Patent Publication Number: US-2022227873-A1

Title: Anti-gal9 immune-inhibiting binding molecules

Description:
1. CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit under 35 U.S.C. 119(e) of prior co-pending U.S. Provisional Patent Application No. 62/900,105, filed on Sep. 13, 2019 and U.S. Provisional Patent Application No. 62/855,590, filed on May 31, 2019. 
    
    
     2. SEQUENCE LISTING 
     The instant application contains a Sequence Listing which has been submitted via EFS-Web and is hereby incorporated herein by reference in its entirety. Said ASCII copy, created on Month XX, 2020, is named XXXXXUS_sequencelisting.txt, and is X,XXX,XXX bytes in size. 
     3. BACKGROUND 
     Autoimmune diseases arise from an imbalance within the immune system that results in immune-mediated attack on the body&#39;s own cells and tissues. The current “gold standard” of care for autoimmune diseases is systemic immune suppression by immunosuppressive agents, including corticosteroids, anti-cytokine antibodies such as anti-TNF-α, anti-IL-1, anti-IL-5, anti-IL-6, anti-IL-17 antibodies, and anti-IL-23 antibodies, and small molecule drugs that reduce inflammatory cytokine signaling, such as JAK/STAT inhibitors. However, nonspecific systemic immune suppression predisposes the patient to infectious disease and can have other serious side effects. 
     Immune therapy has great potential for the treatment of autoimmune disease. Galectin-9 (GAL9) is an S-type lectin beta-galacto side-binding protein with N- and C-terminal carbohydrate-binding domains connected by a linker peptide. GAL9 has been implicated in modulating cell-cell and cell-matrix interactions. GAL9 has been shown to bind soluble PD-L2, and at least some of the immunological effects of PD-L2 have been suggested to be mediated through binding of multimeric PD-L2 to GAL9, rather than through PD-1 (WO 2016/008005, which is incorporated herein by reference in its entirety). However, mechanisms by which GAL9 and PD-L2 impact immune effector function are not yet fully characterized. 
     There remains a need for more targeted therapies that can reestablish balance of the immune system by modulating immune effector cells to establish a more clinically favorable cytokine profile. Such therapeutic agents may be useful for improving treatment for autoimmune and inflammatory disease. 
     4. SUMMARY 
     The present invention has arisen in part from the unexpected discovery that PD-L2 is overexpressed in autoimmune disease and that inhibiting the Galectin-9/PD-L2 pathway modulates immune effector cells to produce a more clinically favorable cytokine profile. 
     Accordingly, disclosed herein are various GAL9 binding molecules, antigen binding portions thereof, and antibodies that specifically bind to and antagonize human GAL9 (Galectin-9). Inhibiting GAL9 using the anti-human GAL9 binding molecules disclosed herein decreases the secretion and production of proinflammatory cytokines, increases the secretion and production of anti-inflammatory cytokines, and decreases surface expression of stimulatory molecules. 
     Pharmaceutical compositions comprising the GAL9 binding molecules are also disclosed. The anti-GAL9 binding molecules, antigen binding portions thereof, and antibodies disclosed herein can be used per se, as a pharmaceutical composition, or in combination with other therapeutic agents or procedures to treat, prevent, and/or diagnose autoimmune disease, inflammatory disease, or a condition that invokes an inflammation response such as an infection. The anti-GAL9 binding molecules are particularly useful for a disease or condition in which GAL9/PD-L2 interaction contributes prominently to pathogenesis. The anti-GAL9 binding molecules are useful in treating, reducing inflammation, reducing autoimmune response, prolonging remission, inducing remission, re-establishing immune tolerance, improving organ function, reducing progression of a disease, reducing the risk of development of a second disease, or increasing overall survival in a subject. 
     In a first aspect, the disclosure provides a Galectin-9 (GAL9) antigen binding molecule comprising a first antigen binding site specific (ABS) for a first epitope of a first GAL9 antigen, wherein the first antigen binding site comprises all three VH CDRs from any one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. 
     In a second aspect, the disclosure provides a Galectin-9 (GAL9) antigen binding molecule, comprising a first antigen binding site specific for a first epitope of a first GAL9 antigen, wherein the first antigen binding site comprises all three VL CDRs from any one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. 
     In a third aspect, the disclosure provides a Galectin-9 (GAL9) antigen binding molecule, comprising a first antigen binding site specific for a first epitope of a first GAL9 antigen, wherein the first antigen binding site comprises all three VH CDRs and all three VL CDRs from any one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. 
     In a fourth aspect, the disclosure provides a Galectin-9 (GAL9) antigen binding molecule, comprising a first antigen binding site specific for a first epitope of a first GAL9 antigen, comprising the VL sequence and the VH sequence from any one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. 
     In some embodiments, the GAL9 antigen binding molecule comprises a full immunoglobulin heavy chain “IgG1” sequence comprising the VH sequence and a full immunoglobulin light chain sequence comprising the VL sequence, wherein the VH sequence and the VL sequence are from any one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. 
     In some embodiments, the GAL9 antigen binding molecule comprises a full immunoglobulin heavy chain “IgG4” sequence comprising the VH sequence and a full immunoglobulin light chain sequence comprising the VL sequence, wherein the VH sequence and the VL sequence are from any one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. 
     In some embodiments, the GAL9 antigen binding molecule can comprise a GAL9 antigen that is a human GAL9 antigen. 
     In some embodiments, the GAL9 antigen binding molecule can further comprises a second antigen binding site. 
     In certain embodiments, the second antigen binding site is specific for the GAL9 antigen. In other embodiments, the second antigen binding site is identical to the first antigen binding site. 
     In other embodiments, the second antigen binding site is specific for a second epitope of the first GAL9 antigen. 
     In some embodiments, the second antigen binding site comprises all three VH CDRs, all three VL CDRs, or all three VH CDRs and all three VL CDRs from another ABS clone selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. 
     In some embodiments, the second antigen binding site comprises the VL sequence and the VH sequence from the other ABS clone. 
     In some embodiments, the second antigen binding site comprises a full immunoglobulin heavy chain sequence comprising the VH sequence and a full immunoglobulin light chain sequence comprising the VL sequence from the other ABS clone. 
     In some embodiments, the second antigen binding site is specific for an antigen other than the first GAL9 antigen. 
     In some embodiments, the first antigen binding site comprises all three VH CDRs, all three VL CDRs, or all three VH CDRs and all three VL CDRs from any one of the ABS clones selected from: P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. 
     In some embodiments, the first antigen binding site comprises all three VH CDRs, all three VL CDRs, or all three VH CDRs and all three VL CDRs from any one of the ABS clones selected from: P9-11, P9-24, P9-34, and P9-37. 
     In some embodiments, the first antigen binding site comprises all three VH CDRs, all three VL CDRs, or all three VH CDRs and all three VL CDRs from any one of the ABS clones selected from: P9-11, P9-24, and P9-34. 
     In some embodiments the first antigen binding site comprises all three VH CDRs, all three VL CDRs, or all three VH CDRs and all three VL CDRs from ABS clone P9-11. 
     In some embodiments, the first antigen binding site comprises all three VH CDRs, all three VL CDRs, or all three VH CDRs and all three VL CDRs from ABS clone P9-24. 
     In some embodiments, the first antigen binding site comprises all three VH CDRs, all three VL CDRs, or all three VH CDRs and all three VL CDRs from ABS clone P9-34. 
     In some embodiments, the first antigen binding site comprises all three VH CDRs, all three VL CDRs, or all three VH CDRs and all three VL CDRs from ABS clone P9-37. 
     In some embodiments, the GAL9 antigen binding molecule comprises an antibody format selected from the group consisting of: full-length antibodies, Fab fragments, F(ab)′2 fragments, Fvs, scFvs, tandem scFvs, diabodies, scDiabodies, DARTs, single chain VHH camelid antibodies, tandAbs, minibodies, and B-bodies. B-bodies are described in US pre-grant publication number US 2018/0118811, which is incorporated herein by reference in its entirety. 
     In some embodiments, the GAL9 antigen binding molecule decreases TNF-α secretion by activated immune cells upon contact, wherein the decrease is about at least a 30%, 35%, 40%, 45%, 50%, 55%, or 60% decrease relative to activated immune cells treated with a control agent. 
     In some embodiments, the GAL9 antigen binding molecule decreases IFN-γ secretion by activated immune cells upon contact, wherein the decrease is about at least a 20%, 25%, 30%, 35%, 40%, 45%, or 50% decrease relative to activated immune cells treated with a control agent. 
     In some embodiments, the GAL9 antigen binding molecule increases IL-10 secretion by activated immune cells upon contact, wherein the increase is about at least a 5%, 10%, 15%, 20%, 25%, 30%, 35% or 40% increase relative to activated immune cells treated with a control agent. 
     In some embodiments, the GAL9 antigen binding molecule does not modulate PD-1 surface expression on activated immune cells relative to activated immune cells treated with a control agent. 
     In some embodiments, the GAL9 antigen binding molecule does not modulate PD-L1 surface expression on activated immune cells relative to activated immune cells treated with a control agent. 
     In some embodiments, the GAL9 antigen binding molecule does not modulate CTLA-4 surface expression on activated immune cells relative to activated immune cells treated with a control agent. 
     In some embodiments, the GAL9 antigen binding molecule does not modulate TIM3 surface expression on activated immune cells relative to activated immune cells treated with a control agent. 
     In some embodiments, the GAL9 antigen binding molecule does not modulate LAG3 surface expression on activated immune cells relative to activated immune cells treated with a control agent. 
     In some embodiments, the GAL9 antigen binding molecule decreases 4-1BB surface expression on activated CD8 +  T-cells, relative to activated CD8 +  T-cells treated with a control agent. 
     In some embodiments, the GAL9 antigen binding molecule decreases CD40L surface expression on activated CD8 +  T-cells, relative to activated CD8 +  T-cells treated with a control agent. 
     In some embodiments, the GAL9 antigen binding molecule decreases OX40 surface expression activated on CD8 +  T-cells, relative to activated CD8 +  T-cells treated with a control agent. 
     In some embodiments, the control agent is a negative control agent or positive control agent. 
     In some embodiments, the control agent is a control antibody. 
     In some embodiments, the control antibody is selected from the group consisting of: an ECA42 clone anti-GAL9 antibody, an RG9.1 clone anti-GAL9 antibody, an RG9.35 clone anti GAL9 antibody, an anti-PD1 antibody, an 108A2 clone anti-GAL9 antibody, and a non-GAL9 binding isotype control antibody. 
     In some embodiments, the activated immune cells, activated CD8 +  T-cells, or activated DCs were activated by were activated by peptide stimulation, anti-CD3, or dendritic cells. 
     In a fifth aspect, the disclosure provides a GAL9 antigen binding molecule that decreases TNF-α secretion by activated immune cells, wherein the decrease is about at least a 30%, 35%, 40%, 45%, 50%, 55%, or 60% decrease relative to activated immune cells treated with a control agent. 
     In a sixth aspect, the disclosure provides a GAL9 antigen binding molecule that decreases IFN-γ secretion by activated immune cells, wherein the decrease is about at least a 20%, 25%, 30%, 35%, 40%, 45%, or 50% decrease relative to activated immune cells treated with a control agent. 
     In a seventh aspect, the disclosure provides a GAL9 antigen binding molecule that increases IL-10 secretion by activated immune cells, wherein the increase is about at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% increase relative to activated immune cells treated with a control agent 
     In an eighth aspect, the disclosure provides a GAL9 antigen binding molecule does not modulate PD-1 surface expression on activated immune cells relative to activated immune cells treated with a control agent. 
     In a ninth aspect, the disclosure provides a GAL9 antigen binding molecule does not modulate PD-L1 surface expression on activated immune cells relative to activated immune cells treated with a control agent. 
     In a tenth aspect, the disclosure provides a GAL9 antigen binding molecule does not modulate CTLA-4 surface expression on activated immune cells relative to activated immune cells treated with a control agent. 
     In an eleventh aspect, the disclosure provides a GAL9 antigen binding molecule does not modulate TIM3 surface expression on activated immune cells relative to activated immune cells treated with a control agent. 
     In a twelfth aspect, the disclosure provides a GAL9 antigen binding molecule does not modulate LAG3 surface expression on activated immune cells relative to activated immune cells treated with a control agent. 
     In a thirteenth aspect, the disclosure provides a GAL9 antigen binding molecule decreases 4-1BB surface expression on activated CD8 +  T-cells, relative to activated CD8 +  T-cells treated with a control agent. 
     In a fourteenth aspect, the disclosure provides a GAL9 antigen binding molecule decreases CD40L surface expression on activated CD8 +  T-cells, relative to activated CD8 +  T-cells treated with a control agent. 
     In a fifteenth aspect, the disclosure provides a GAL9 antigen binding molecule decreases OX40 surface expression on activated CD8 +  T-cells, relative to activated CD8 +  T-cells treated with a control agent. 
     In a sixteenth aspect, the disclosure provides a GAL9 antigen binding molecule demonstrates one or more of the following properties: A) decreases TNF-α secretion by activated immune cells, wherein the decrease is about at least a 30%, 35%, 40%, 45%, 50%, 55%, or 60% decrease relative to activated immune cells treated with a control agent; B) decreases IFN-γ secretion by activated immune cells, wherein the decrease is about at least a 20%, 25%, 30%, 35%, 40%, 45%, or 50% decrease relative to activated immune cells treated with a control agent; C) increases IL-10 secretion by activated immune cells, wherein the increase is about at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% increase relative to activated immune cells treated with a control agent; D) does not modulate PD-1 surface expression on activated immune cells relative to activated immune cells treated with a control agent; E) does not modulate PD-L1 surface expression on activated immune cells relative to activated immune cells treated with a control agent; F) does not modulate CTLA-4 surface expression on activated immune cells relative to activated immune cells treated with a control agent; G) does not modulate TIM3 surface expression on activated immune cells relative to activated immune cells treated with a control agent; H) does not modulate LAG3 surface expression on activated immune cells relative to activated immune cells treated with a control agent; I) decreases 4-1BB surface expression on activated CD8 +  T-cells, relative to activated CD8 +  T-cells treated with a control agent; J); decreases CD40L surface expression on activated CD8 +  T-cells, relative to activated CD8 +  T-cells treated with a control agent; or K) decreases OX40 surface expression on activated CD8 +  T-cells, relative to activated CD8 +  T-cells treated with a control agent. 
     In some embodiments, the control agent is a negative control agent or positive control agent. 
     In some embodiments, the control agent is a control antibody. 
     In some embodiments, the control antibody is selected from the group consisting of: an ECA42 clone anti-GAL9 antibody, an RG9.1 clone anti-GAL9 antibody, an RG9.35 clone anti GAL9 antibody, an anti-PD1 antibody, an 108A2 clone anti-GAL9 antibody, and an non-GAL9 binding isotype control antibody. 
     In some embodiments, the activated immune cells, were activated by were activated by peptide stimulation, anti-CD3 or dendritic cells. 
     In some embodiments, the GAL9 antigen binding molecule of the fifth-fifteenth aspects provided herein comprise a first antigen binding site specific for a first epitope of a first GAL9 antigen, wherein the first antigen binding site comprises all three VH CDRs and all three VL CDRs from any one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9- 57. 
     In some embodiments, the VL sequence and the VH sequence from any one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. 
     In some certain embodiments, the GAL9 antigen binding molecule comprises a full immunoglobulin heavy chain sequence comprising the VH sequence and a full immunoglobulin light chain sequence comprising the VL sequence, wherein the VH sequence and the VL sequence are from any one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. 
     In some embodiments, the GAL9 antigen is a human GAL9 antigen. 
     In some embodiments, the GAL9 antigen binding molecule further comprises a second antigen binding site. 
     In some embodiments, the second antigen binding site is specific for the GAL9 antigen. 
     In some embodiments, the second antigen binding site is identical to the first antigen binding site. 
     In some embodiments, the second antigen binding site is specific for a second epitope of the first GAL9 antigen. 
     In some embodiments, the second antigen binding site comprises all three VH CDRs and all three VL CDRs from another ABS clone selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. 
     In some embodiments, the second antigen binding site comprises the VL sequence and the VH sequence from the other ABS clone. 
     In some embodiments, the second antigen binding site comprises a full immunoglobulin heavy chain sequence comprising the VH sequence and a full immunoglobulin light chain sequence comprising the VL sequence from the other ABS clone. 
     In some embodiments, the second antigen binding site is specific for an antigen other than the first GAL9 antigen. 
     In some embodiments, the first antigen binding site comprises all three VH CDRs and all three VL CDRs from any one of the ABS clones selected from: P9-11, P9-24, P9-34, and P9-37. 
     In some embodiments, the first antigen binding site comprises all three VH CDRs and all three VL CDRs from any one of the ABS clones selected from: P9-11, P9-24, and P9-34. 
     In some embodiments, the first antigen binding site comprises all three VH CDRs and all three VL CDRs from ABS clone P9-11. 
     In some embodiments, the first antigen binding site comprises all three VH CDRs and all three VL CDRs from ABS clone P9-24. 
     In some embodiments, the first antigen binding site comprises all three VH CDRs and all three VL CDRs from ABS clone P9-34. 
     In some embodiments, the first antigen binding site comprises all three VH CDRs and all three VL CDRs from ABS clone P9-37. 
     In some embodiments, the GAL9 antigen binding molecule comprises an antibody format selected from the group consisting of: full-length antibodies, Fab fragments, Fvs, scFvs, tandem scFvs, Diabodies, scDiabodies, DARTs, tandAbs, minibodies, and B-bodies. 
     In a seventeenth aspect, the disclosure provides a GAL9 antigen binding molecule which binds to the same epitope as a GAL9 antigen binding molecule of any one of the preceding claims. 
     In an eighteenth aspect, the disclosure provides a GAL9 antigen binding molecule which competes for binding with a GAL9 antigen binding molecule of any one of the preceding claims. 
     In some embodiments, the GAL9 antigen binding molecule is purified. 
     In a nineteenth aspect, the disclosure provides a pharmaceutical composition comprising the GAL9 antigen binding molecule of any one of the preceding claims and a pharmaceutically acceptable diluent. 
     In a twentieth aspect, the disclosure provides a method for treating a subject with an autoimmune disease comprising administering a therapeutically effective amount of the pharmaceutical composition as provided herein to the subject. 
     In some embodiments, the subject with an autoimmune disease has increased expression of PD-L2 on dendritic cells, as compared to dendritic cells from a healthy control. 
     In some embodiments, the autoimmune disease is selected from the group consisting of: inflammatory bowel disease, Crohn&#39;s disease, ulcerative colitis, colitis, celiac disease, rheumatoid arthritis, Behçet&#39;s disease, amyloidosis, psoriasis, psoriatic arthritis, systemic lupus erythematosus nephritis, graft-versus-host disease (GVHD), nonalcoholic steatohepatitis (NASH), and ankylosing spondylitis. 
     In some embodiments, administering a therapeutically effective amount of the GAL binding molecule per se or a pharmaceutical composition results in reducing inflammation, reducing autoimmune response, prolonging remission, inducing remission, re-establishing immune tolerance, improving organ function, reducing the progression of a disease, reducing the risk of progression or development of a second disease, or increasing overall survival. 
    
