.10
6.72
69.76
0.07


MS-228
95.37
3.59
1.04
70.48
0.02
74.50
0.00


MS-229
93.39
4.03
2.58
70.04
0.05


MS-230
94.00
3.42
2.58
70.25
0.05


MS-231
95.35
3.87
0.79
70.41
0.02
74.50
0.03


MS-232
94.62
3.52
1.86
70.07
0.03


MS-233
95.45
3.94
0.61
70.30
0.00
76.69
0.15


MS-234
96.70
2.94
0.36
70.40
0.06
76.85
0.11


MS-235
92.77
3.46
3.77
69.74
0.05


MS-236
93.06
3.78
3.16
69.92
0.10


MS-237
94.61
4.03
1.36
70.47
0.02
74.50
0.00


MS-238
91.73
3.94
4.33
69.36
0.01


MS-200
94.64
4.56
0.80
70.15
0.01
74.62
0.33


MS-239
95.99
3.35
0.66
70.28
0.01
75.42
0.09


MS-240
94.87
3.61
1.52
69.99
0.01


MS-241
94.36
4.93
0.71
70.11
0.02
76.41
0.04


MS-201
94.58
4.68
0.73
70.28
0.04
76.69
0.01


MS-242
94.82
4.52
0.66
70.25
0.02
77.30
0.03


MS-243
91.81
4.51
3.67
69.57
0.06


MS-244
93.97
5.04
0.99
70.17
0.02
74.70
0.18


MS-202
93.88
5.04
1.08
70.42
0.00
75.43
0.15


MS-245
93.40
5.61
0.99
70.36
0.02
76.15
0.04


MS-246
94.88
4.59
0.53
70.19
0.05
77.13
0.09


MS-247
94.37
4.88
0.75
69.44
0.05
















TABLE 14







Additional biophysical characterization for the combination variants (Round 2)
















Shoulder

Inflection Pt

pH 3.3

PEG



Molecule
Score

of Unfolding

HMW %

solubility


Set
(Avg. n = 2)
(Std Dev)
(Avg n = 3)
Std Dev
(Avg n = 2)
Std Dev
(avg. n = 2)
Std Dev


