    
     
       5. BRIEF DESCRIPTION OF THE DRAWINGS 
         FIGS. 1A and 1B  show an illustrative example of various CDR and framework numbering systems—Chothia, Martin (ABA), and Kabat—as applied to the P9-01 anti-human Gal9 candidate antibody provided herein. 
         FIG. 2  shows density contour plots of the percentage of CD11c +  blood dendritic cells from a Crohn&#39;s Disease patient detected as positive for PD-L1 or PD-L2 expression compared to labelling isotype IgG control. 
         FIGS. 3A and 3B  show scatter plots of the percentage of PD-L1 or PD-L2 expressing blood dendritic cells in healthy controls or Crohn&#39;s Disease patients.  FIGS. 3C and 3D  show scatter plots of the Geometric Mean Fluorescence (GMI) of PD-L1 or PD-L2 surface expression on blood dendritic cells in healthy controls or Crohn&#39;s Disease patients. 
         FIGS. 4A and 4B  show representative confocal images of DNA (DAPI; blue), PD-L1 (green), and PD-L2 (red) expression on dendritic cells from two healthy control donors ( 4 A) and three Crohn&#39;s Disease patients ( 4 B); rendered in gray scale in the attached figures. 
         FIGS. 5A-5C  show the mean concentration of cytokines secreted by PMBCs from Crohn&#39;s Disease (CD) patients after treatment with anti-CD3 to mimic TCR activation and either anti-PD-L2 (αPD-L2) or IgG control.  FIGS. 5A-5B  show the mean concentration of TNF-α and IFN-γ after treatment with anti-PD-L2 or IgG control in PMBCs from CD patients.  FIG. 5C  shows the mean ratio of IL-10:TNF-α secretion after treatment with anti-PD-L2 and IgG control in PMBCs from CD patients. 
         FIG. 6  shows TNF-α secretion by anti-CD3 activated mouse CD4 +  T-cells after treatment with either sPD-L2 or both sPD-L2 and inhibitory anti-mouse anti-GAL9 (108A2). 
         FIG. 7  shows representative confocal images of DNA (DAPI; blue), PD-L1 (green), PD-1 (red) and OX40 (yellow) expression in CD4 +  T-cells from malaria-infected mice after treatment with mouse inhibitory anti-mouse GAL9 (108A2) and activating anti-mouse GAL9 (RG9.1) antibodies; rendered in gray scale in the attached figures. 
         FIGS. 8A and 8B  show bar graphs of the percentage of surviving mouse CD4 +  and CD8 +  T-cells after treatment with either sPD-L2 or sPD-L2 and mouse inhibitory anti-GAL9 (108A2) antibody. 
         FIGS. 9A and 9B  show bar graphs of INF-γ ( 9 A) and TNF-α ( 9 B) secretion from mouse CD4 +  T-cells co-cultured with dendritic cells (stimulated) and treated with either blocking anti-PD-L2 (clone Ty25) or inhibitory anti-GAL9 (108A2) mouse antibodies, compared to control, unstimulated CD4 +  T-cells. 
         FIGS. 10A and 10B  show INF-γ ( 10 A) and TNF-α ( 10 B) secretion from HCMV peptide, in vitro-stimulated PBMCs after treatment with various anti-human GAL9 candidates, a known activating tool antibody (Tool mAb), an anti-PD-1 antibody, a IgG control antibody (IgG Ctrl), and a vehicle control (PBS Ctrl). Black diamond shapes show secretion from activated PBMCs stimulated by Tool mAb and anti-PD-1 antibody. 
         FIGS. 11A-11C  show INF-γ and TNF-α secretion from HCMV peptide, in vitro-stimulated PBMCs after treatment with anti-human GAL9 P9-11, P9-37, or P9-57 compared to IgG control antibody (IgG). 
         FIGS. 12A-12C  show TNF-α ( 12 A), INF-γ ( 12 B), and IL-10 ( 12 C) secretion from HCMV peptide, in vitro-stimulated PBMCs after treatment with anti-human GAL9 candidates P9-11, P9-24, or P9-34 compared to IgG control antibody (IgG). 
         FIGS. 13A and 13B  show bar graphs of the ratio of TNF-α:IL-10 secretion ( 13 A) and ratio of IFN-γ:IL-10 secretion ( 13 B) from anti-CD3 activated mouse CD3 +  T-cells after treatment with inhibitory anti-mouse GAL9 (108A2) and anti-human GAL9 P9-11, P9-24, or P9-34. 
     
    
    
     6. DETAILED DESCRIPTION 
     6.1. Definitions 
     Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. As used herein, the following terms have the meanings ascribed to them below. 
     By “antigen binding site” or “ABS” is meant a region of a GAL9 binding molecule that specifically recognizes or binds to a given antigen or epitope. 
     As used herein, the terms “treat” or “treatment” are used in their broadest accepted clinical sense. The terms include, without limitation, lessening a sign or symptom of disease; improving a sign or symptom of disease; alleviation of symptoms; diminishment of extent of disease; stabilized (i.e., not worsening) state of disease; delay or slowing of disease progression; amelioration or palliation of the disease state; remission (whether partial or total), whether detectable or undetectable; cure; prolonging survival as compared to expected survival if not receiving treatment. Unless explicitly stated otherwise, “treat” or “treatment” do not intend prophylaxis or prevention of disease. 
     By “subject” or “individual” or “animal” or “patient” or “mammal,” is meant any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include humans, domestic animals, farm animals, and zoo, sports, or pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, and so on. Unless otherwise stated, “patient” intends a human “subject.” 
     The term “sufficient amount” means an amount sufficient to produce a desired effect, e.g., an amount sufficient to modulate protein aggregation in a cell. 
     The term “therapeutically effective amount” is an amount that is effective to ameliorate a symptom of a disease. 
     The term “prophylactically effective amount” is an amount that is effective to prevent a symptom of a disease. 
     6.2. Other Interpretational Conventions 
     Unless otherwise specified, all references to sequences herein are to amino acid sequences. 
     Unless otherwise specified, antibody constant region residue numbering is according to the Eu index as described at www.imgt.org/IMGTScientificChart/Numbering/Hu_IGHGnber.html#refs (accessed Aug. 22, 2017), which is hereby incorporated by reference in its entirety, and residue numbers identify the residue according to its location in an endogenous constant region sequence regardless of the residue&#39;s physical location within a chain of the GALS binding molecules described herein. 
     Unless otherwise specified as “Kabat CDR”, “Chothia CDR”, “Contact CDR”, or “IMGT CDR”, all references to “CDRs” are to CDRs defined using the Martin (ABA) definition. 
     By “endogenous sequence” or “native sequence” is meant any sequence, including both nucleic acid and amino acid sequences, which originates from an organism, tissue, or cell and has not been artificially modified or mutated. 
     Polypeptide chain numbers (e.g., a “first” polypeptide chains, a “second” polypeptide chain. Etc. or polypeptide “chain 1,” “chain 2,” etc.) are used herein as a unique identifier for specific polypeptide chains that form a binding molecule and is not intended to connote order or quantity of the different polypeptide chains within the binding molecule. 
     In this disclosure, “comprises,” “comprising,” “containing,” “having,” “includes,” “including,” and linguistic variants thereof have the meaning ascribed to them in U.S. Patent law, permitting the presence of additional components beyond those explicitly recited. 
     As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise. The terms “include,” “such as,” and the like are intended to convey inclusion without limitation, unless otherwise specifically indicated. 
     Ranges provided herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50. 
     Unless specifically stated or otherwise apparent from context, as used herein the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. 
     6.3. General Overview 
     The present disclosure provides Galectin-9 (GAL9) antigen binding molecules, such as anti-GAL9 antibodies and antigen-binding fragments thereof; compositions comprising the GAL9-binding molecules; pharmaceutical compositions comprising the GAL9-binding molecules; and methods of using the GAL9 binding molecules to treat subjects with a disease or a condition. The disclosure particularly provides various GAL9 antigen binding molecules that are inhibitory, acting as inhibitors of the immune system, decreasing the secretion and production of pro-inflammatory cytokines and increasing the secretion and production of anti-inflammatory cytokines in various immune cells and decreasing surface expression of stimulatory molecules. 
     The GAL9 antigen binding molecules are particularly useful for the treatment of an autoimmune disease or inflammatory disease in a subject. In some embodiments, the compositions and methods are used to treat an infection that causes an inflammatory response in a subject. The anti-GAL9 binding molecules are particularly useful for treating a disease or condition in which GAL9/PD-L2 interaction contributes prominently to pathogenesis. In some embodiments, the anti-GAL9 binding molecules are administered to a subject per se, as a pharmaceutical composition, or in combination with other therapeutic agents or procedures. 
     6.4. GAL9 Antigen Binding Molecules 
     In a first aspect, antigen binding molecules are provided. In every embodiment, the antigen binding molecule includes at least a first antigen binding site specific for a GAL9 antigen; the binding molecules are therefore termed GAL9 antigen binding molecules or GAL9 binding molecules. 
     The GAL9 antigen binding molecules described herein bind specifically to GAL9 antigens. 
     As used herein, “GAL9 antigens” refer to Galectin-9 family members and homologs. GAL9 is also referred to as LGALS9, HUAT, LGALS9A, tumor antigen HOM-HD-21, and ecalectin. In particular embodiments, the GAL9 binding molecule has antigen binding sites that specifically bind to at least a portion of more than one GAL9 domain, such as the junction between a first and a second GAL9 domain. 
     In specific embodiments, the GAL9 antigen is human. GenBank Accession #NP_033665.1 describes a canonical human GAL9 protein, including its sequences and domain features, and is hereby incorporated by reference in its entirety. SEQ ID NO:6 provides the full-length GAL9 protein sequence. 
     
       
         
           
               
            
               
                 [SEQ ID NO: 6] 
               
               
                 MAFSGSQAPYLSPAVPFSGTIQGGLQDGLQITVNGTVLSSSGTRFAVNF 
               
               
                   
               
               
                 QTGFSGNDIAFHFNPRFEDGGYVVCNTRQNGSWGPEERKTHMPFQKGMP 
               
               
                   
               
               
                 FDLCFLVQSSDFKVMVNGILFVQYFHRVPFHRVDTISVNGSVQLSYISF 
               
               
                   
               
               
                 QNPRTVPVQPAFSTVPFSQPVCFPPRPRGRRQKPPGVWPANPAPITQTV 
               
               
                   
               
               
                 IHTVQSAPGQMFSTPAIPPMMYPHPAYPMPFITTILGGLYPSKSILLSG 
               
               
                   
               
               
                 TVLPSAQRFHINLCSGNHIAFHLNPRFDENAVVRNTQIDNSWGSEERSL 
               
               
                   
               
               
                 PRKMPFVRGQSFSVWILCEAHCLKVAVDGQHLFEYYHRLRNLPTINRLE 
               
               
                   
               
               
                 VGGDIQLTHVQT 
               
            
           
         
       