MS-194
7.65
0.17
2.44
0.01
39.76
0.19
0.14
0.02


MS-225
7.22
0.97
2.37
0.03
40.43
14.01
0.18
0.02


MS-226
7.72
0.16
2.49
0.04
14.33
6.02
0.19
0.01


MS-227
8.12
0.61
2.53
0.03
28.13
14.86
0.18
0.02


MS-228
16.25
0.55
2.64
0.02
9.10
6.29
0.17
0.02


MS-229
9.03
0.98
2.60
0.01
9.77
2.43
0.19
0.02


MS-230
10.03
0.39
2.62
0.05
12.14
2.04
0.18
0.02


MS-231
20.80
0.22
2.63
0.02
3.35
0.16
0.14
0.02


MS-232
9.70
0.25
2.65
0.06
8.67
1.77
0.19
0.01


MS-233
20.00
0.23
2.98
0.03
2.48
0.03
0.17
0.02


MS-234
28.36
2.18
2.97
0.19
2.61
0.51
0.15
0.02


MS-235
7.79
0.22
2.60
0.03
13.92
1.48
0.19
0.01


MS-236
8.32
0.07
2.53
0.00
22.13
6.12
0.19
0.02


MS-237
16.01
0.05
2.65
0.05
4.58
0.49
0.15
0.03


MS-238
8.21
0.56
2.57
0.01
31.37
25.30
0.20
0.01


MS-200
16.12
0.42
2.93
0.04
2.93
0.01
0.19
0.02


MS-239
22.28
0.72
2.98
0.04
3.19
0.49
0.18
0.02


MS-240
9.98
0.18
2.71
0.03
9.63
4.33
0.19
0.02


MS-241
21.39
0.09
2.98
0.06
3.12
0.06
0.17
0.03


MS-201
29.39
0.45
3.15
0.03
2.21
0.06
0.17
0.02


MS-242
23.85
0.29
2.89
0.14
2.49
0.06
0.19
0.02


MS-243
7.62
0.22
2.57
0.03
9.86
1.38
0.18
0.01


MS-244
16.12
0.51
2.90
0.08
3.25
0.16
0.18
0.02


MS-202
22.49
1.53
3.08
0.09
3.64
0.09
0.17
0.02


MS-245
18.77
0.55
3.06
0.07
3.29
0.30
0.18
0.02


MS-246
22.39
0.97
3.29
0.03
2.32
0.23
0.17
0.03


MS-247
7.22
0.97
2.91
0.07
3.14
0.24
0.19
0.02
















TABLE 15





Neutralization analysis of selected variants in Round 2 in TZM.bl


cells. Loss of potency are values > 3-fold of control value





















Molecule
SC422661.8
WITO4160.33
CAAN5342.A2
DU156.12
DU172.17
CNE17



















Set
IC50
IC80
IC50
IC80
IC50
IC80
IC50
IC80
IC50
IC80
IC50
IC80





Control
0.045
0.157
0.205
1.439
0.005
0.019
0.008
0.034
0.055
0.156
1.34
4.574


MS-228
0.03
0.114
0.097
0.71
0.002
0.01
0.003
0.017
0.036
0.134
0.928
3.21


MS-231
0.032
0.092
0.092
0.646
0.001
0.012
0.003
0.017
0.034
0.125
0.796
2.719


MS-233
0.037
0.128
0.172
0.789
0.005
0.015
0.004
0.02
0.033
0.124
0.625
3.085


MS-234
0.04
0.136
0.22
0.932
0.003
0.011
0.004
0.017
0.058
0.232
0.734
2.646


MS-237
0.028
0.126
0.113
0.744
0.004
0.016
0.004
0.019
0.037
0.117
0.792
3.673


MS-200
0.036
0.156
0.13
0.794
0.005
0.02
0.007
0.028
0.037
0.152
0.922
3.21


MS-239
0.033
0.114
0.199
0.951
0.003
0.012
0.005
0.017
0.03
0.125
0.63
2.887


MS-241
0.034
0.106
0.229
0.999
0.004
0.014
0.008
0.02
0.038
0.137
0.81
2.939


MS-201
0.027
0.104
0.177
1.153
0.002
0.011
0.005
0.016
0.028
0.102
0.782
2.62


MS-242
0.04
0.116
0.145
0.889
0.003
0.012
0.006
0.021
0.034
0.161
0.762
3.331


MS-244
0.041
0.123
0.172
1.169
0.005
0.017
0.003
0.017
0.045
0.167
0.694
3.637


MS-202
0.028
0.135
0.185
0.708
0.003
0.011
0.004
0.021
0.028
0.104
0.825
2.903


MS-245
0.029
0.102
0.132
0.774
0.002
0.012
0.006
0.022
0.038
0.139
0.991
4.443


MS-246
0.037
0.128
0.145
0.82
0.004
0.017
0.006
0.025
0.039
0.146
0.907
3.175


MS-247
0.034
0.151
0.107
0.611
0.003
0.014
0.009
0.032
0.03
0.149
0.642
3.141
















Molecule
CNE30
CNE53
235-47
X1193_c1
X1254_c3
3301.v1.c24



















Set
IC50
IC80
IC50
IC80
IC50
IC80
IC50
IC80
IC50
IC80
IC50
IC80





Control
0.258
0.709
0.017
0.049
0.029
0.116
0.04
0.139
0.055
0.154
0.008
0.021


MS-228
0.215
0.595
0.007
0.028
0.019
0.086
0.03
0.13
0.039
0.117
0.003
0.013


MS-231
0.184
0.517
0.007
0.025
0.016
0.078
0.028
0.12
0.035
0.116
0.002
0.012


MS-233
0.186
0.649
0.006
0.023
0.03
0.113
0.03
0.133
0.041
0.129
0.003
0.016


MS-234
0.184
0.5
0.008
0.037
0.019
0.077
0.031
0.142
0.03
0.122
0.003
0.014


MS-237
0.17
0.46
0.005
0.027
0.022
0.086
0.042
0.146
0.035
0.101
0.002
0.014


MS-200
0.17
0.583
0.007
0.027
0.022
0.085
0.059
0.177
0.047
0.133
0.005
0.019


MS-239
0.175
0.588
0.004
0.02
0.023
0.088
0.03
0.182
0.036
0.102
0.002
0.011


MS-241
0.181
0.498
0.006
0.023
0.028
0.08
0.042
0.155
0.034
0.119
0.003
0.01


MS-201
0.173
0.471
0.003
0.025
0.011
0.067
0.033
0.154
0.037
0.1
0.003
0.008


MS-242
0.197
0.535
0.004
0.023
0.028
0.092
0.042
0.185
0.031
0.107
0.003
0.009


MS-244
0.18
0.639
0.001
0.014
0.032
0.113
0.041
0.184
0.027
0.108
0.001
0.005


MS-202
0.16
0.568
0.005
0.021
0.022
0.084
0.037
0.139
0.028
0.117
0.005
0.018


MS-245
0.156
0.553
0.004
0.019
0.028
0.1
0.049
0.172
0.04
0.137
0.006
0.019


MS-246
0.204
0.557
0.002
0.021
0.037
0.128
0.046
0.199
0.047
0.164
0.007
0.021


MS-247
0.197
0.554
0.005
0.027
0.036
0.126
0.043
0.203
0.029
0.113
0.008
0.023
















TABLE 16







Reasons for excluding combinatorial variants


based on biophysical analysis (Round 2)








Molecule
Reasons for exclusion of molecules from


Set
further in-depth analysis





MS-225
Excluded: Lack of Tm2, Aggregation at 65° C., Lower



chemical unfolding stability, aggregation at pH 3.3 > 5%


MS-226
Excluded: Lack of Tm2, Aggregation at 65° C., Lower



chemical unfolding stability, aggregation at pH 3.3 > 5%


MS-227
Excluded: Lack of Tm2, Aggregation at 65° C., Lower



chemical unfolding stability, aggregation at pH 3.3 > 5%


MS-228
Excluded: Lower chemical unfolding stability, aggregation



at pH 3.3 > 5%


MS-229
Excluded: Lack of Tm2, Aggregation at 65° C., Lower



chemical unfolding stability, aggregation at pH 3.3 > 5%


MS-230
Excluded: Lack of Tm2, Aggregation at 65° C., Lower



chemical unfolding stability, aggregation at pH 3.3 > 5%


MS-231
Excluded: Aggregation at 65° C., Lower chemical



unfolding stability


MS-232
Excluded: Lack of Tm2, Aggregation at 65° C., Lower



chemical unfolding stability, aggregation at pH 3.3 > 5%


MS-233
Excluded: Aggregation at 65° C.


MS-234
Excluded: Low titer


MS-235
Excluded: Lack of Tm2, Aggregation at 65° C., Lower



chemical unfolding stability, aggregation at pH 3.3 > 5%


MS-236
Excluded: Lack of Tm2, Aggregation at 65° C., Lower



chemical unfolding stability, aggregation at pH 3.3 > 5%


MS-237
Excluded: Lower chemical unfolding stability


MS-238
Excluded: Lack of Tm2, Aggregation at 65° C., Lower



chemical unfolding stability, aggregation at pH 3.3 > 5%


MS-200
Include


MS-239
Excluded: Low Titer


MS-240
Excluded: Lack of Tm2, Aggregation at 65° C., Lower



chemical unfolding stability, aggregation at pH 3.3 > 5%


MS-241
Excluded: Similar to 19, but slightly less stability to



chemical unfolding


MS-201
Include


MS-242
Exclude: Decreased chemical unfolding stability compared



to 19


MS-243
Excluded: Lack of Tm2, Aggregation at 65° C., Lower



chemical unfolding stability, aggregation at pH 3.3 > 5%


MS-244
Excluded: Aggregation at 65° C.


MS-202
Include


MS-245
Exclude: No improvement over variants 15, 19, or 23


MS-246
Excluded: Low titer (less than parental)


MS-247
Excluded: Low titer (less than parental)









The foregoing examples and description of the preferred embodiments should be taken as illustrating, rather than as limiting the present invention as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features set forth above can be utilized without departing from the present invention as set forth in the claims. Such variations are not regarded as a departure from the scope of the invention, and all such variations are intended to be included within the scope of the following claims. All references cited herein are incorporated herein in their entireties.