     
     In various embodiments, the GAL9 binding molecule additionally binds specifically to at least one antigen additional to a GAL9 antigen. 
     6.4.1. Functional Characteristics of the GAL9 Antigen Binding Molecules 
     In typical embodiments, upon contact therewith, the GAL9 antigen binding molecule modulates cytokine secretion (e.g., increases or decreases cytokine secretion) of immune cells or activated immune cells. In some embodiments, the immune cells are peripheral blood mononuclear cells (PBMCs). In some embodiments, the immune cells are T cells. In some embodiments, the T cells are effector T cells. In some embodiments, the T cells are CD8 +  T cells. In embodiments, the T cells are CD4 +  T cells. In some embodiments, the T cells are CD3 +  T cells. 
     The impact of the GAL9 antigen binding molecule on immune cell cytokine secretion may be determined by any suitable means. For instance, the impact of the GAL9 antigen binding molecule on immune cell cytokine secretion may be determined in vivo, ex vivo, or in vitro. In some embodiments, cytokine secretion is determined in activated immune cells contacted with a GAL9 antigen binding molecule, as compared to activated immune cells contacted with a control agent, e.g., a control antigen binding molecule or vehicle control. The immune cells may be activated by peptide stimulation. For example, the immune cells may be activated by a peptide or plurality of peptides known to induce an immune response. A plurality of peptides known to induce an immune response can be from an infection from a pathogen such as a viral infection or bacterial infection. 
     The control agent can be a negative control or a positive control. In some embodiments, the GAL9 antigen binding molecule increases cytokine secretion in immune cells, relative to a negative control agent or negative control antigen binding molecule. In some embodiments, the negative control antigen binding molecule is an isotype control binding molecule that does not bind GAL9. In some embodiments, the positive control antibody is an anti-PD1 antibody, such as nivolumab. In some embodiments, the positive control antibody is a GAL9 control antibody. The GAL9 control antibody can be Gal9 antibody clone RG9.1 (Cat. No. BE0218, InVivoMab Antibodies) or RG9.35. RG9.1 and RG9.35 are both described in Fukushima A, Sumi T, Fukuda K, Kumagai N, Nishida T, et al. (2008), which is incorporated herein by reference in its entirety. Roles of galectin-9 in the development of experimental allergic conjunctivitis in mice.  Int Arch Allergy Immunol  146: 36-43, which is hereby incorporated by reference in its entirety. The GAL9 control antibody can be GAL9 antibody clone ECA42 (Cat. No. LS-C179449, LifeSpan BioScience). The GAL9 control antibody can be GAL9 antibody clone 108A2 (BioLegend® San Diego, Calif.). In some embodiments, the GAL9 antigen binding molecule decreases cytokine secretion of proinflammatory cytokine in immune cells, relative to a control antibody. In some embodiments, the GAL9 antigen binding molecule increases cytokine secretion of inhibitory cytokine in immune cells, relative to a control antibody. 
     Cytokine secretion by the immune cells can be assessed by any suitable means. By way of example only, cytokine secretion by in vitro or ex vivo immune cell culture models may be assessed by analyzing cytokine content of the cultured cell supernatants, e.g., by cytokine bead array. 
     In some embodiments, the cytokine is TNF-α. In some embodiments, the GAL9 antigen binding molecule decreases TNF-α secretion in activated immune cells by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, as compared to a control agent described herein. In some embodiments, the GAL9 antigen binding molecule decreases TNF-α secretion in activated immune cells by at least 1%-5%, 5-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35%-40%, 40%-45%, 45%-50%, 50%-55%, 55%-60%, 60%-65%, 70%-75%, 75%-80%, 80%-85%, or 85%-90% decrease, as compared to a control agent described herein. In some embodiments, the GAL9 antigen binding molecule decreases TNF-α secretion in activated immune cells by about 30%-50% decrease, as compared to a control agent described herein. 
     In some embodiments, the cytokine is IFN-γ. In some embodiments, the GAL9 antigen binding molecule decreases IFN-γ secretion in activated immune cells by at least at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% as compared to a control agent described herein. In some embodiments, the GAL9 antigen binding molecule decreases IFN-γ secretion in activated immune cells by at least 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35%-40%, 40%-45%, 45%-50%, 50%-55%, 55%-60%, 60%-65%, or 70%-75% decrease, as compared to a control agent described herein. In some embodiments, the GAL9 antigen binding molecule decreases IFN-γ secretion in activated immune cells by about 20%-40% decrease, as compared to a control agent described herein. 
     In some embodiments, the cytokine is IL-10. In some embodiments, the GAL9 antigen binding molecule increases IL-10 secretion in activated immune cells by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% increase, as compared to a control agent described herein. In some embodiments, the GAL9 antigen binding molecule increases IL-10 secretion in activated immune cells by at least 1%-5%, 5%-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35%-40%, 40%-45%, or 45%-50% increase, as compared to a control agent described herein. In some embodiments, the GAL9 antigen binding molecule increases IL-10 secretion in activated immune cells by about 5%-30% increase, as compared to a control agent described herein. 
     In some embodiments, upon contact therewith, the GAL9 antigen binding molecule does not modulate surface expression of immune checkpoint molecule(s) (e.g., stimulatory or inhibitory checkpoint molecules) relative to activated immune cells treated with a control agent. The term “does not modulate” means that there is no substantial increase or decrease in the expression of the immune checkpoint molecule after treatment with a GAL9 binding molecule provided herein, compared to a control agent. In some embodiments, no substantial increase in surface expression (e.g., does not modulate expression) is an increase of cell surface expression that is no more than 1.01×, 1.02×, 1.03×, 1.04×, 1.05×, 1.06×, 1.07×, 1.08×, 1.09×, 1.1×, 1.2×, or 1.3× fold change, relative to activated immune cells treated with a control agent. In some embodiments, no substantial decrease in surface expression (e.g., does not modulate expression) is a decrease of cell surface expression that is no more than 0.01×, 0.02×, 0.03×, 0.04×, 0.05×, 0.06×, 0.07×, 0.08×, 0.09×, 0.1×, or 0.2× fold change, relative to activated immune cells treated with a control agent. 
     In some embodiments, no substantial increase in surface expression (e.g., does not modulate expression) is an increase of surface expression about a 1% increase, 2% increase, 3% increase, 4% increase, 5% increase, 6% increase, 7% increase, 8% increase, 9% increase, 10% increase, 11% increase, 12% increase, 13% increase, 14% increase, or 15% increase, relative to activated immune cells treated with a control agent. In some embodiments, no substantial decrease in surface expression (e.g., does not modulate expression) is a decrease of surface expression about a 1% decrease, 2% decrease, 3% decrease, 4% decrease, 5% decrease, 6% decrease, 7% decrease, 8% decrease, 9% decrease, 10% decrease, 11% decrease, 12% decrease, 13% decrease, 14% decrease, or 15% decrease, relative to activated immune cells treated with a control agent. 
     In some embodiments, no substantial increase or decrease in surface expression is determined by comparing the level of surface expression to the level of noise in the assay (e.g., in vivo, ex vivo, or in vitro). In some embodiments, no substantial increase or decrease in surface expression is determined by comparing the level of surface expression to the standard deviation in the assay (e.g., in vivo, ex vivo, or in vitro). 
     The impact of the GAL9 antigen binding molecule on surface expression of the one or more immune checkpoint molecules may be determined by any suitable means. For instance, the impact of the GAL9 antigen binding molecule on surface expression of the one or more costimulatory molecules may be determined in vivo, ex vivo, or in vitro. 
     In some embodiments, one or more immune checkpoint molecules are selected from PD-1, PD-L1, CTLA-4, TIM3, LAG3, TIGIT, and PVRIG. In some embodiments, one or more checkpoint molecules is selected from PD-1, PD-L1, TIM3, and LAG3. In some embodiments, the immune checkpoint molecule is PD-1 or PD-L1. In various embodiments, the activated (e.g., stimulated) immune cells are T-cells, CD8 +  T cells, CD4 +  T cells, CD3 +  T cells, or PBMCs. 
     In some embodiments, the immune checkpoint molecule is PD-1. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits an increase that is no more than 1.01×, 1.02×, 1.03×, 1.04×, 1.05×, 1.06×, 1.07×, 1.08×, 1.09×, 1.1×, 1.2×, or 1.3× fold change in PD-1 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits a decrease in surface expression that is no more than 0.01×, 0.02×, 0.03×, 0.04×, 0.05×, 0.06×, 0.07×, 0.08×, 0.09×, 0.1×, or 0.2× fold change in PD-1 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. 
     In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits an increase that is no more than about a 1% increase, 2% increase, 3% increase, 4% increase, 5% increase, 6% increase, 7% increase, 8% increase, 9% increase, 10% increase, 11% increase, 12% increase, 13% increase, 14% increase, or 15% increase in PD-1 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits an decrease that is no more than about a 1% decrease, 2% decrease, 3% decrease, 4% decrease, 5% decrease, 6% decrease, 7% decrease, 8% decrease, 9% decrease, 10% decrease, 11% decrease, 12% decrease, 13% decrease, 14% decrease, or 15% decrease in PD-1 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. 
     In some embodiments, the immune checkpoint molecule is PD-L1. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits an increase that is no more than fold change in PD-L1 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits an increase that is no more than 1.01×, 1.02×, 1.03×, 1.04×, 1.05×, 1.06×, 1.07×, 1.08×, 1.09×, 1.1×, 1.2×, or 1.3× fold change in PD-L1 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits a decrease in surface expression that is no more than 0.01×, 0.02×, 0.03×, 0.04×, 0.05×, 0.06×, 0.07×, 0.08×, 0.09×, 0.1×, or 0.2× fold change in PD-L1 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. 
     In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibit an increase that is no more than about a 1% increase, 2% increase, 3% increase, 4% increase, 5% increase, 6% increase, 7% increase, 8% increase, 9% increase, 10% increase, 11% increase, 12% increase, 13% increase, 14% increase, or 15% increase in PD-L1 surface expression relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits a decrease that is no more than about a 1% decrease, 2% decrease, 3% decrease, 4% decrease, 5% decrease, 6% decrease, 7% decrease, 8% decrease, 9% decrease, 10% decrease, 11% decrease, 12% decrease, 13% decrease, 14% decrease, or 15% decrease in PD-L1 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. 
     In some embodiments, the immune checkpoint molecule is CTLA-4. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits an increase that is no more than 1.01×, 1.02×, 1.03×, 1.04×, 1.05×, 1.06×, 1.07×, 1.08×, 1.09×, 1.1×, 1.2×, or 1.3× fold change in CTLA-4 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits a decrease in surface expression that is no more than 0.01×, 0.02×, 0.03×, 0.04×, 0.05×, 0.06×, 0.07×, 0.08×, 0.09×, 0.1×, or 0.2× fold change in CTLA-4 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. 
     In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits an increase that is no more than about a 1% increase, 2% increase, 3% increase, 4% increase, 5% increase, 6% increase, 7% increase, 8% increase, 9% increase, 10% increase, 11% increase, 12% increase, 13% increase, 14% increase, or 15% increase in CTLA-4 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits a decrease that is no more than about a 1% decrease, 2% decrease, 3% decrease, 4% decrease, 5% decrease, 6% decrease, 7% decrease, 8% decrease, 9% decrease, 10% decrease, 11% decrease, 12% decrease, 13% decrease, 14% decrease, or 15% decrease in CTLA-4 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. 
     In some embodiments, the immune checkpoint molecule is TIM3. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits an increase that is no more than 1.01×, 1.02×, 1.03×, 1.04×, 1.05×, 1.06×, 1.07×, 1.08×, 1.09×, 1.1×, 1.2×, or 1.3× fold change in TIM3 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits a decrease in surface expression that is no more than 0.01×, 0.02×, 0.03×, 0.04×, 0.05×, 0.06×, 0.07×, 0.08×, 0.09×, 0.1×, or 0.2× fold change in TIM3 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. 
     In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits an increase that is no more than about a 1% increase, 2% increase, 3% increase, 4% increase, 5% increase, 6% increase, 7% increase, 8% increase, 9% increase, 10% increase, 11% increase, 12% increase, 13% increase, 14% increase, or 15% increase in TIM3 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits a decrease that is no more than about a 1% decrease, 2% decrease, 3% decrease, 4% decrease, 5% decrease, 6% decrease, 7% decrease, 8% decrease, 9% decrease, 10% decrease, 11% decrease, 12% decrease, 13% decrease, 14% decrease, or 15% decrease in TIM3 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. 
     In some embodiments, the immune checkpoint molecule is LAG3. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits an increase that is no more than 1.01×, 1.02×, 1.03×, 1.04×, 1.05×, 1.06×, 1.07×, 1.08×, 1.09×, 1.1×, 1.2×, or 1.3× fold change in LAG3 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits a decrease in surface expression that is no more than 0.01×, 0.02×, 0.03×, 0.04×, 0.05×, 0.06×, 0.07×, 0.08×, 0.09×, 0.1×, or 0.2× fold change in LAG3 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits an increase that is no more than about a 1% increase, 2% increase, 3% increase, 4% increase, 5% increase, 6% increase, 7% increase, 8% increase, 9% increase, 10% increase, 11% increase, 12% increase, 13% increase, 14% increase, or 15% increase in LAG3 surface expression, relative to activated CD4 +  or CD8 +  T-cells treated with a control agent. In some embodiments, activated CD8 +  or CD4 +  T-cells treated with the GAL9 antigen binding molecule exhibits a decrease that is no more than about a 1% decrease, 2% decrease, 3% decrease, 4% decrease, 5% decrease, 6% decrease, 7% decrease, 8% decrease, 9% decrease, 10% decrease, 11% decrease, 12% decrease, 13% decrease, 14% decrease, or 15% decrease in LAG3 surface expression, relative activated to CD4 +  or CD8 +  T-cells treated with a control agent. 
     In some embodiments, the GAL9 antigen binding molecule decreases surface expression of one or more costimulatory molecules on immune cells, e.g., human immune cells. In certain embodiments, the GAL9 antigen binding molecule decreases surface expression of the one or more costimulatory molecules in activated immune cells. In particular embodiments, the activated immune cells are T cells. In specific embodiments, the activated immune cells are CD8 +  T cells. In some embodiments, the one or more costimulatory molecules is selected from 4-1BB, CD40L, and OX40. In some embodiments, the one or more costimulatory molecules is selected from 4-1BB and CD40L. In some embodiments, the costimulatory molecule is OX40. 
     The impact of the GAL9 antigen binding molecule on surface expression of the one or more costimulatory molecules may be determined by any suitable means. For instance, the impact of the GAL9 antigen binding molecule on surface expression of the one or more costimulatory molecules may be determined in vivo, ex vivo, or in vitro. 
     In some embodiments, the GAL9 antigen binding molecule decreases surface expression of the one or more costimulatory molecules on activated immune cells as compared to activated immune cells treated with a control agent. Exemplary control agents are described herein. In particular embodiments, a control agent is an isotype control binding molecule that does not bind GAL9. 
     In some embodiments, the GAL9 antigen binding molecule decreases 4-1BB surface expression on activated CD8 +  T-cells, relative to activated CD8 +  T-cells treated with the control agent. In some embodiments, activated CD8 +  T-cells treated with the GAL9 antigen binding molecule exhibits at least about a 0.1× decrease, 0.2× decrease, 0.3× decrease, 0.4× decrease, 0.5× decrease, or a 0.6× decrease in 4-1BB surface expression, relative to activated CD8 +  T-cells treated with the control agent. In some embodiments, activated CD8 +  T-cells treated with the GAL9 antigen binding molecule exhibits about a 0.1×-0.2× decrease, 0.2×-0.3× decrease, 0.3×-0.4× decrease, 0.4×-0.5× decrease, or a 0.5×-0.6× decrease in 4-1BB surface expression, relative to activated CD8 +  T-cells treated with the control agent. 
     In some embodiments, the GAL9 antigen binding molecule decreases CD40L surface expression of activated CD8 +  T-cells, relative to activated CD8 +  T-cells treated with the control agent. In some embodiments, activated CD8 +  T-cells treated with the GAL9 antigen binding molecule exhibits at least about a 0.1× decrease, 0.2× decrease, 0.3× decrease, 0.4× decrease, or a 0.5× decrease in CD40L surface expression relative to activated CD8 +  T-cells treated with the control agent. In some embodiments, activated CD8 +  T-cells treated with the GAL9 antigen binding molecule exhibits about a 0.1×-0.2× decrease, 0.2×-0.3× decrease, 0.3×-0.4× decrease, or a 0.4×-0.5× decrease in CD40L surface expression, relative to activated CD8 +  T-cells treated with the control agent. 
     In some embodiments, the GAL9 antigen binding molecule decreases OX40 surface expression of activated CD8 +  T-cells, relative to activated CD8 +  T-cells treated with the control agent. In some embodiments, activated CD8 +  T-cells treated with the GAL9 antigen binding molecule exhibits about at least a 0.1× decrease, 0.2× decrease, 0.3× decrease, 0.4× decrease, 0.5× decrease, or a 0.6× decrease in OX40 surface expression relative to activated CD8 +  T-cells treated with the control agent. In some embodiments, activated CD8 +  T-cells treated with the GAL9 antigen binding molecule exhibits about a 0.1×-0.2× decrease, 0.2×-0.3× decrease, 0.3×-0.4× decrease, 0.4×-0.5× decrease, or a 0.5×-0.6× decrease in OX40 surface expression, relative to activated CD8 +  T-cells treated with the control agent. 
     The disclosure also provides for GAL9 antigen binding molecules that have various clinical benefits that improve the health of a subject with an autoimmune or inflammatory disease. The subject can be a mammal. The mammal can be a mouse. In some embodiments, the mammal is a human. 
     In some embodiments, the GAL9 antigen binding molecule reduces an autoimmune response in a subject. In some embodiments, the GAL9 antigen binding molecule reduces inflammation in the subject Inflammation can be systemic or localized in an organ or tissue. In some embodiments, the GAL9 antigen binding molecule prolongs remission of a disease or condition in a subject. In some embodiments, the GAL9 antigen binding molecule induces remission in a subject. In some embodiments, the GAL9 antigen binding molecule re-establishes immune tolerance (e.g., improved cytokine profile or environment) in a subject. Re-establishing immune tolerance can be a decrease in a proinflammatory cytokine, an increase in an inhibitory cytokine, or a combination thereof. In some embodiments, the GAL9 antigen binding molecule improves organ function in a subject. In some embodiments, the GAL9 antigen binding molecule reduces the risk/likelihood of disease progression or development of a second disease, such as cancer or an infection. In some embodiments, the GAL9 antigen binding molecule increases the overall survival of a subject. 
     6.4.2. Variable Regions 
     In typical embodiments, the GAL9 binding molecules have variable region domain amino acid sequences of an antibody, including VH and VL antibody domain sequences. VH and VL sequences are described in greater detail below in Sections 6.4.2.1 and 6.4.2.2, respectively. 
     6.4.2.1. VII Regions 
     In typical embodiments, the GAL9 binding molecules described herein comprise antibody heavy chain variable domain sequences. In a typical antibody arrangement in both nature and in the GAL9 binding molecules described herein, a specific VH amino acid sequence associates with a specific VL amino acid sequence to form an antigen-binding site. In various embodiments, VH amino acid sequences are mammalian sequences, including human sequences, synthesized sequences, or combinations of non-human mammalian, mammalian, and/or synthesized sequences, as described in further detail above in Sections 6.4.2.3 and 6.4.2.4. In various embodiments, VH amino acid sequences are mutated sequences of naturally occurring sequences. 
     6.4.2.2. VL Regions 
     The VL amino acid sequences useful in the GAL9 binding molecules described herein are antibody light chain variable domain sequences. In a typical arrangement in both natural antibodies and the antibody constructs described herein, a specific VL amino acid sequence associates with a specific VH amino acid sequence to form an antigen-binding site. In various embodiments, the VL amino acid sequences are mammalian sequences, including human sequences, synthesized sequences, or combinations of human, non-human mammalian, mammalian, and/or synthesized sequences, as described in further detail below in Sections 6.4.2.3 and 6.4.2.4. 
     In various embodiments, VL amino acid sequences are mutated sequences of naturally occurring sequences. In certain embodiments, the VL amino acid sequences are lambda (λ) light chain variable domain sequences. In certain embodiments, the VL amino acid sequences are kappa (κ) light chain variable domain sequences. In a preferred embodiment, the VL amino acid sequences are kappa (κ) light chain variable domain sequences. 
     6.4.2.3. Complementarity Determining Regions 
     The VH and VL amino acid sequences comprise highly variable sequences termed “complementarity determining regions” (CDRs), typically three CDRs (CDR1, CDR2, and CDR3). In a variety of embodiments, the CDRs are mammalian sequences, including, but not limited to, mouse, rat, hamster, rabbit, camel, donkey, goat, and human sequences. In a preferred embodiment, the CDRs are human sequences. In various embodiments, the CDRs are naturally occurring sequences. In various embodiments, the CDRs are naturally occurring sequences that have been mutated to alter the binding affinity of the antigen-binding site for a particular antigen or epitope. In certain embodiments, the naturally occurring CDRs have been mutated in an in vivo host through affinity maturation and somatic hypermutation. In certain embodiments, the CDRs have been mutated in vitro through methods including, but not limited to, PCR-mutagenesis and chemical mutagenesis. In various embodiments, the CDRs are synthesized sequences including, but not limited to, CDRs obtained from random sequence CDR libraries and rationally designed CDR libraries. Martin numbering scheme was used to determine the CDR boundaries. See  FIGS. 1A-1B  as applied to the P9-01 anti-human GALS candidate provided herein. 
     In various embodiments, CDRs identified as binding an antigen of interest are further mutated (i.e., “affinity matured”) to achieve a desired binding characteristic, such as an increased affinity for the antigen of interest relative to the original CDR. For example, targeted introduction of diversity into the CDRs, including those CDRs identified to bind an antigen of interest, can be introduced using degenerate oligonucleotides. Various randomization schemes can be employed. For example, “soft-randomization” can be used that provides a high bias towards the identity of wild-type sequence at a given amino acid position, such as allowing a given position in CDRs to vary among all twenty amino acids while biasing towards the wild-type sequence by doping the four bases at each codon position at non-equivalent level. As an illustrative example of soft-randomization, if achieving approximately 50% of the wild-type sequence is desired, each base of each codon is kept 70% wild-type and 10% each of other nucleotides and the degenerate oligonucleotides are used to make a focused phage library around the selected CDRs with the resulting phage particles used for phage panning under various stringent selection conditions depending on the need. 
     6.4.2.4. Framework Regions and CDR Grafting 
     The VH and VL amino acid sequences comprise “framework region” (FR) sequences. FRs are generally conserved sequence regions that act as a scaffold for interspersed CDRs (see Section 6.4.2.3), typically in a FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 arrangement (from N-terminus to C-terminus). In a variety of embodiments, the FRs are mammalian sequences, including, but not limited to mouse, rat, hamster, rabbit, camel, donkey, goat, and human sequences. In a preferred embodiment, the FRs are human sequences. In various embodiments, the FRs are naturally occurring sequences. In various embodiments, the FRs are synthesized sequences including, but not limited, rationally designed sequences. 
     In a variety of embodiments, the FRs and the CDRs are both from the same naturally occurring variable domain sequence. In a variety of embodiments, the FRs and the CDRs are from different variable domain sequences, wherein the CDRs are grafted onto the FR scaffold with the CDRs providing specificity for a particular antigen. In certain embodiments, the grafted CDRs are all derived from the same naturally occurring variable domain sequence. In certain embodiments, the grafted CDRs are derived from different variable domain sequences. In certain embodiments, the grafted CDRs are synthesized sequences including, but not limited to, CDRs obtained from random sequence CDR libraries and rationally designed CDR libraries. In certain embodiments, the grafted CDRs and the FRs are from the same species. In certain embodiments, the grafted CDRs and the FRs are from different species. In a preferred grafted CDR embodiment, an antibody is “humanized”, wherein the grafted CDRs are non-human mammalian sequences including, but not limited to, mouse, rat, hamster, rabbit, camel, donkey, and goat sequences, and the FRs are human sequences. Humanized antibodies are discussed in more detail in U.S. Pat. No. 6,407,213, the entirety of which is hereby incorporated by reference for all it teaches. In various embodiments, portions or specific sequences of FRs from one species are used to replace portions or specific sequences of another species&#39; FRs. 
     6.4.3. Exemplary Amino Acid Sequences of the GAL9 Binding Molecules 
     In various embodiments, the GAL9 binding molecule comprises a particular VH CDR3 (CDR-H3) sequence and a particular VL CDR3 (CDR-L3) sequence. 
     In some embodiments, the GAL9 binding molecule comprises the CDR-H3 and the CDR-L3 from any one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. VH CDR amino acid sequences of the ABS clones are disclosed in Table 3. VL CDR amino acid sequences of the ABS clones are disclosed in Table 4. For clarity, each GAL9 ABS clone is assigned a unique ABS clone number which is used throughout this disclosure. 