Claims
  • 1. An isolated anti-HIV antibody, or antigen-binding portion thereof, comprising a light chain variable region having a light chain amino acid sequence that is at least 75% identical to a polypeptide sequence selected from the group consisting of the light chain variable regions of SEQ ID NOs: 3-13, 22, 24-28, 35-39, 43-45, and 47, wherein the isolated anti-HIV antibody, or antigen-binding portion thereof comprises one or more light chain substitutions at one or more residues selected from the group consisting of LmdV:Y2, LmdV:R7, LmdV:P9, LmdV:E17, LmdV:H46, LmdV:P81.1, LmdV:I81.3, LmdV:N82, LmdV:R88, LmdV:D110, and LmdV:A142.
  • 2. An isolated anti-HIV antibody, or antigen-binding portion thereof, comprising a heavy chain variable region having a heavy chain amino acid sequence that is at least 75% identical to a polypeptide sequence selected from the group consisting of the heavy chain variable regions of SEQ ID NOs: 61-94, wherein the isolated anti-HIV antibody, or antigen-binding portion thereof comprises one or more heavy chain substitutions at one or more residues selected from the group consisting of HV:D29, HV:S47, HV:N75, HV:V79, HV:R82, HV:L89, HV:T108, and HV:K141.
  • 3. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 1, further comprising a heavy chain variable region having an heavy chain amino acid sequence that is at least 75% identical to a polypeptide sequence selected from the group consisting of the heavy chain variable regions of SEQ ID NOs: 61-94, wherein the isolated anti-HIV antibody, or antigen-binding portion thereof comprises one or more heavy chain substitutions at one or more residues selected from the group consisting of HV:D29, HV:S47, HV:N75, HV:V79, HV:R82, HV:L89, HV:T108, and HV:K141.
  • 4. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 1, comprising the one or more light chain substitutions selected from the group consisting of LmdV:Y2P, LmdV:R7P, LmdV:P9S, LmdV:E17Q, LmdV:H46Q, LmdV:P81.1N, LmdV:I81.3S, LmdV:N82G, LmdV:R88T, LmdV:D110E, and LmdV:A142G or conservative substitutions thereof.
  • 5. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 2, comprising the one or more heavy chain substitutions selected from the group consisting of HV:D29G, HV:S47P, HV:N75Q, HV:V79T, HV:R82V, HV:L89F, HV:T108R, and HV:K141Q or conservative substitutions thereof.
  • 6. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 3, comprising the one or more light chain substitutions selected from the group consisting of LmdV:Y2P, LmdV:R7P, LmdV:P9S, LmdV:E17Q, LmdV:H46Q, LmdV:P81.1N, LmdV:I81.3S, LmdV:N82G, LmdV:R88T, LmdV:D110E, and LmdV:A142G or conservative substitutions thereof and the one or more heavy chain substitutions selected from the group consisting of HV:D29G, HV:S47P, HV:N75Q, HV:V79T, HV:R82V, HV:L89F, HV:T108R, and HV:K141Q or conservative substitutions thereof.
  • 7. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 1, wherein the light chain amino acid sequence is at least 75% identical to the light chain variable region of SEQ ID NO.: 3 and comprises a LmdV:Y2P substitution or a conservative substitution of proline at LmdV:Y2.
  • 8. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 2, wherein the heavy chain amino acid sequence is at least 75% identical to the heavy chain variable region of SEQ ID NO.: 63 and comprises an HV:V79T substitution or a conservative substitution of threonine at HV:V79.
  • 9. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 2, wherein the heavy chain amino acid sequence is at least 75% identical to the heavy chain variable region of SEQ ID NO.: 64 and comprises an HV:R82V substitution or a conservative substitution of valine at HV:R82.
  • 10. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 2, wherein the heavy chain amino acid sequence is at least 75% identical to the heavy chain variable region of SEQ ID NO.: 65 and comprises an HV:L89F substitution or a conservative substitution of phenylalanine of HV:L89.
  • 11. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 2, wherein the heavy chain amino acid sequence is at least 75% identical to the heavy chain variable region of SEQ ID NO.: 66 and comprises an HV:T108R substitution or a conservative substitution of arginine at HV:T108.
  • 12. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 3, wherein the light chain amino acid sequence is at least 75% identical to the light chain variable region of SEQ ID NO.: 22 and comprises a LmdV:Y2P substitution or a conservative substitution of proline at LmdV:Y2, and wherein the heavy chain amino acid sequence is at least 75% identical to the heavy chain variable region of SEQ ID NO.: 69 and comprises: an HV:R82V substitution or a conservative substitution of valine at HV:R82,and an HV:T108R substitution or a conservative substitution of arginine at HV:T108.