     In one currently preferred embodiment, the GAL9 binding molecule comprises the CDR-H3 and CDR-L3 of ABS clone P9-11. 
     In some embodiments, the GAL9 binding molecule comprises all three VH CDRs from one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. In one currently preferred embodiment, the GAL9 binding molecule comprises all three VH CDRs from ABS clone P9-11. 
     In some embodiments, the GAL9 binding molecule comprises all three VL CDRs from one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. In one currently preferred embodiment, the GAL9 binding molecule comprises all three VL CDRs from ABS clone P9-11. 
     In some embodiments, the GAL9 binding molecule comprises all six CDRs from any one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. In one currently preferred embodiment, the GAL9 binding molecule comprises all six CDRs from ABS clone P9-11. 
     In some embodiments, the GAL9 binding molecule comprises a VH amino acid sequence, a VL amino acid sequence, or a VH and VL amino acid sequence from any one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. Full immunoglobulin heavy chain and immunoglobulin light chain sequences, as well as VH and VL amino acid sequences, are provided in Table 6. In one currently preferred embodiment, the GAL9 binding molecule comprises a VH amino acid sequence, a VL amino acid sequence, or a VH and VL amino acid sequence from ABS clone P9-11. 
     In some embodiments, the GAL9 binding molecule comprises the full IgG heavy chain sequence and the full IgG light chain sequence from any one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. In one currently preferred embodiment, the GAL9 binding molecule comprises the full IgG heavy chain sequence and the full IgG light chain sequence from ABS clone P9-11. 
     6.4.4. Constant Regions 
     In some embodiments, the GAL9 binding molecules comprise an antibody constant region domain sequence. Constant region domain amino acid sequences, as described herein, are sequences of a constant region domain of an antibody. Constant regions can refer to CH1, CH2, CH3, CH4, or CL constant domain. 
     In a variety of embodiments, the constant region sequences are mammalian sequences, including, but not limited to, mouse, rat, hamster, rabbit, camel, donkey, goat, and human sequences. In a preferred embodiment, the constant region sequences are human sequences. In certain embodiments, the constant region sequences are from an antibody light chain. In particular embodiments, the constant region sequences are from a lambda or kappa light chain. In certain embodiments, the constant region sequences are from an antibody heavy chain. In particular embodiments, the constant region sequences are an antibody heavy chain sequence that is an IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, or IgM isotype. In a specific embodiment, the constant region sequences are from an IgG isotype. In a preferred embodiment, the constant region sequences are from an IgG1 isotype. 
     Exemplary constant regions and modifications thereof are described in WO2018075692, which is hereby incorporated by reference in its entirety. 
     6.4.4.1. CH1 and CL Regions 
     CH1 amino acid sequences, as described herein, are sequences of the second domain of an antibody heavy chain, with reference from the N-terminus to C-terminus of a native antibody heavy chain architecture. In certain embodiments, the CH1 sequences are endogenous sequences. In a variety of embodiments, the CH1 sequences are mammalian sequences, including, but not limited to mouse, rat, hamster, rabbit, camel, donkey, goat, and human sequences. In a preferred embodiment, the CH1 sequences are human sequences. In certain embodiments, the CH1 sequences are from an IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, or IgM isotype. In a preferred embodiment, the CH1 sequences are from an IgG1 isotype. In preferred embodiments, the CH1 sequence is UniProt accession number P01857 amino acids 1-98. 
     The CL amino acid sequences useful in the GALS binding molecules described herein are antibody light chain constant domain sequences, with reference to a native antibody light chain architecture. In certain embodiments, the CL sequences are endogenous sequences. In a variety of embodiments, the CL sequences are mammalian sequences, including, but not limited to mouse, rat, hamster, rabbit, camel, donkey, goat, and human sequences. In a preferred embodiment, CL sequences are human sequences. 
     In certain embodiments, the CL amino acid sequences are lambda (λ) light chain constant domain sequences. In particular embodiments, the CL amino acid sequences are human lambda light chain constant domain sequences. In preferred embodiments, the lambda (λ) light chain sequence is UniProt accession number P0CG04. 
     In certain embodiments, the CL amino acid sequences are kappa (κ) light chain constant domain sequences. In a preferred embodiment, the CL amino acid sequences are human kappa (κ) light chain constant domain sequences. In a preferred embodiment, the kappa light chain sequence is UniProt accession number P01834. 
     In certain embodiments, the CH1 sequence and the CL sequences are both endogenous sequences. In certain embodiments, the CH1 sequence and the CL sequences separately comprise respectively orthogonal modifications in endogenous CH1 and CL sequences, as discussed below in greater detail in Section 6.4.4.1. CH1 and CL sequences can also be portions thereof, either of an endogenous or modified sequence, such that a domain having the CH1 sequence, or portion thereof, can associate with a domain having the CL sequence, or portion thereof. 
     6.4.4.2. CH1 and CL Orthogonal Modifications 
     In certain embodiments, the CH1 sequence and the CL sequences separately comprise respectively orthogonal modifications in endogenous CH1 and CL sequences. Orthogonal mutations, in general, are described in more detail below in Sections 6.4.6.1-6.4.6.3. 
     In particular embodiments, the orthogonal modifications in endogenous CH1 and CL sequences are an engineered disulfide bridge selected from engineered cysteines at position 138 of the CH1 sequence and position 116 of the CL sequence, at position 128 of the CH1 sequence and position 119 of the CL sequence, or at position 129 of the CH1 sequence and position 210 of the CL sequence, as numbered and discussed in more detail in U.S. Pat. Nos. 8,053,562 and 9,527,927, each incorporated herein by reference in its entirety. In a preferred embodiment, the engineered cysteines are at position 128 of the CH1 sequence and position 118 of the CL Kappa sequence, as numbered by the Eu index. 
     In a series of preferred embodiments, the mutations that provide non-endogenous cysteine amino acids are a F118C mutation in the CL sequence with a corresponding A141C in the CH1 sequence, or a F118C mutation in the CL sequence with a corresponding L128C in the CH1 sequence, or a S162C mutations in the CL sequence with a corresponding P171C mutation in the CH1 sequence, as numbered by the Eu index. 
     In a variety of embodiments, the orthogonal mutations in the CL sequence and the CH1 sequence are charge-pair mutations. In specific embodiments the charge-pair mutations are a F118S, F118A or F118V mutation in the CL sequence with a corresponding A141L in the CH1 sequence, or a T129R mutation in the CL sequence with a corresponding K147D in the CH1 sequence, as numbered by the Eu index and described in greater detail in Bonisch et al. (Protein Engineering, Design &amp; Selection, 2017, pp. 1-12), herein incorporated by reference for all that it teaches. In a series of preferred embodiments, the charge-pair mutations are a N138K mutation in the CL sequence with a corresponding G166D in the CH1 sequence, or a N138D mutation in the CL sequence with a corresponding G166K in the CH1 sequence, as numbered by the Eu index. 
     6.4.4.3. CH2 Regions 
     In the GAL9 binding molecules described herein, the GAL9 binding molecules can have a CH2 amino acid sequence. CH2 amino acid sequences, as described herein, are CH2 amino acid sequences of the third domain of an antibody heavy chain, with reference from the N-terminus to C-terminus of a native antibody heavy chain architecture. In a variety of embodiments, the CH2 sequences are mammalian sequences, including but not limited to mouse, rat, hamster, rabbit, camel, donkey, goat, and human sequences. In a preferred embodiment, the CH2 sequences are human sequences. In certain embodiments, the CH2 sequences are from an IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, or IgM isotype. In a preferred embodiment, the CH2 sequences are from an IgG1 isotype. 
     In certain embodiments, the CH2 sequences are endogenous sequences. In particular embodiments, the sequence is UniProt accession number P01857 amino acids 111-223. 
     In a series of embodiments, a GAL9 binding molecule has more than one paired set of CH2 domains that have CH2 sequences, wherein a first set has CH2 amino acid sequences from a first isotype and one or more orthologous sets of CH2 amino acid sequences from another isotype. The orthologous CH2 amino acid sequences, as described herein, are able to interact with CH2 amino acid sequences from a shared isotype, but not significantly interact with the CH2 amino acid sequences from another isotype present in the GAL9 binding molecule. In particular embodiments, all sets of CH2 amino acid sequences are from the same species. In preferred embodiments, all sets of CH2 amino acid sequences are human CH2 amino acid sequences. In other embodiments, the sets of CH2 amino acid sequences are from different species. In particular embodiments, the first set of CH2 amino acid sequences is from the same isotype as the other non-CH2 domains in the GAL9 binding molecule. In a specific embodiment, the first set has CH2 amino acid sequences from an IgG isotype and the one or more orthologous sets have CH2 amino acid sequences from an IgM or IgE isotype. In certain embodiments, one or more of the sets of CH2 amino acid sequences are endogenous CH2 sequences. In other embodiments, one or more of the sets of CH2 amino acid sequences are endogenous CH2 sequences that have one or more mutations. In particular embodiments, the one or more mutations are orthogonal knob-hole mutations, orthogonal charge-pair mutations, or orthogonal hydrophobic mutations. Orthologous CH2 amino acid sequences useful for the GAL9 binding molecules are described in more detail in international PCT applications WO2017/011342 and WO2017/106462, herein incorporated by reference in their entirety. 
     6.4.4.4. CH3 Regions 
     CH3 amino acid sequences, as described herein, are sequences of the C-terminal domain of an antibody heavy chain, with reference from the N-terminus to C-terminus of a native antibody heavy chain architecture. 
     In a variety of embodiments, the CH3 sequences are mammalian sequences, including, but not limited to, mouse, rat, hamster, rabbit, camel, donkey, goat, and human sequences. In a preferred embodiment, the CH3 sequences are human sequences. In certain embodiments, the CH3 sequences are from an IgA1, IgA2, IgD, IgE, IgM, IgG1, IgG2, IgG3, IgG4 isotype or CH4 sequences from an IgE or IgM isotype. In a specific embodiment, the CH3 sequences are from an IgG isotype. In a preferred embodiment, the CH3 sequences are from an IgG1 isotype. 
     In certain embodiments, the CH3 sequences are endogenous sequences. In particular embodiments, the CH3 sequence is UniProt accession number P01857 amino acids 224-330. In various embodiments, a CH3 sequence is a segment of an endogenous CH3 sequence. In particular embodiments, a CH3 sequence has an endogenous CH3 sequence that lacks the N-terminal amino acids G224 and Q225. In particular embodiments, a CH3 sequence has an endogenous CH3 sequence that lacks the C-terminal amino acids P328, G329, and K330. In particular embodiments, a CH3 sequence has an endogenous CH3 sequence that lacks both the N-terminal amino acids G224 and Q225 and the C-terminal amino acids P328, G329, and K330. In preferred embodiments, a GALS binding molecule has multiple domains that have CH3 sequences, wherein a CH3 sequence can refer to both a full endogenous CH3 sequence as well as a CH3 sequence that lacks N-terminal amino acids, C-terminal amino acids, or both. 
     In certain embodiments, the CH3 sequences are endogenous sequences that have one or more mutations. In particular embodiments, the mutations are one or more orthogonal mutations that are introduced into an endogenous CH3 sequence to guide specific pairing of specific CH3 sequences, as described in more detail below in Sections 6.4.6.1-6.4.6.3. 
     In certain embodiments, the CH3 sequences are engineered to reduce immunogenicity of the antibody by replacing specific amino acids of one allotype with those of another allotype and referred to herein as isoallotype mutations, as described in more detail in Stickler et al. (Genes Immun. 2011 April; 12(3): 213-221), which is herein incorporated by reference for all that it teaches. In particular embodiments, specific amino acids of the Glml allotype are replaced. In a preferred embodiment, isoallotype mutations D356E and L358M are made in the CH3 sequence. 
     In some embodiments, an IgG1 CH3 amino acid sequence comprises the following mutational changes: P343V; Y349C; and a tripeptide insertion, 445P, 446G, 447K. In other preferred embodiments, domain B has a human IgG1 CH3 sequence with the following mutational changes: T366K; and a tripeptide insertion, 445K, 446S, 447C. In still other preferred embodiments, domain B has a human IgG1 CH3 sequence with the following mutational changes: Y349C and a tripeptide insertion, 445P, 446G, 447K. 
     In some embodiments, an IgG1 CH3 amino acid sequence comprises a 447C mutation incorporated into an otherwise endogenous CH3 sequence. 
     6.4.5. Antigen Binding Sites 
     In some embodiments, a VL or VH amino acid sequence and a cognate VL or VH amino acid sequence are associated and form a first antigen binding site (ABS). The antigen binding site (ABS) is capable of specifically binding an epitope of an antigen. Antigen binding by an ABS is described in greater detail below in Section 6.4.5.1. 
     In alternative embodiments, e.g., wherein the GAL9 binding molecule is a single domain antibody, a VH or VL amino acid sequence forms the first ABS. 
     In some embodiments, the GAL9 antigen binding molecule comprises a second ABS. In some embodiments, the second ABS is specific for the same GAL9 antigen as the first ABS. In some embodiments, the second ABS specifically binds the same epitope of the same GAL9 antigen as the first ABS. In some embodiments, the second ABS is identical to the first ABS. 
     In some embodiments, the second ABS is specific for a different epitope of the first GAL9 antigen. For example if the first ABS comprises CDRs or variable domains from any one of the ABS clones selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. The second ABS may comprise CDRs or variable domains from another ABS clone selected from P9-01, P9-02A, P9-03, P9-06, P9-07, P9-11, P9-12, P9-14, P9-23, P9-24, P9-25, P9-29, P9-30, P9-34, P9-37, P9-38, P9-40, P9-41, P9-42, P9-43, P9-44, P9-45, P9-46, P9-50, P9-51, P9-52, P9-53, P9-56, and P9-57. 
     In some embodiments, the GAL9 antigen binding molecule is multispecific, e.g., the second ABS of the GAL9 antigen binding molecule specifically binds an antigen that is different than the GAL9 antigen specifically bound by the first ABS. 
     6.4.5.1. Binding of Antigen by ABS 
     An ABS, and the GAL9 binding molecule comprising such ABS, is said to “recognize” the epitope (or more generally, the antigen) to which the ABS specifically binds, and the epitope (or more generally, the antigen) is said to be the “recognition specificity” or “binding specificity” of the ABS. 
     The ABS is said to bind to its specific antigen or epitope with a particular affinity. As described herein, “affinity” refers to the strength of interaction of non-covalent intermolecular forces between one molecule and another. The affinity, i.e. the strength of the interaction, can be expressed as a dissociation equilibrium constant (K D ), wherein a lower K D  value refers to a stronger interaction between molecules. K D  values of antibody constructs are measured by methods well known in the art including, but not limited to, bio-layer interferometry (e.g., Octet/FORTEBIO®), surface plasmon resonance (SPR) technology (e.g., Biacore®), and cell binding assays. For purposes herein, affinities are dissociation equilibrium constants measured by bio-layer interferometry using Octet/FORTEBIO®. 
     “Specific binding,” as used herein, refers to an affinity between an ABS and its cognate antigen or epitope in which the K D  value is below 10 −6 M, 10 −7 M, 10 −8 M, 10 −9 M, or 10 −1 ° M. 
     The number of ABSs in a GAL9 binding molecule as described herein defines the “valency” of the GAL9 binding molecule. A GAL9 binding molecule having a single ABS is “monovalent”. A GAL9 binding molecule having a plurality of ABSs is said to be “multivalent”. A multivalent GAL9 binding molecule having two ABSs is “bivalent.” A multivalent GAL9 binding molecule having three ABSs is “trivalent.” A multivalent GAL9 binding molecule having four ABSs is “tetravalent.” 
     In various multivalent embodiments, all of the plurality of ABSs have the same recognition specificity. Such a GAL9 binding molecule is a “monospecific” “multivalent” binding construct. In other multivalent embodiments, at least two of the plurality of ABSs have different recognition specificities. Such GAL9 binding molecules are multivalent and “multispecific”. In multivalent embodiments in which the ABSs collectively have two recognition specificities, the GAL9 binding molecule is “bispecific.” In multivalent embodiments in which the ABSs collectively have three recognition specificities, the GAL9 binding molecule is “trispecific.” 
     In multivalent embodiments in which the ABSs collectively have a plurality of recognition specificities for different epitopes present on the same antigen, the GAL9 binding molecule is “multiparatopic.” Multivalent embodiments in which the ABSs collectively recognize two epitopes on the same antigen are “biparatopic.” 
     In various multivalent embodiments, multivalency of the GAL9 binding molecule improves the avidity of the GAL9 binding molecule for a specific target. As described herein, “avidity” refers to the overall strength of interaction between two or more molecules, e.g., a multivalent GAL9 binding molecule for a specific target, wherein the avidity is the cumulative strength of interaction provided by the affinities of multiple ABSs. Avidity can be measured by the same methods as those used to determine affinity, as described above. In certain embodiments, the avidity of a GAL9 binding molecule for a specific target is such that the interaction is a specific binding interaction, wherein the avidity between two molecules has a K D  value below 10 −6 M, 10 −7 M, 10 −8 M, 10 −9 M, or 10 −10 M. In certain embodiments, the avidity of a GAL9 binding molecule for a specific target has a K D  value such that the interaction is a specific binding interaction, wherein the one or more affinities of individual ABSs do not have has a K D  value that qualifies as specifically binding their respective antigens or epitopes on their own. In certain embodiments, the avidity is the cumulative strength of interaction provided by the affinities of multiple ABSs for separate antigens on a shared specific target or complex, such as separate antigens found on an individual cell. In certain embodiments, the avidity is the cumulative strength of interaction provided by the affinities of multiple ABSs for separate epitopes on a shared individual antigen. 
     6.4.6. Orthogonal Modifications 
     In the GAL9 binding molecules described herein, a GAL9 binding molecule can have constant region domains comprising orthogonal modifications. Constant region domain amino acid sequences are described in greater detail above in Section 6.4.4. 
     “Orthogonal modifications” or synonymously “orthogonal mutations” as described herein are one or more engineered mutations in an amino acid sequence of an antibody domain that increase the affinity of binding of a first domain having orthogonal modification for a second domain having a complementary orthogonal modification. In certain embodiments, the orthogonal modifications decrease the affinity of a domain having the orthogonal modifications for a domain lacking the complementary orthogonal modifications. In certain embodiments, orthogonal modifications are mutations in an endogenous antibody domain sequence. In a variety of embodiments, orthogonal modifications are modifications of the N-terminus or C-terminus of an endogenous antibody domain sequence including, but not limited to, amino acid additions or deletions. In particular embodiments, orthogonal modifications include, but are not limited to, engineered disulfide bridges, knob-in-hole mutations, and charge-pair mutations, as described in greater detail below in Sections 6.4.6.1-6.4.6.3. In particular embodiments, orthogonal modifications include a combination of orthogonal modifications selected from, but not limited to, engineered disulfide bridges, knob-in-hole mutations, and charge-pair mutations. In particular embodiments, the orthogonal modifications can be combined with amino acid substitutions that reduce immunogenicity, such as isoallotype mutations, as described in greater detail above in Section 6.4.4.4. 
     6.4.6.1. Orthogonal Engineered Disulfide Bridges 
     In a variety of embodiments, the orthogonal modifications comprise mutations that generate engineered disulfide bridges between a first and a second domain. As described herein, “engineered disulfide bridges” are mutations that provide non-endogenous cysteine amino acids in two or more domains such that a non-native disulfide bond forms when the two or more domains associate. Engineered disulfide bridges are described in greater detail in Merchant et al. ( Nature Biotech  (1998) 16:677-681), the entirety of which is hereby incorporated by reference for all it teaches. In certain embodiments, engineered disulfide bridges improve orthogonal association between specific domains. In a particular embodiment, the mutations that generate engineered disulfide bridges are a K392C mutation in one of a first or second CH3 domains, and a D399C in the other CH3 domain. In a preferred embodiment, the mutations that generate engineered disulfide bridges are a S354C mutation in one of a first or second CH3 domains, and a Y349C in the other CH3 domain. In another preferred embodiment, the mutations that generate engineered disulfide bridges are a 447C mutation in both the first and second CH3 domains that are provided by extension of the C-terminus of a CH3 domain incorporating a KSC tripeptide sequence. 
     6.4.6.2. Orthogonal Knob-Hole Mutations 
     In a variety of embodiments, orthogonal modifications comprise knob-hole (synonymously, knob-in-hole) mutations. As described herein, knob-hole mutations are mutations that change the steric features of a first domain&#39;s surface such that the first domain will preferentially associate with a second domain having complementary steric mutations relative to association with domains without the complementary steric mutations. Knob-hole mutations are described in greater detail in U.S. Pat. Nos. 5,821,333 and 8,216,805, each of which is incorporated herein in its entirety. In various embodiments, knob-hole mutations are combined with engineered disulfide bridges, as described in greater detail in Merchant et al. ( Nature Biotech  (1998) 16:677-681)), incorporated herein by reference in its entirety. In various embodiments, knob-hole mutations, isoallotype mutations, and engineered disulfide mutations are combined. 
     In certain embodiments, the knob-in-hole mutations are a T366Y mutation in a first domain, and a Y407T mutation in a second domain. In certain embodiments, the knob-in-hole mutations are a F405A in a first domain, and a T394W in a second domain. In certain embodiments, the knob-in-hole mutations are a T366Y mutation and a F405A in a first domain, and a T394W and a Y407T in a second domain. In certain embodiments, the knob-in-hole mutations are a T366W mutation in a first domain, and a Y407A in a second domain. In certain embodiments, the combined knob-in-hole mutations and engineered disulfide mutations are a S354C and T366W mutations in a first domain, and a Y349C, a T366S, a L368A, and a Y407V mutation in a second domain. In a preferred embodiment, the combined knob-in-hole mutations, isoallotype mutations, and engineered disulfide mutations are a S354C and T366W mutations in a first domain, and a Y349C, D356E, L358M, T366S, L368A, and a Y407V mutation in a second domain. 
     6.4.6.3. Orthogonal Charge-pair Mutations 
     In a variety of embodiments, orthogonal modifications are charge-pair mutations. As used herein, charge-pair mutations are mutations that affect the charge of an amino acid in a domain&#39;s surface such that the domain will preferentially associate with a second domain having complementary charge-pair mutations relative to association with domains without the complementary charge-pair mutations. In certain embodiments, charge-pair mutations improve orthogonal association between specific domains. Charge-pair mutations are described in greater detail in U.S. Pat. Nos. 8,592,562, 9,248,182, and 9,358,286, each of which is incorporated by reference herein for all they teach. In certain embodiments, charge-pair mutations improve stability between specific domains. In a preferred embodiment, the charge-pair mutations are a T366K mutation in a first domain, and a L351D mutation in the other domain. 
     In specific embodiments, the orthogonal mutations are charge-pair mutations at the VH/VL interface. In preferred embodiments, the charge-pair mutations at the VH/VL interface are a Q39E in VH with a corresponding Q38K in VL, or a Q39K in VH with a corresponding Q38E in VL, as described in greater detail in Igawa et al. (Protein Eng. Des. Sel., 2010, vol. 23, 667-677), herein incorporated by reference for all it teaches. 
     6.4.7. Trivalent and Tetravalent GAL9 binding molecules 
     In another series of embodiments, the GAL9 binding molecules have three antigen binding sites and are therefore termed “trivalent.” In a variety of embodiments, the GAL9 binding molecules have 4 antigen binding sites and are therefore termed “tetravalent.” 
     6.5. GAL9 binding molecule architecture 
     The antigen binding sites described herein, including specific CDR subsets, can be formatted into any binding molecule architecture including, but not limited to, full-length antibodies, Fab fragments, Fvs, scFvs, tandem scFvs, Diabodies, scDiabodies, DARTs, tandAbs, minibodies, camelid VHH, and other antibody fragments or formats known to those skilled in the art. Exemplary antibody and antibody fragment formats are described in detail in Brinkmann et al. ( MABS,  2017, Vol. 9, No. 2, 182-212), herein incorporated by reference for all that it teaches. The antigen binding sites described herein, including specific CDR subsets, can also be formatted into a “B-body” format, as described in more detail in US pre-grant publication no. US 2018/0118811 and International Application Pub. No. WO 2018/075692, each of which is herein incorporated by reference in their entireties. 
     6.6. Further modifications 
     In a further series of embodiments, the GAL9 binding molecule has additional modifications. 
     6.6.1. Antibody-Drug Conjugates 
     In various embodiments, the GAL9 binding molecule is conjugated to a therapeutic agent (i.e. drug) to form a GAL9 binding molecule-drug conjugate. Therapeutic agents include, but are not limited to, chemotherapeutic agents, imaging agents (e.g. radioisotopes), immune modulators (e.g. cytokines, chemokines, or checkpoint inhibitors), and toxins (e.g. cytotoxic agents). In certain embodiments, the therapeutic agents are attached to the GAL9 binding molecule through a linker peptide, as discussed in more detail below in Section 6.6.3. 
     Methods of preparing antibody-drug conjugates (ADCs) that can be adapted to conjugate drugs to the GAL9 binding molecules disclosed herein are described, e.g., in U.S. Pat. No. 8,624,003 (pot method), U.S. Pat. No. 8,163,888 (one-step), U.S. Pat. No. 5,208,020 (two-step method), U.S. Pat. Nos. 8,337,856, 5,773,001, 7,829,531, 5,208,020, 7,745,394, WO 2017/136623, WO 2017/015502, WO 2017/015496, WO 2017/015495, WO 2004/010957, WO 2005/077090, WO 2005/082023, WO 2006/065533, WO 2007/030642, WO 2007/103288, WO 2013/173337, WO 2015/057699, WO 2015/095755, WO 2015/123679, WO 2015/157286, WO 2017/165851, WO 2009/073445, WO 2010/068759, WO 2010/138719, WO 2012/171020, WO 2014/008375, WO 2014/093394, WO 2014/093640, WO 2014/160360, WO 2015/054659, WO 2015/195925, WO 2017/160754, Storz ( MAbs.  2015 November-December; 7(6): 989-1009), Lambert et al. ( Adv Ther,  2017 34: 1015), Diamantis et al. ( British Journal of Cancer,  2016, 114, 362-367), Carrico et al. ( Nat Chem Biol,  2007. 3: 321-2), We et al. ( Proc Natl Acad Sci USA,  2009. 106: 3000-5), Rabuka et al. ( Curr Opin Chem Biol.,  2011 14: 790-6), Hudak et al. ( Angew Chem Int Ed Engl.,  2012: 4161-5), Rabuka et al. ( Nat Protoc.,  2012 7:1052-67), Agarwal et al. ( Proc Natl Acad Sci USA.,  2013, 110: 46-51), Agarwal et al. ( Bioconjugate Chem.,  2013, 24: 846-851), Barfield et al. ( Drug Dev. and D.,  2014, 14:34-41), Drake et al. ( Bioconjugate Chem.,  2014, 25:1331-41), Liang et al. ( J Am Chem Soc.,  2014, 136:10850-3), Drake et al. ( Curr Opin Chem Biol.,  2015, 28:174-80), and York et al. ( BMC Biotechnology,  2016, 16(1):23), each of which is hereby incorporated by reference in its entirety for all that it teaches. 
     6.6.2. Additional Binding Moieties 
     In various embodiments, the GAL9 binding molecule has modifications that comprise one or more additional binding moieties. In certain embodiments the binding moieties are antibody fragments or antibody formats including, but not limited to, full-length antibodies, Fab fragments, Fvs, scFvs, tandem scFvs, Diabodies, scDiabodies, DARTs, tandAbs, minibodies, camelid VHH, and other antibody fragments or formats known to those skilled in the art. Exemplary antibody and antibody fragment formats are described in detail in Brinkmann et al. ( MABS,  2017, Vol. 9, No. 2, 182-212), herein incorporated by reference for all that it teaches. 
     In particular embodiments, the one or more additional binding moieties are attached to the C-terminus of the first or third polypeptide chain. In particular embodiments, the one or more additional binding moieties are attached to the C-terminus of both the first and third polypeptide chain. In particular embodiments, the one or more additional binding moieties are attached to the C-terminus of both the first and third polypeptide chains. In certain embodiments, individual portions of the one or more additional binding moieties are separately attached to the C-terminus of the first and third polypeptide chains such that the portions form the functional binding moiety. 
     In particular embodiments, the one or more additional binding moieties are attached to the N-terminus of any of the polypeptide chains (e.g. the first, second, third, fourth, fifth, or sixth polypeptide chains). In certain embodiments, individual portions of the additional binding moieties are separately attached to the N-terminus of different polypeptide chains such that the portions form the functional binding moiety. 
     In certain embodiments, the one or more additional binding moieties are specific for a different antigen or epitope of the ABSs within the GAL9 binding molecule. In certain embodiments, the one or more additional binding moieties are specific for the same antigen or epitope of the ABSs within the GAL9 binding molecule. In certain embodiments, wherein the modification is two or more additional binding moieties, the additional binding moieties are specific for the same antigen or epitope. In certain embodiments, wherein the modification is two or more additional binding moieties, the additional binding moieties are specific for different antigens or epitopes. 
     In certain embodiments, the one or more additional binding moieties are attached to the GAL9 binding molecule using in vitro methods including, but not limited to, reactive chemistry and affinity tagging systems, as discussed in more detail below in Section 6.6.3. In certain embodiments, the one or more additional binding moieties are attached to the GAL9 binding molecule through Fc-mediated binding (e.g. Protein A/G). In certain embodiments, the one or more additional binding moieties are attached to the GAL9 binding molecule using recombinant DNA techniques, such as encoding the nucleotide sequence of the fusion product between the GAL9 binding molecule and the additional binding moieties on the same expression vector (e.g., plasmid). 
     6.6.3. Functional/Reactive Groups 
     In various embodiments, the GAL9 binding molecule has modifications that comprise functional groups or chemically reactive groups that can be used in downstream processes, such as linking to additional moieties (e.g., drug conjugates and additional binding moieties, as discussed in more detail above in Sections 6.6.1. and 6.6.2.) and downstream purification processes. 
     In certain embodiments, the modifications are chemically reactive groups including, but not limited to, reactive thiols (e.g. maleimide based reactive groups), reactive amines (e.g., N-hydroxysuccinimide based reactive groups), “click chemistry” groups (e.g. reactive alkyne groups), and aldehydes bearing formylglycine (FGly). In certain embodiments, the modifications are functional groups including, but not limited to, affinity peptide sequences (e.g., HA, HIS, FLAG, GST, MBP, and Strep systems etc.). In certain embodiments, the functional groups or chemically reactive groups have a cleavable peptide sequence. In particular embodiments, the cleavable peptide is cleaved by means including, but not limited to, photocleavage, chemical cleavage, protease cleavage, reducing conditions, and pH conditions. In particular embodiments, protease cleavage is carried out by intracellular proteases. In particular embodiments, protease cleavage is carried out by extracellular or membrane associated proteases. ADC therapies adopting protease cleavage are described in more detail in Choi et al. ( Theranostics,  2012; 2(2): 156-178), which is hereby incorporated by reference for all it teaches. 
     6.6.4. Reduced Effector Function 
     In certain embodiments, the GAL9 binding molecule has one or more engineered mutations in an amino acid sequence of an antibody domain that reduce the effector functions naturally associated with antibody binding. Effector functions include, but are not limited to, cellular functions that result from an Fc receptor binding to an Fc portion of an antibody, such as antibody-dependent cellular cytotoxicity (ADCC, also referred to as antibody-dependent cell-mediated cytotoxicity), complement fixation (e.g. C1q binding), antibody dependent cellular-mediated phagocytosis (ADCP), and opsonization. Exemplary engineered mutations that reduce the effector functions are described in more detail in U.S. Pub. No. 2017/0137530, Armour, et al. (Eur. J. Immunol. 29(8) (1999) 2613-2624), Shields, et al. (J. Biol. Chem. 276(9) (2001) 6591-6604), and Oganesyan, et al. (Acta Cristallographica D64 (2008) 700-704), each of which are herein incorporated by reference in its entirety. 
     6.7. Methods of Purification 
     Methods of purifying a GAL9 binding molecule are provided herein. Purification steps include, but are not limited to, purifying the GAL9 binding molecules based on protein characteristics, such as size (e.g., size exclusion chromatography), charge (e.g., ion exchange chromatography), or hydrophobicity (e.g., hydrophobicity interaction chromatography). In one embodiment, cation exchange chromatograph is performed. Other purification methods known to those skilled in the art can be performed including, but not limited to, use of Protein A, Protein G, or Protein A/G reagents. Multiple iterations of a single purification method can be performed. A combination of purification methods can be performed. 
     6.7.1. Assembly and Purity of Complexes 
     In the embodiments of the present invention, at least four distinct polypeptide chains associate together to form a complete complex, i.e., the GAL9 binding molecule. However, incomplete complexes can also form that do not contain the at least four distinct polypeptide chains. For example, incomplete complexes may form that only have one, two, or three of the polypeptide chains. In other examples, an incomplete complex may contain more than three polypeptide chains, but does not contain the at least four distinct polypeptide chains, e.g., the incomplete complex inappropriately associates with more than one copy of a distinct polypeptide chain. The method of the invention purifies the complex, i.e., the completely assembled GAL9 binding molecule, from incomplete complexes. 
     Methods to assess the efficacy and efficiency of the purification steps are well known to those skilled in the art and include, but are not limited to, SDS-PAGE analysis, ion exchange chromatography, size exclusion chromatography, and mass spectrometry. Purity can also be assessed according to a variety of criteria. Examples of criterion include, but are not limited to: 1) assessing the percentage of the total protein in an eluate that is provided by the completely assembled GAL9 binding molecule, 2) assessing the fold enrichment or percent increase of the method for purifying the desired products, e.g., comparing the total protein provided by the completely assembled GAL9 binding molecule in the eluate to that in a starting sample, 3) assessing the percentage of the total protein or the percent decrease of undesired products, e.g., the incomplete complexes described above, including determining the percent or the percent decrease of specific undesired products (e.g., unassociated single polypeptide chains, dimers of any combination of the polypeptide chains, or trimers of any combination of the polypeptide chains). Purity can be assessed after any combination of methods described herein. 
     6.8. Methods of Manufacturing 
     The GAL9 binding molecules described herein can readily be manufactured by expression using standard cell free translation, transient transfection, and stable transfection approaches currently used for antibody manufacture. In specific embodiments, Expi293 cells (ThermoFisher) can be used for production of the GAL9 binding molecules using protocols and reagents from ThermoFisher, such as ExpiFectamine, or other reagents known to those skilled in the art, such as polyethylenimine as described in detail in Fang et al. ( Biological Procedures Online,  2017, 19:11), herein incorporated by reference for all it teaches. 
     The expressed proteins can be readily separated from undesired proteins and protein complexes using various purification strategies including, but not limited to, use of Protein A, Protein G, or Protein A/G reagents. Further purification can be affected using ion exchange chromatography as is routinely used in the art. 
     6.9. Pharmaceutical Compositions 
     In another aspect, pharmaceutical compositions are provided that comprise a GAL9 binding molecule as described herein and a pharmaceutically acceptable carrier or diluent. In typical embodiments, the pharmaceutical composition is sterile. 
     In various embodiments, the pharmaceutical composition comprises the GAL9 binding molecule at a concentration of 0.1 mg/ml-100 mg/ml. In specific embodiments, the pharmaceutical composition comprises the GAL9 binding molecule at a concentration of 0.5 mg/ml, 1 mg/ml, 1.5 mg/ml, 2 mg/ml, 2.5 mg/ml, 5 mg/ml, 7.5 mg/ml, or 10 mg/ml. In some embodiments, the pharmaceutical composition comprises the GAL9 binding molecule at a concentration of more than 10 mg/ml. In certain embodiments, the GAL9 binding molecule is present at a concentration of 20 mg/ml, 25 mg/ml, 30 mg/ml, 35 mg/ml, 40 mg/ml, 45 mg/ml, or even 50 mg/ml or higher. In particular embodiments, the GAL9 binding molecule is present at a concentration of more than 50 mg/ml. 
     In various embodiments, the pharmaceutical compositions are described in more detail in U.S. Pat. Nos. 8,961,964, 8,945,865, 8,420,081, 6,685,940, 6,171,586, 8,821,865, 9,216,219, U.S. application Ser. No. 10/813,483, WO 2014/066468, WO 2011/104381, and WO 2016/180941, each of which is incorporated herein in its entirety. 
     6.10. Methods of Treatment 
     In another aspect, methods of treatment are provided, the methods comprising administering a GAL9 binding molecule as described herein to a patient (e.g., subject) with a disease or condition in an amount effective (e.g., therapeutically effective amount) to treat the patient. 
     6.10.1. Subjects 
     In some embodiments, the subject is a mammal. In some embodiments, the mammal is a mouse. In a preferred embodiment, the mammal is a human. In some embodiments, the subject&#39;s immune cells have increased PD-L2 expression, relative to immune cells from healthy individuals (e.g., healthy control), such as blood dendritic cells. 
     6.10.2. Combination therapy 
     The GAL9 binding molecule can be used alone or in combination with other therapeutic agents or procedures to treat or prevent a disease or condition. The GAL9 binding molecule can be administered either simultaneously or sequentially dependent upon the disease or condition to be treated. 
     The anti-GAL9 binding molecules can be used in combination with an agent or procedure that is used in the clinic or is within the current standard of care to treat or prevent a disease or condition. 
     In some embodiments, the GAL9 binding molecule is administered in combination with a second immunosuppressive agent. In certain embodiments, the second immunosuppressive agent is a glucocorticoid (e.g., prednisone, dexamethasone, or hydrocortisone), a cytostatic, anti-cytokine antibodies including anti-TNFα, anti-IL1, anti-ILS, anti-IL-6, anti-IL-17 antibodies, and anti-IL-23 antibodies, and small molecule drugs that reduce inflammatory cytokine signaling, such as JAK/STAT inhibitors, methotrexate, hydroxychloroquine, chloroquine, an anti-CD25 or anti-CD52 antibody, or drugs acting on immunophilins (e.g., cyclosporine or Sirolimus, or any other drug known to inhibit or prevent activity of the immune system. 
     In some embodiments, the GAL9 binding molecule is administered in combination with one or more anti-inflammatory drugs. 
     6.10.3. Autoimmune or Inflammatory Diseases 
     In some embodiments, the treatment comprises administration of a GAL9 binding molecule as described herein to a subject with an autoimmune or inflammatory disease in an amount effective to treat the subject. 
     In some embodiments, the autoimmune disease is amyotrophic lateral sclerosis (ALS), achalasia, Addison&#39;s disease, adult still&#39;s disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBM nephritis, Antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal &amp; neuronal neuropathy (AMAN), Baló disease, Behcet&#39;s disease, benign mucosal pemphigoid, bullous pemphigoid, castleman disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic recurrent multifocal osteomyelitis, Churg-Strauss Syndrome, Eosinophilic Granulomatosis, Cicatricial pemphigoid, Cogan&#39;s syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn&#39;s disease, dermatitis herpetiformis, dermatomyositis, Devic&#39;s disease (neuromyelitis optica), discoid lupus, dressler&#39;s syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, goodpasture&#39;s syndrome, granulomatosis with polyangiitis, Graves&#39; disease, Guillain-Barre syndrome, Hashimoto&#39;s thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis Suppurativa (HS) (Acne Inversa), Hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), lupus, lyme disease chronic, Meniere&#39;s disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren&#39;s ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism (PR), PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (pa), POEMS syndrome, polyarteritis nodosa, polyglandular syndromes type I, II, or III, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud&#39;s phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren&#39;s syndrome, sperm &amp; testicular autoimmunity, stiff person syndrome, subacute bacterial endocarditis, Susac&#39;s syndrome, sympathetic ophthalmia, Takayasu&#39;s arteritis, temporal arteritis, giant cell arteritis, thrombocytopenic purpura, Tolosa-Hunt syndrome, transverse myelitis, type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, or Vogt-Koyanagi-Harada disease. 
     In some embodiments, the autoimmune disease is selected from the group consisting of: inflammatory bowel disease, Crohn&#39;s disease, ulcerative colitis, colitis, celiac disease, rheumatoid arthritis, Behçet&#39;s disease, amyloidosis, psoriasis, psoriatic arthritis, systemic lupus erythematosus nephritis, graft-versus-host disease (GVHD), nonalcoholic steatohepatitis (NASH), and ankylosing spondylitis. In a preferred embodiment, the disease is Crohn&#39;s Disease. 
     In some embodiments, the treatment comprises administration of a GAL9 binding molecule as described herein to a subject at risk for transplantation rejection in an amount effective to reduce transplant rejection. In some embodiments, the treatment comprises administration of a GAL9 binding molecule as described herein to a subject with graft-versus-host disease in an amount effective to reduce GvHD. In some embodiments, the treatment comprises administration of a GAL9 binding molecule as described herein to a subject with post-traumatic immune responses in an amount effective to reduce inflammation. In some embodiments, the treatment comprises administration of a GAL9 binding molecule as described herein to a subject with ischemia in an amount effective to treat the subject. In some embodiments, the treatment comprises administration of a GAL9 binding molecule as described herein to a subject who has undergone a stroke in an amount effective to treat the subject. 
     In some embodiments, the treatment comprises administration of a GAL9 binding molecule to a subject who has a viral infection in an amount effective to reduce acute respiratory distress syndrome and/or acute cytokine release syndrome (cytokine storm). In particular embodiments, the viral infection is infection with SARS-CoV-2 virus and the disease is COVID-19. 
     6.10.4. Administration 
     The GAL9 binding molecule may be administered to a subject by any route known in the art. For example, the GAL9 binding molecule may be administered to a human subject via, e.g., intraarterial, intramuscular, intradermal, intravenous, intraperitoneal, intranasal, parenteral, pulmonary, subcutaneous administration, topical, oral, sublingual, intratumoral, peritumoral, intralesional, intrasynovial, intrathecal, intra-cerebrospinal, or perilesional administration. The GAL9 binding molecule may be administered to a subject per se or as a pharmaceutical composition. Exemplary pharmaceutical compositions are described herein. 
     The anti-GAL9 binding molecules disclosed herein can be administered alone or in combination with other therapeutic agents or procedures to treat or prevent a disease or condition. 
     Depending on the condition or disease to be treated, the treatment with a GAL9 binding molecule can improve one or more clinical endpoints in a subject. Examples of clinical endpoints improved in a subject with a disease or condition include but are not limited to, reducing inflammation, reducing autoimmune response, prolonging remission, inducing remission, re-establishing immune tolerance, improving organ function, reducing the risk of progression or development of a disease or a condition, reducing the risk of progression or development of a second disease, increasing overall survival in the subject or a combination thereof. 
     6.11. EXAMPLES 
     The following examples are provided by way of illustration, not limitation. In particular, methods for the expression and purification of the various antigen-binding proteins and their use in various assays described below are non-limiting and illustrative. 
     6.11.1. Methods 
     6.11.1.1. Expi293 Expression 
     Various antigen-binding proteins tested were expressed using the Expi293 transient transfection system according to manufacturer&#39;s instructions. Briefly, plasmids coding for individual chains were mixed at 1:1 mass ratio, unless otherwise stated, and transfected into Expi 293 cells with ExpiFectamine 293 transfection kit. Cells were cultured at 37° C. with 8% CO 2 , 100% humidity and shaking at 125 rpm. Transfected cells were fed once after 16-18 hours of transfections. The cells were harvested at day 5 by centrifugation at 2000 g for 10 minutes. The supernatant was collected for affinity chromatography purification. 
     6.11.1.2. ExpiCHO Expression 
     Various GALS antigen-binding proteins are expressed using the ExpiCHO transient transfection system according to manufacturer&#39;s instructions. Briefly, plasmids coding for individual chains are mixed at, for example, a 1:1 mass ratio, and transfected with ExpiFectamine CHO transfection kit into ExpiCHO. 
     Cells are cultured at 37° C. with 8% CO 2 , 100% humidity and shaking at 125 rpm. Transfected cells are generally be fed once after 16-18 hours of transfections. The cells are harvested at day 5 by centrifugation at 2000 g for 10 munities. The supernatant is then collected for affinity chromatography purification. 
     6.11.1.3. Protein A Purification 
     Cleared supernatants containing the various antigen-binding proteins were separated using either a Protein A (ProtA) resin or an anti-CH1 resin on an Gravity flow purifier. In examples where a head-to-head comparison was performed, supernatants containing the various antigen-binding proteins were split into two equal samples. For ProtA purification, a 1 mL Protein A column (GE Healthcare) was equilibrated with PBS (5 mM sodium potassium phosphate pH 7.4, 150 mM sodium chloride). The sample was loaded onto the column at 5 ml/min. The sample was eluted using 0.1M Sodium acetate pH 3.5. The elution was monitored by absorbance at 280 nm and the elution peaks were pooled for analysis. The elution was monitored by absorbance at 280 nm and the elution peaks were pooled for analysis. 
     6.11.1.4. SDS-Page Analysis 
     Samples containing the various separated antigen-binding proteins were analyzed by reducing and non-reducing SDS-PAGE for the presence of complete product, incomplete product, and overall purity. 2 μg of each sample was added to 15 μL SDS loading buffer. Reducing samples were incubated in the presence of 10 mM reducing agent at 75° C. for 10 minutes. Non-reducing samples were incubated at 70° C.—for 5 minutes without reducing agent. The reducing and non-reducing samples were loaded into a 4-15% gradient TGX gel (BioRad) with running buffer and run for 30 minutes at 220 volts. Upon completion of the run, the gel was washed with DI water and stained using GelCode Blue Safe Protein Stain (ThermoFisher). The gels were destained with DI water prior to analysis. Densitometry analysis of scanned images of the destained gels was performed using standard image analysis software to calculate the relative abundance of bands in each sample. 
     6.11.1.5. IEX Chromatography 
     Samples containing the various separated antigen-binding proteins were analyzed by cation exchange chromatography for the ratio of complete product to incomplete product and impurities. Cleared supernatants were analyzed with a 5-ml MonoS (GE Lifesciences) on an AKTA Purifier FPLC. The MonoS column was equilibrated with buffer A 10 mM MES pH 6.0. The samples were loaded onto the column at 2 ml/min. The sample was eluted using a 0-30% gradient with buffer B (10 mM MES pH 6.0, 1 M sodium chloride) over 6 CV. The elution was monitored by absorbance at 280 nm and the purity of the samples were calculated by peak integration to identify the abundance of the monomer peak and contaminants peaks. The monomer peak and contaminant peaks were separately pooled for analysis by SDS-PAGE as described above. 
     Analytical SEC Chromatography of each sample at 1 mg/mL was loaded onto the column at 1 ml/min. The sample was eluted using an isocratic flow of PBS for 1.5 CV. The elution was monitored by absorbance at 280 nm and the elution peaks were analyzed by peak integration. 
     6.11.1.6. Mass Spectrometry 
     Samples containing the various separated antigen-binding proteins were analyzed by mass spectrometry to confirm the correct species by molecular weight. All analysis was performed by a third-party research organization. Briefly, samples were treated with a cocktail of enzymes to remove glycosylation. Samples were both tested in the reduced format to specifically identify each chain by molecular weight. Samples were all tested under non-reducing conditions to identify the molecular weights of all complexes in the samples. Mass spec analysis was used to identify the number of unique products based on molecular weight. 
     6.11.1.7. Antibody discovery by phage display 
     Phage display of human Fab libraries was carried out using standard protocols. Human GAL9 protein was purchased from Acro Biosystems (Human Gal9 His-tag Cat #LG9-H5244) and biotinylated using EZ-Link NHS-PEG12-Biotin (ThermoScientific Cat #21312) using standard protocols. Phage clones were screened for the ability to bind the GAL9 protein by phage ELISA using standard protocols. 
     Briefly, Fab-formatted phage libraries were constructed using expression vectors capable of replication and expression in phage (also referred to as a phagemid). Both the heavy chain and the light chain were encoded for in the same expression vector, where the heavy chain was fused to a truncated variant of the phage coat protein pIII. The light chain and heavy chain-pIII fusion were expressed as separate polypeptides and assembled in the bacterial periplasm, where the redox potential enables disulfide bond formation, to form the phage display antibody containing the candidate ABS. 
     The library was created using sequences derived from a specific human heavy chain variable domain (VH3-23) and a specific human light chain variable domain (W-1). For the screened library, all three CDRs of the VH domain were diversified to match the positional amino acid frequency by CDR length found in the human antibody repertoire. Light chain variable domains within the screened library were generated with diversity introduced solely into the VL CDR3 (L3); the light chain VL CDR1 (L1) and CDR2 (L2) retained the human germline sequence. 
     The heavy chain scaffold (SEQ ID NO:2), light chain scaffold (SEQ ID NO:4), full heavy chain Fab polypeptide (SEQ ID NO:1), and full light chain Fab polypeptide (SEQ ID NO:3) used in the phage display library are shown below, where a lower case “x” represents CDR amino acids that were varied to create the library. 
     