  • 13. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 3, wherein the heavy chain amino acid sequence is at least 75% identical to the heavy chain variable region of SEQ ID NO.: 70 and comprises: an HV:V79T substitution or a conservative substitution of threonine at HV:V79,an HV:L89F substitution or a conservative substitution of phenylalanine at HV:L89, andan HV:T108R substitution or a conservative substitution of arginine at HV:T108.
  • 14. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 3, wherein the light chain amino acid sequence is at least 75% identical to the light chain variable region of SEQ ID NO.: 24 and comprises a LmdV:Y2P substitution or a conservative substitution of proline at LmdV:Y2, and wherein the heavy chain amino acid sequence is at least 75% identical to the heavy chain variable region of SEQ ID NO.: 71 and comprises: an HV:V79T substitution or a conservative substitution of threonine at HV:V79,an HV:L89F substitution or a conservative substitution of phenylalanine at HV:L89, andan HV:T108R substitution or a conservative substitution of arginine at HV:T108.
  • 15. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 1, comprising SEQ NO.: 3.
  • 16. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 2, comprising SEQ NO.: 63, 64, 65, 66, or 70.
  • 17. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 3, wherein the light chain variable region comprises the light variable region of SEQ NO.: 22 and the heavy chain variable region comprises the heavy variable region of SEQ No.: 69.
  • 18. The isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 3, wherein the light chain variable region comprises the light variable region of SEQ NO.: 24 and the heavy chain variable region comprises the heavy variable region of SEQ No.: 71.
  • 19. A pharmaceutical composition comprising the isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 1, and a pharmaceutically acceptable carrier or excipient.
  • 20. The pharmaceutical composition further comprising a second therapeutic agent.
  • 21. A nucleic acid, or a codon-optimized nucleic acid, encoding the isolated anti-HIV antibody, or antigen-binding portion thereof, of claim 1.
  • 22. A vector or vector system comprising at least one nucleic acid of claim 21.
  • 23. A cell comprising the nucleic acid of claim 21.
  • 24. A method of making recombinant anti-HIV antibody, or antigen-binding portion thereof, comprising: a. obtaining the cell of claim 23;b. culturing the cell in a medium under conditions permitting expression of a polypeptide encoded by the vector and assembling of an antibody or fragment thereof, andc. purifying the antibody or fragment from the cultured cell or the medium of the cell.
  • 25. A method of preventing or treating an HIV infection or an HIV-related disease comprising the steps of: a. identifying a patient in need of such prevention or treatment, andb. administering to said patient a first therapeutic agent comprising a therapeutically effective amount of at least one anti-HIV antibody of claim 1, or antigen-binding portion thereof.
  • 26. The method of claim 25, further comprising administering a second therapeutic agent.
  • 27. The method of claim 26, wherein the second therapeutic agent is administered before, concurrently with or after the administration of the anti-HIV antibody or antigen-binding portion thereof.
  • 28. The method of claim 24 and the pharmaceutical composition of claim 20, wherein the second therapeutic agent is an anti-HIV-1 broadly neutralizing antibody (bNAb).
  • 29. The method of claim 26, wherein the anti-HIV-1 broadly neutralizing antibody is 3BNC117.
  • 30. A kit comprising a pharmaceutically acceptable dose unit of a pharmaceutically effective amount of at least one isolated anti-HIV antibody according to claim 1, or antigen-binding portion thereof.
  • 31. The kit of claim 30 further comprising a pharmaceutically acceptable dose unit of a pharmaceutically effective amount of an anti-HIV agent, wherein the two pharmaceutically acceptable dose units can optionally take the form of a single pharmaceutically acceptable dose unit.
  • 32. The kit of claim 31, wherein the anti-HIV agent is one selected from the group consisting of a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, an entry or fusion inhibitor, and an integrase inhibitor.
  • 33. The kit of claim 31, wherein the anti-HIV agent is an anti-HIV broadly neutralizing antibody.
  • 34. The kit of claim 33, wherein the anti-HIV broadly neutralizing antibody is 3BNC117.
CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62/731,356, filed Sep. 14, 2018. The foregoing application is incorporated by reference herein in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under Grant No. P01 AI081677 awarded the NIH. The government has certain rights in the invention.

PCT Information
Filing Document Filing Date Country Kind
PCT/US19/50823 9/12/2019 WO 00
Provisional Applications (1)
Number Date Country
62731356 Sep 2018 US