       
         
           
               
            
               
                 Phage display VH scaffold [SEQ ID NO: 2]: 
               
               
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFxxxxIHWVRQAPGKGLEWVA 
               
               
                   
               
               
                 xxxxxxxxxxxYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCA 
               
               
                   
               
               
                 RxxxxxxxxxxxxxDYWGQGTLVTVSSAS 
               
               
                   
               
               
                 Phage display VL scaffold [SEQ ID NO: 4]: 
               
               
                 DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIY 
               
               
                   
               
               
                 SASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQxxxxxxTF 
               
               
                   
               
               
                 GQGTKVEIKRT 
               
               
                   
               
               
                 Phage display heavy chain Fab polypeptide [SEQ 
               
               
                 ID NO: 1]: 
               
               
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFxxxxIHWVRQAPGKGLEWVA 
               
               
                   
               
               
                 xxxxxxxxxxxYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCA 
               
               
                   
               
               
                 RxxxxxxxxxxxxxDYWGQGTLVTVSSASTKGPSVFPLAPSSKSISGGT 
               
               
                   
               
               
                 AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV 
               
               
                   
               
               
                 PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
               
               
                 Phage display light chain Fab polypeptide [SEQ 
               
               
                 ID NO: 3]: 
               
               
                 DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIY 
               
               
                   
               
               
                 SASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQxxxxxxTF 
               
               
                   
               
               
                 GQGTKVEIKRTVAAPSVFIFPPSDSQLKSGTASVVCLLNNFYPREAKVQ 
               
               
                   
               
               
                 WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV 
               
               
                   
               
               
                 THQGLSSPVTKSFNRGEC 
               
            
           
         
       
     
     Diversity was created through Kunkel mutagenesis using primers to introduce diversity into VH CDR1 (H1), CDR2 (H2) and CDR3 (H3) and VL CDR3 to mimic the diversity found in the natural antibody repertoire, as described in more detail in Kunkel, T A (PNAS Jan. 1, 1985. 82 (2) 488-492), incorporated herein by reference in its entirety. Briefly, single-stranded DNA was prepared from isolated phage using standard procedures and Kunkel mutagenesis carried out. Chemically synthesized DNA was then electroporated into MC1061F-cells. Phagemid obtained from overnight culture was digested with restriction enzymes (Bam HI and Xba I) to remove the wild-type sequence. The digested sample was electroporated into TG1 cells, followed by recovery. Recovered cells were sub-cultured and infected with M13K07 helper phage to produce the phage library. 
     Phage panning was performed using standard procedures. Briefly, the first round of phage panning was performed with target immobilized on streptavidin magnetic beads which were subjected to ˜5×10 12  phages from the prepared library in a volume of 1 mL in PBST-2% BSA. After a one-hour incubation, the bead-bound phage were separated from the supernatant using a magnetic stand. Beads were washed three times to remove non-specifically bound phage and were then added to ER2738 cells (5 mL) at OD 600 ˜0.6. After 20 minutes, infected cells were sub-cultured in 25 mL 2×YT +  Ampicillin and M13K07 helper phage (final concentration, ˜10 10  pfu/ml) and allowed to grow overnight at 37° C. with vigorous shaking. The next day, phage were prepared using standard procedures by PEG precipitation. Pre-clearance of phage specific to SAV-coated beads was performed prior to panning. The second round of panning was performed using the KingFisher magnetic bead handler with 100 nM bead-immobilized antigen using standard procedures. In total, 3-4 rounds of phage panning were performed to enrich in phage displaying Fabs specific for the target antigen. Target-specific enrichment was confirmed using polyclonal and monoclonal phage ELISA. DNA sequencing was used to determine isolated Fab clones containing a candidate ABS. 
     The VL and VH domains identified in the phage screen described above were reformatted into a bivalent monospecific native human full-length IgG1 architecture. 
     
       
         
           
               
            
               
                 Native human full-length IgG1 heavy chain 
               
               
                 architecture [SEQ ID NO: 5]: 
               
               
                 [SEQ ID NO: 5] 
               
               
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFxxxxIHWVRQAPGKGLEWVA 
               
               
                   
               
               
                 xxxxxxxxxxxYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCA 
               
               
                   
               
               
                 RxxxxxxxxxxxxxDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGT 
               
               
                   
               
               
                 AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV 
               
               
                   
               
               
                 PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG 
               
               
                   
               
               
                 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN 
               
               
                   
               
               
                 AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT 
               
               
                   
               
               
                 ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN 
               
               
                   
               
               
                 GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH 
               
               
                   
               
               
                 NHYTQKSLSLSPGK 
               
            
           
         
       
     
     Native Human Full-Length IgG1 Light Chain Architecture: 
     Equivalent to phage display light chain Fab, see SEQ ID NO:3 
     6.11.1.8. Octet Determination of Binding Kinetics 
     To measure qualitative binding affinity in GAL9 binder discovery campaigns, IgG1 reformatted binders were immobilized to a biosensor on an Octet (Pall ForteBio) biolayer interferometer. 
     Soluble GAL9 antigen was then added to the system and binding measured. Qualitative binding affinity was assessed by visualizing the slope of the dissociation phase of the octet sensogram from weakest ( + ) to strongest ( +++ ). A slow off rate represented by a negligible drop in the dissociation phase of the sensogram and indicated a tight binding antibody ( +++ ). To obtain accurate kinetic constants for monovalent affinities, a dilution series involving of at least five concentrations of the GAL9 analyte (ranging from approximately 10 to 20× K D  to 0.1× K D  value, 2-fold dilutions) were measured in the association step. In the dissociation step, the sensor was dipped into buffer solution that did not contain the GAL9 analyte and where the bound complex on the surface of the sensor dissociates. Octet kinetic analysis software was used to calculate the kinetic and equilibrium binding constants based on the rate of association and dissociation curves. Analysis was performed globally (global fit) where kinetic constants were derived simultaneously from all analyte concentration included in the experiment. 
     6.11.1.9. Epitope Binning 
     Anti-GAL9 candidates formatted into a bivalent monospecific native human full-length IgG1, as described above, were tested for GAL9 binding in a pair-wise manner using an octet-based ‘tandem’ assay. Briefly, biotinylated GAL9 was immobilized on a streptavidin sensor and two anti-GAL9 candidates were bound in tandem. A competitive blocking profile was generated determining whether a given anti-GAL9 candidate blocked binding of a panel of other anti-GAL9 candidates to GAL9. Anti-GAL9 candidates that competed for the same or non-overlapping binding regions were grouped together and referred to as belonging to the same bin. 
     6.11.1.10. PBMC Activation and Galectin 9 Antibody Treatment 
     Individual aliquots of PepMix HCMVA (pp65) (&gt;90%) Protein ID: P06725 (Cat. No. PM-PP65-2, JPT Peptide Technologies) were prepared according to manufacturer&#39;s instructions. PepMix™ HCMVA (pp65) are complete protein-spanning mixtures of overlapping 15mer peptides through 65 kDa phosphoprotein (pp65) (Swiss-Prot ID: P06725) of Human cytomegalovirus (HHV-5), used for immunostimulation of immune cell responses. 
     Frozen human peripheral blood mononuclear cells (PBMCs) were thawed according to standard conditions, then resuspended in growth media (10% FBS in RPMI). 
     Resuspended PBMCs were seeded at 5×10 5  cells in 96-well plates. Cells were incubated with 2 μg/mL PepMix™ HCMVA (pp65) plus 40 μg/mL of candidate GAL9 antibodies or control antibodies in growth media for 24 hours at 37° C., 5% CO 2 . 
     6.11.1.11. LEGENDplex Human Th Cytokine Assay 
     Following PBMC activation and Galectin 9 antibody treatment as described herein, cytokine secretion by PBMCs and immune cell subpopulations was assessed at 24 hours and 72 hours post-treatment by cytokine bead array as follows. 
     200 μl cell culture supernatant was collected and centrifuged to pellet cell debris. The resulting supernatants were analyzed using the LEGENDplex™ Human Th1 Panel (5-plex) (Cat. No. 740009, Biolegend). The LEGENDplex™ Human Th1 Panel is a bead-based assay to allows for simultaneous quantification of human cytokines IL-2, IL-6, IL-10, IFN-γ and TNF-α using flow cytometry. 
     Briefly, cytokine standards and capture bead mixtures were prepared according to manufacturer&#39;s instructions. Assay master mixes of 1:1:1 capture bead mixture: biotinylated detection antibodies; assay buffers were prepared. 
     12.5 μl of supernatant samples or cytokine standards were incubated with 37.5 μl assay master mix. Plates were sealed, covered with foil, and shaken at 600 rpm for 2 hours at room temperature. Wells were then incubated, with shaking at 600 rpm, with streptavidin-phycoerythrin (SA-PE) for 30 minutes at room temperature. Beads were then washed twice and resuspended before proceeding to flow cytometry analysis according to manufacturer&#39;s instructions. 
     6.11.1.12. PBMC Staining with Marker Antibodies 
     Following PBMC activation and Galectin 9 antibody treatment as described herein, PBMCs immune cells were stained with marker antibodies according to the following procedures. 
     Cells were resuspended at 5×10 6  cells/mL in growth media (10% FBS in RPMI). 200 μL of resuspended cells were aliquoted to 96 well plates, then incubated with Fixable Viability Dye eFluor® 780 for 30 minutes at 2-8° C. to irreversibly label dead cells. Cells were then washed and then incubated with human Fc Block solution (Cat. No. 14-9161-73, eBiosciences) for 10 minutes at room temperature. 
     An antibody cocktail working solution was prepared according to the following table. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Antibody Staining Working Solutions 
               
            
           
           
               
               
               
            
               
                   
                 Antibody 
                 Dilution 
               
               
                   
               
               
                 T cell surface markers 
                 BV510 anti-human CD3 (Cat. No. 
                 1 in 20 
               
               
                   
                 563109, BD Biosciences) 
                   
               
               
                   
                 PerCP/Cy5.5 anti-human CD56 (Cat. 
                 1 in 20 
               
               
                   
                 No. 362505, BD Biosciences) 
                   
               
               
                 Monocyte surface markers 
                 FITC anti-human CD14 (Cat. No. 
                 1 in 20 
               
               
                   
                 367115, BD Biosciences) 
                   
               
               
                   
                 Alexa Fluor ® 700 anti-human CD16 
                 1 in 20 
               
               
                   
                 (Cat. No. 302025, Biolegend) 
                   
               
               
                 Dendritic cell surface 
                 Brilliant Violet 421 ™ anti-human 
                 1 in 20 
               
               
                 makers 
                 CD11c (Cat. No. 301627, Biolegend) 
                   
               
               
                   
                 Alexa Fluor 647 anti-human CD123 
                 1 in 40 
               
               
                   
                 (Cat. No. 306023, Biolegend) 
                   
               
               
                   
                 BV510 anti-human Lineage Cocktail 
                 1 in 10 
               
               
                   
                 (CD3, CD14, CD16, CD19, CD20, 
                   
               
               
                   
                 CD56) (Cat. No. 348807, Biolegend) 
                   
               
               
                   
                 FITC anti-human HLA-DR (Cat. No. 
                 1 in 20 
               
               
                   
                 307603, Biolegend) 
                   
               
               
                 B cell surface markers 
                 PerCP/Cy5.5 anti-human CD19 (Cat. 
                 1 in 20 
               
               
                   
                 No. 363015, Biolegend) 
                   
               
               
                 Galectin-9 
                 PE anti-human galectin 9 (Cat. No. 
                 1 in 10 
               
               
                   
                 348905, Biolegend) 
               
               
                   
               
            
           
         
       
     
     Wells were incubated with 10 μL of diluted antibody cocktail for 30 minutes at 2-8° C. Cells were then washed and resuspended and analyzed by flow cytometry analysis. 
     To analyze immune stimulatory markers CD27, CD40L, ICOS, 4-1BB, and OX40, the same protocol provided above was followed, but cells were incubated with the alternative antibody cocktail as detailed in Table 2 below: 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Antibody Staining Working Solutions 
               
            
           
           
               
               
               
            
               
                   
                 Antibody 
                 Dilution 
               
               
                   
                   
               
               
                   
                 FITC anti-human CD134 (OX40) (Cat. No. 
                 1 in 50 
               
               
                   
                 350006, BioLegend) 
                   
               
               
                   
                 PerCP/Cy5.5 anti-human CD3 (Cat. No. 
                 1 in 100 
               
               
                   
                 560835, BD Biosciences) 
                   
               
               
                   
                 AF700 anti-human CD4 (Cat. No. 344622, 
                 1 in 100 
               
               
                   
                 BioLegend) 
                   
               
               
                   
                 eFluor ™ Fixable Viability Dye (Cat. No. 
                 1 in 2000 
               
               
                   
                 65-0865-14, eBioscienceTM) 
                   
               
               
                   
                 BV421 anti-human CD8 (Cat. No. 344748, 
                 1 in 100 
               
               
                   
                 BioLegend) 
                   
               
               
                   
                 BV650 anti-human CD137 (4-1BB) (Cat. 
                 1 in 50 
               
               
                   
                 No. 309828, BioLegend) 
                   
               
               
                   
                 BV711 anti-human ICOS (Cat. No. 563833, 
                 1 in 100 
               
               
                   
                 BD Biosciences) 
                   
               
               
                   
                 PE anti-human CD154 (CD40L) (Cat. No. 
                 1 in 50 
               
               
                   
                 310806, BioLegend) 
                   
               
               
                   
                 PE/Cy7 anti-mouse/rat/human CD27 (Cat. 
                 1 in 100 
               
               
                   
                 No. 124216, BioLegend) 
               
               
                   
                   
               
            
           
         
       
     
     6.11.2. Example 1: Blood Dendritic Cells from Crohn&#39;s Disease Patients have Increased PD-L2 Expression 
     Programmed death 1 (PD-1)-deficient mice develop a variety of autoimmune-like diseases, which suggests that the PD-1 receptor plays an important role in immunity and autoimmunity. PD-1 has two endogenous ligands, PD-L1 and PD-L2. The PD-1/PD-L1 interaction has been implicated in autoimmunity; however, PD-L2&#39;s role in autoimmunity is less understood. 
     Crohn&#39;s disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. While the specific cause of the disease is not well understood, it is clear that CD patients have an overactive immune system that causes inflammation and damage to the gastrointestinal tract. This study was conducted to determine the expression of PD-L2 and PD-L1 on blood dendritic cells from Crohn&#39;s Disease patients. 
     Study Participants 
     Peripheral blood was drawn from 29 adults confirmed by colonoscopy to have Crohn&#39;s disease. Patients were selected at different stages of treatment, but were excluded if they had received anti-TNF-α treatment. For a control, peripheral blood was drawn from 13 healthy adults undergoing colorectal cancer family history screening. 
     Immunostaining 
     Single-cell suspensions obtained from 10 ml whole blood were incubated with an Fc receptor binding antibody to block nonspecific Fc binding by specific antibodies. Fixable Viability Dye eFluor780 (ebioscience, San Diego, Calif.) was used to exclude dead cells from analysis. The following anti-human monoclonal antibodies were used to assess cells: HLA-DR PerCP-Cy5.5 (clone G46-6; BD Bioscience, San Jose, Calif.); lineage cocktail BV510 [CD3 (clone OKT3)/CD14 (clone M5E2)/CD16 (clone 3G8)/CD19 (clone HIB19)/CD20 (clone 2H7) and CD56 (clone HCD56)]; CD11c BV605 (clone 3.9; BioLegend, San Diego, Calif.). 
     Anti-human PD-L2 monoclonal antibody (clone MIH18; BioLegend, San Diego, Calif.) and anti-human PD-L1 monoclonal antibody (clone 29E.2A3; BioLegend, San Diego, Calif.) or control IgGs were labelled in-house using the Lightning-Link Rapid DyLight 647 and Lightning-Link Rapid DyLight 488, respectively (BioNovus Life Sciences, Cherrybrook, NSW, Australia). Cells were stained with anti-HLA-DR, anti-PD-L2, or anti-PD-L1 or IgG control for 30 mins at room temperature, and then washed twice with PBS for 5 mins, and then fixed in 1% paraformaldehyde—PBS, pH 7.25. 
     Flow Cytometry 
     Cells were stained with Fixable Viability Dyes (FVD) and gated to capture only viable cells in the mononuclear cell region of a side scatter versus forward scatter plot. Dendritic cells were defined as HLA-DR +  and Lint, followed by gating CD11c +  within the total peripheral blood population. For each donor at least 1×10 4  events were collected. 
     Cells were analyzed using a BD LSR Fortessa flow cytometer and data analyzed using either BD FACSDiva software (Becton &amp; Dickinson, Franklin Lakes, N.J.), FCS express (De Novo software, Glendale, Calif.) or FlowJo software (Tree Star; a subsidiary of Becton, Dickinson and Company, Ashland, Oreg.). 
     Statistical Analyses 
     Non-parametric Mann-Whitney U test based on 2-sided tail was conducted using GraphPad Prism (GraphPad Software). 
     Microscopy 
     Microscopy samples were made by mounting stained, sorted cells onto a glass slide. Images were collected using a confocal microscope. 
     Results/Conclusion 
       FIG. 2  shows contour plots of CD11c +  dendritic cells (DCs) cells from Crohn&#39;s patients stained with either IgG control, anti-PD-L1, or anti-PD-L2. We observed that the IgG control had 2.23% non-specific binding to DC cells, whereas the anti-PD-L1 antibody stained 28.6% of DC cells as PD-L1 + . Likewise, in the second experiment, the IgG control bound to only 3.22% of CD11c +  DC, whereas the anti-PD-L2 antibody detected 62.7% of DC cells as PD-L2 + . 
       FIGS. 3A-3B  show scatter plots of the percentage of PD-L1+ cells among CD11c +  blood dendritic cells ( FIG. 3A ) and the percentage of PD-L2 +  cells among CD11c +  blood dendritic cells ( FIG. 3B ) from healthy control donors and CD patients. The horizontal bars on the scatter plots show the mean.  FIGS. 3C-3D  show scatter plots of the amount (GMI) of PD-L1 expression ( FIG. 3C ) and the amount (GMI) of PD-L2 expression on CD11c +  blood dendritic cells from healthy control donors and Crohn&#39;s patients ( FIG. 3D ). The horizontal bars on the scatter plots indicate the mean. A single asterisk “*” indicates a P-value=0.0292. A double asterisk “**” indicates a P-value=0.0032. 
       FIGS. 4A-4B  show representative immunostaining of dendritic cells (DC) cells from the blood of two healthy control donors and three Crohn&#39;s Disease patients. DCs from healthy controls show high PD-L1 (green) and PD-L2 (red) staining throughout the cell; rendered in gray scale in the attached figures. In contrast, dendritic cells from Crohn&#39;s patients show low PD-L1 expression and high levels of PD-L2 which appear aggregated. In some cells, we observed high staining of aggregated PD-L1. 
     The results demonstrate that the PD-L2 protein is more highly expressed in blood dendritic cells from Crohn&#39;s patients as compared to healthy control donors (P-value=0.0032), yielding a higher statistical difference than PD-L1 (P-value=0.0292). These results suggest that the PD-L2 pathway may play an important role in Crohn&#39;s Disease and other autoimmune diseases. 
     6.11.3. Example 2: Inhibiting PD-L2 in PBMCs from Crohn&#39;s Disease Patients Results in a Clinically Favorable Cytokine Profile 
     This study was conducted to determine the effect of inhibiting PD-L2 protein on the cytokine profile in PBMCs from Crohn&#39;s Disease (CD) patients, compared to an IgG control. 
     Study Participants 
     Blood samples were obtained from 14 different Crohn&#39;s disease patients. Peripheral blood mononuclear cells (PBMC) were isolated using heparinized blood by density centrifugation on Ficoll-Paque (Pharmacia, Freiburg, Germany). Isolated PBMCs from control and CD patients were added to wells (2×10 5  cells/well) pre-coated with anti-CD3. R10 media, supplemented with penicillin (100 IU/ml), streptomycin (0.1 mg/ml) and L-glutamine (0.29 gm/1). Control IgG or blocking anti-PD-L2 (MIH18) antibodies were added to the culture at 20 μg/ml. 
     Treatment 
     Matched PBMCs samples were treated with either IgG control or anti-human PD-L2 antibody clone MIH18 (BioLegend) for 36 hours and then assayed. 
     Cytokine Assay 
     The concentration of TNF-α, IFN-γ, and IL-10 were measured using BD™ Cytometric Bead Array (CBA) following manufacturer&#39;s instructions. 
     Statistical Analyses 
     Wilcoxon matched-pairs signed rank test was conducted using GraphPad Prism (GraphPad Software). 
     Results/Conclusion 
     The mean concentrations of TNF-α and IFN-γ from the matched samples are shown in  FIGS. 5A-5B , respectively.  FIG. 5C  shows the mean IL-10:TNF-α ratio. These results demonstrate that inhibiting PD-L2 results in a clinically favorable cytokine profile in PMBCs from CD patients, by decreasing the levels of pro-inflammatory cytokines TNF-α and IFN-γ, and increasing the levels of inhibitory cytokine IL-10. 
     6.11.4. Example 3: Stimulating or Blocking the GAL9/PD-L2 Pathway Modulates TNF-α Secretion in Mouse CD4 +  T Cells 
     Previously, we showed that GAL9 can bind soluble PD-L2, and that some of the immunological effects of PD-L2 are mediated through binding of multimeric PD-L2 to GAL9, rather than through PD-1/PD-L1 (WO 2016/008005, which is incorporated herein by reference in its entirety). The current study was conducted to determine if stimulating or blocking the GAL9/PD-L2 pathway can modulate the TNF-α secretion in mouse CD4 +  T cells. 
     Animals 
     C57BL6/J mice were used for the study. All animals used in the study were housed and cared for in accordance with the National Health Medical Research Council (NHMRC) Guidelines for Animal Use. 
     sPD-L2 
     Soluble mouse PD-L2 (sPD-L2) with a human IgG1 Fc was custom produced by Geneart (Germany). 
     Antibodies 
     For treatment, inhibitory anti-mouse GAL9 antibody clone 108A2 (BioLegend® San Diego, Calif.) or rat IgG2a control antibody was used. The anti-mouse GAL9 clone (108A2) binds the linker peptide of murine Galectin-9 (Oomizu, S. et al., PLoS One 7(11):e48574 (2012); Doi: 10.1371/journal.pone.0048574, which is herein incorporated by reference). Anti-CD3 (clone 145.2C11) (Aviva Systems Biology Corp. San Diego, Calif.) was used for stimulation. 
     Cell Separation and Stimulation of CD4 +  T cells 
     A suspension of mouse spleen cells was made from five mice. CD4 +  T-cells were isolated using Miltenyi Biotec Inc. (Auburn, Calif.) kit for untouched CD4 +  T cells. Mouse CD4 +  T cells were stimulated with anti-CD3 clone 145.2C11 (Aviva Systems Biology Corp. San Diego, Calif.) at 5 μg/ml. Next, the stimulated CD4 +  T cells were treated either with IgG control or sPD-L2 at 20 μg/ml, or with sPD-L2 and anti-GAL9 mAb clone 108A2, both at 20 μg/ml, and then cultured for 36 hours. 
     Cytokine Assays 
     After 36 hrs of treatment, the concentration of TNF-α was measured using BD™ Cytometric Bead Array following manufacturer&#39;s instructions. 
     Statistical Analyses 
     Non-parametric Mann-Whitney U test was conducted using GraphPad Prism (GraphPad Software). 
     Results/Conclusion 
       FIG. 6  shows bar graphs of the concentration levels of TNF-α for each treatment group. Treatment of activated CD4 +  T cells with sPD-L2 alone resulted in significantly increased TNF-α secretion by CD4 +  T cells, as compared to IgG control, * p-value &lt;0.0001. Addition of inhibitory anti-mouse GAL9 antibody (108A2) significantly decreased TNF-α secretion from activated CD4 +  T cells, both as compared to activated CD4 +  T cells treated with 108A2, and as compared to IgG control, * p-value &lt;0.0001. 
     sPD-L2, which binds GAL9 on T cells, induces TNF-α secretion, while inhibiting GAL9 blocks sPD-L2-mediated TNF-α secretion in CD4 +  T cells. These results demonstrate that the GAL9/PD-L2 pathway modulates TNF-α levels in stimulated CD4 +  T cells. 
     6.11.5. Example 4: Inhibitory Anti-Mouse GAL9 (108A2) Antibodies Works Independently from PD-1/PD-L1 in CD4 +  T Cells from Malaria-Infected Mice, while Activating Anti-GAL9 Antibodies do not 
     This study was conducted to investigate the dependence of inhibitory and activating GAL9 antibodies on the PD-1/PD-L1 pathway. 
     Mouse models of malaria-infected mice can be used to study immune mechanisms and susceptibility to drugs. Wykes, M N et al.  Eur J Immunol . (2009) 39:2004-7, which is incorporated herein by reference in its entirety. Further, it has been shown that  Plasmodium  parasites that cause malaria can exploit the PD-1 pathway to ‘deactivate’ T cell functions. A definitive role for PD-1 in malarial pathogenesis was demonstrated when PD-1-deficient mice were shown to rapidly and completely clear  P. chabaudi  infections. As such, malarial infection models can be used to understand the relative contribution of PD-1 and its ligands, PD-L1 and PD-L2, in immunity. 
     Antibodies 
     The inhibitory anti-mouse GAL9 antibody (108A2) and the activating anti-mouse GAL9 antibody (RG9.1) (Cat. No. BE0218, InVivoMab Antibodies) were used for this study. 
     Malaria-Infected Mouse Model 
     Cohorts of C57BL/6 mice were infected with non-lethal malaria ( P. yoelii  17XNL). After intravenous injection the of 10 5    P. yoelii  infected red cells, the mice were incubated for 7 days to allow infection to take place. 
     CD4 +  T Cell Isolation and Treatment 
     CD4 +  T cells were isolated from malaria-infected mice using Miltenyi Biotec untouched CD4 +  T cell isolation kits. Next, the isolated T cells were cultured and treated overnight with either control IgG antibody, inhibitory anti-mouse GAL9 antibody (108A2), or the activating anti-mouse GAL9 antibody (RG9.1). 
     Immunostaining and Microscopy 
     After treatment, the cells were stained with DAPI (to detect DNA), and anti-OX40 (CD134), anti-PD-1, and anti-PD-L1 (BioXCell, Lebanon, N.H.) antibodies labelled using Lightning-Link Rapid DyLight 647, 594 or 488 kits. Immunostaining was observed by confocal imaging. 
     Results/Conclusion 
       FIG. 7  shows representative confocal images of CD4 +  T cells treated with either IgG control, inhibitory anti-mouse GAL9 antibody (108A2), or the activating anti-mouse GAL9 antibody (RG9.1). The red staining shows the PD-1 receptor, the green staining shows the PD-L1 ligand, the yellow staining shows the OX40 receptor, and the blue staining shows DNA (DAPI), rendered in gray scale in the attached figures. 
     We observed that treatment with the activating anti-mouse GAL9 (RG9.1) antibody reduces the expression of PD-1 receptor (low levels of staining) and the PD-L1 ligand (very reduced levels of staining). In contrast, we observed that treatment with inhibitory anti-GAL9 (108A2) had no effect on the expression PD-1 receptor (staining levels similar to IgG control levels) or the PD-L1 ligand (staining levels similar to IgG control levels). In addition, we observed that treatment with inhibitory anti-GAL9 (108A2) resulted in decreased expression of OX40. These results suggest that inhibiting GAL9 antibodies work independently from PD-1/PD-L1 pathway in CD4 +  T cells. 
     6.11.6. Example 5: Treatment with Inhibitory Anti-Mouse GAL9 (108A2) Decreases PD-L2-Mediated Survival of CD4 +  and CD8 +  T Cells from Malaria-Infected Mice 
     This study was conducted to determine the effect of an inhibitory anti-mouse GAL9 (108A2) antibody on PD-L2-mediated survival of CD4 +  and CD8 +  T cells from malaria-infected mice. 
     PD-L2 has been shown to mediate the survival of CD4 +  and CD8 +  T cells in malaria-infected mice, by increasing the numbers of parasite-specific CD4 +  and CD8 +  T cells to protect the mice from the lethal malaria infection. See Karunarathne et al.  Immunity  (2016). Aug. 16; 45(2):333-45), which is incorporated herein by reference in its entirety. 
     Malaria-Infected Mouse Model 
     Cohorts of five C57BL/6 mice were infected with non-lethal malaria ( P. yoelii  17XNL). After intravenous injection of 10 5    P. yoelii  infected red cells, the mice were incubated for 7 days to allow infection to take place. All animals used in the study were housed and cared for in accordance with the National Health Medical Research Council (NHMRC) Guidelines for Animal Use. 
     sPD-L2 
     As a positive control, CD4 +  and CD8 +  T cells were treated with soluble PD-L2 “sPD-L2” custom produced by Geneart (Germany). 
     Cell Isolation, Treatment, and Viability Assay 
     CD4 +  and CD8 +  T cells were isolated from infected mice by FACS using Miltenyi Biotec Inc. (Auburn, Calif.) kits for untouched CD4 +  and CD8 +  T cells and then cultured for 36 hours at 37° C. Next, CD4 +  and CD8 +  T cells were treated with either 20 mg/ml of sPD-L2 or 20 mg/ml anti-mouse GAL9 (108A2). After treatment, cells were assayed for viability using a viability dye and flow cytometry. 
     Results/Conclusion 
     The results for the viability assays for CD4 +  T cells and CD8 +  T cell are shown in  FIG. 8A  and  FIG. 8B , respectively. Treatment with sPD-L2 increased PD-L2-mediated survival in CD4 +  and CD8 +  T cells. In contrast, treatment with sPD-L2 and anti-GAL9 (108A2) decreased PD-L2-mediated survival in both CD4 +  and CD8 +  T cells. These results suggest that PD-L2 works with GAL9 to mediate survival of CD4 +  and CD8 +  T cells. 
     6.11.7. Example 6: Blocking the GAL9/PD-L2 Pathway Decreases Proinflammatory Cytokines in Activated CD4 +  T Cells from Malaria-Infected Mice 
     This study was conducted to determine if blocking the GAL9/PD-L2 pathway by either a blocking anti-PD-L2 antibody or an inhibitory anti-mouse GAL9 (108A2) antibody can decrease secretion of proinflammatory cytokines in activated CD4 +  T cells from malaria-infected mice. 
     Malaria-Infected Mouse Model 
     Cohorts of five C57BL/6 mice were infected with malaria strain  P. yoelii  17XNL and incubated for 7 days, to allow infection to take place. All animals used in the study were housed and cared for in accordance with the NHMRC Guidelines for Animal Use. 
     Antibodies 
     The blocking anti-mouse PD-L2 mAb clone TY25 (BioXCell, Lebanon, N.H.) or the inhibitory anti-mouse GAL9 clone 108A2 (BioLegend® San Diego, Calif.) were used. 
     Cell Isolation and Co-Culture Stimulation 
     CD4 +  T cells and DC cells were isolated from malaria-infected mice by using Miltenyi Biotec kits (Auburn, Calif.) for CD4 +  T cell isolation and CD11c +  beads for DC isolation. Next, approximately 1×10 6  T cells were cultured with 2×10 5  DCs in at least triplicate wells and then cultured with either 20 ug/ml of anti-PD-L2 mAb or 20 ug/ml of anti-Gal9 mAb for 36 hours. 
     Cytokine Assays 
     After treatment, the concentration of INF-γ or TNF-α was measured using BD™ Cytometric Bead Array (CBA) following manufacturer&#39;s instructions. 
     Statistical Analyses 
     Unpaired t-test with Welch&#39;s correction was conducted using GraphPad Prism (GraphPad Software). 
     Results/Conclusion 
       FIG. 9A  shows bar graphs of the IFN-γ concentration detected for each treatment group. Treatment with either anti-PD-L2 or anti-GAL9 (108A2) resulted in a significant reduction in IFN-γ levels compared to an untreated co-culture control. 
       FIG. 9B  shows bar graphs of the TNF-α concentration detected for each treatment group. Treatment with either anti-PD-L2 or inhibitory anti-mouse GAL9 antibody (108A2) resulted in a significant reduction of TNF-α levels compared to an untreated co-culture control. The asterisk “*” indicates a statistical significance of p-value &lt;0.05 compared to control. Notably, treatment with anti-PD-L2 and anti-GAL9 (108A2) reduced the IFN-γ and TNF-α to roughly the same concentration level. 
     6.11.8. Example 7: Human GAL9 (Anti-Human GAL9) Binding Arm Discovery Campaign 
     A chemically synthetic Fab phage library with diversity introduced into the Fab CDRs was screened against GAL9 antigens using a monoclonal phage ELISA format as described above. Phage clones expressing Fabs that recognized GAL9 were sequenced. 
     The campaign initially identified 52 GAL9 binding candidates (antigen binding site clones). Functional assays conducted after the variable regions of these clones had been reformatted into a bivalent monospecific human IgG1 format identified 30 antibodies having immune inhibiting properties. 
     Table 3 lists the VH CDR1/2/3 sequences from the 30 inhibiting ABS clones, showing only the residues of the CDRs that had been varied in constructing the library. Table 4 lists the VL CDR1/2/3 sequences from the identified ABS clones; the light chain CDR1 and CDR2 sequences are invariant, and only the residues of CDR3 that were varied in constructing the library are shown. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Candidate anti-human GAL9 VH Antigen Binding Sites 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 CDR1 
                   
                 CDR2 
                   
                 CDR3 
                   
               
               
                 ABS 
                 (variant 
                 SEQ 
                 (variant 
                 SEQ 
                 (variant 
                 SEQ 
               
               
                 clone 
                 residues) 
                 ID # 
                 residues) 
                 ID # 
                 residues) 
                 ID # 
               
               
                   
               
               
                 P9-01 
                 SSYW 
                  7 
                 WIDPDYGTTS 
                  59 
                 AGISYVF 
                 111 
               
               
                   
               
               
                 P9-02A 
                 SSYW 
                  8 
                 WIDPDYGTTS 
                  60 
                 AQYVPGL 
                 112 
               
               
                   
               
               
                 P9-03 
                 SGYY 
                 10 
                 VISPYSGYTS 
                  62 
                 ATYMVPYGF 
                 114 
               
               
                   
               
               
                 P9-06 
                 AYYG 
                 13 
                 YIYPHGYITD 
                  65 
                 DSGVPYYWAVL 
                 117 
               
               
                   
               
               
                 P9-07 
                 SSYY 
                 14 
                 YISPYGGDTS 
                  66 
                 DSYMSYIDGF 
                 118 
               
               
                   
               
               
                 P9-11 
                 SSYY 
                 18 
                 YISPSGGYTY 
                  70 
                 GAVLYSSAM 
                 122 
               
               
                   
               
               
                 P9-12 
                 SSYW 
                 19 
                 SIASYFGQTY 
                  71 
                 GFGYAAM 
                 123 
               
               
                   
               
               
                 P9-14 
                 GSYY 
                 20 
                 DIYPYFSSTY 
                  72 
                 GSHFGF 
                 124 
               
               
                   
               
               
                 P9-23 
                 SQYY 
                 28 
                 TIYPRGGYTF 
                  80 
                 KSYWGM 
                 132 
               
               
                   
               
               
                 P9-24 
                 SSYF 
                 29 
                 SIYPTSHSTS 
                  81 
                 LGYPGVM 
                 133 
               
               
                   
               
               
                 P9-25 
                 SSYY 
                 30 
                 SIYPYGSYTY 
                  82 
                 LGYSSGM 
                 134 
               
               
                   
               
               
                 P9-26 
                 SSYY 
                 31 
                 WIESSSSHTD 
                  83 
                 LPYKYYYLGVF 
                 135 
               
               
                   
               
               
                 P9-29 
                 SSYA 
                 34 
                 YIAPGGSYTY 
                  86 
                 LSYPGVM 
                 138 
               
               
                   
               
               
                 P9-30 
                 STYT 
                 35 
                 WIYPKGGSTD 
                  87 
                 PSGYGF 
                 139 
               
               
                   
               
               
                 P9-34 
                 STYF 
                 38 
                 YIYPQGGYTY 
                  90 
                 QSYPGVF 
                 142 
               
               
                   
               
               
                 P9-37 
                 WKYG 
                 40 
                 YIYPAGGITS 
                  92 
                 SDYYSGMGM 
                 144 
               
               
                   
               
               
                 P9-38 
                 SSYW 
                 41 
                 WIDPDYGTTS 
                  93 
                 SETGAAM 
                 145 
               
               
                   
               
               
                 P9-40 
                 RWYY 
                 43 
                 TIYPDWDYTT 
                  95 
                 SPVTGPYGF 
                 147 
               
               
                   
               
               
                 P9-41 
                 RYYW 
                 44 
                 AIYPSSDSTY 
                  96 
                 SSPYPYGQGVF 
                 148 
               
               
                   
               
               
                 P9-42 
                 SSYY 
                 45 
                 AIYSAWGTTY 
                  97 
                 SYGYVFGYYSGM 
                 149 
               
               
                   
               
               
                 P9-43 
                 HSYW 
                 46 
                 RIDSSKFGTY 
                  98 
                 SYIDYPVSPAVF 
                 150 
               
               
                   
               
               
                 P9-44 
                 SYYW 
                 47 
                 AISPSGSYTS 
                  99 
                 SYYRFRTPYTVM 
                 151 
               
               
                   
               
               
                 P9-45 
                 FSYV 
                 48 
                 AIYPYSGYTT 
                 100 
                 TKYYDYHVF 
                 152 
               
               
                   
               
               
                 P9-46 
                 SRYY 
                 49 
                 FISSDSGYTQ 
                 101 
                 TMSYSAL 
                 153 
               
               
                   
               
               
                 P9-50 
                 SSYV 
                 51 
                 LIYSSGGYTQ 
                 103 
                 VGTTYPSRYLEAL 
                 155 
               
               
                   
               
               
                 P9-51 
                 SSYY 
                 52 
                 GIYPEGSYTY 
                 104 
                 VGYPGVM 
                 156 
               
               
                   
               
               
                 P9-52 
                 STYL 
                 53 
                 AITPYSGYTS 
                 105 
                 VGYPMVM 
                 157 
               
               
                   
               
               
                 P9-53 
                 SRYQ 
                 54 
                 YIASASGTTS 
                 106 
                 VPYVAM 
                 158 
               
               
                   
               
               
                 P9-56 
                 SSYY 
                 56 
                 YIDSSGKYTD 
                 108 
                 YAYPGVM 
                 160 
               
               
                   
               
               
                 P9-57 
                 SSYY 
                 57 
                 TIYPSGGYTY 
                 109 
                 YSYPGVL 
                 161 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Candidate anti-human GAL9 VL Antigen Binding Sites 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 CDR3 
                   
               
               
                 ABS 
                 CDR1 
                 SEQ 
                 CDR2 
                 SEQ 
                 (variant 
                 SEQ 
               
               
                 clone 
                 (Invariant) 
                 ID # 
                 (invariant) 
                 ID # 
                 residues) 
                 ID # 
               
               
                   
               
               
                 P9-01 
                 RASQSVSSA 
                 163 
                 SASSLYS 
                 215 
                 QVSDLL 
                 267 
               
               
                   
               
               
                 P9-02A 
                 RASQSVSSA 
                 164 
                 SASSLYS 
                 216 
                 SYPTLG 
                 268 
               
               
                   
               
               
                 P9-03 
                 RASQSVSSA 
                 166 
                 SASSLYS 
                 218 
                 GGSFPY 
                 270 
               
               
                   
               
               
                 P9-06 
                 RASQSVSSA 
                 169 
                 SASSLYS 
                 221 
                 HFSSPG 
                 273 
               
               
                   
               
               
                 P9-07 
                 RASQSVSSA 
                 170 
                 SASSLYS 
                 222 
                 WTSTLW 
                 274 
               
               
                   
               
               
                 P9-11 
                 RASQSVSSA 
                 174 
                 SASSLYS 
                 226 
                 YYPSPS 
                 278 
               
               
                   
               
               
                 P9-12 
                 RASQSVSSA 
                 175 
                 SASSLYS 
                 227 
                 EYGRPY 
                 279 
               
               
                   
               
               
                 P9-14 
                 RASQSVSSA 
                 176 
                 SASSLYS 
                 228 
                 HASGPL 
                 280 
               
               
                   
               
               
                 P9-23 
                 RASQSVSSA 
                 184 
                 SASSLYS 
                 236 
                 WSVYLE 
                 288 
               
               
                   
               
               
                 P9-24 
                 RASQSVSSA 
                 185 
                 SASSLYS 
                 237 
                 VDSRLA 
                 289 
               
               
                   
               
               
                 P9-25 
                 RASQSVSSA 
                 186 
                 SASSLYS 
                 238 
                 WAPDLT 
                 290 
               
               
                   
               
               
                 P9-26 
                 RASQSVSSA 
                 187 
                 SASSLYS 
                 239 
                 YSSSLY 
                 291 
               
               
                   
               
               
                 P9-29 
                 RASQSVSSA 
                 190 
                 SASSLYS 
                 242 
                 GYSSLL 
                 294 
               
               
                   
               
               
                 P9-30 
                 RASQSVSSA 
                 191 
                 SASSLYS 
                 243 
                 YLSSPY 
                 295 
               
               
                   
               
               
                 P9-34 
                 RASQSVSSA 
                 194 
                 SASSLYS 
                 246 
                 WTIALT 
                 298 
               
               
                   
               
               
                 P9-37 
                 RASQSVSSA 
                 196 
                 SASSLYS 
                 248 
                 YYPSPS 
                 300 
               
               
                   
               
               
                 P9-38 
                 RASQSVSSA 
                 197 
                 SASSLYS 
                 249 
                 GSYFLQ 
                 301 
               
               
                   
               
               
                 P9-40 
                 RASQSVSSA 
                 199 
                 SASSLYS 
                 251 
                 PTYSLW 
                 303 
               
               
                   
               
               
                 P9-41 
                 RASQSVSSA 
                 200 
                 SASSLYS 
                 252 
                 WYSSLW 
                 304 
               
               
                   
               
               
                 P9-42 
                 RASQSVSSA 
                 201 
                 SASSLYS 
                 253 
                 WSSDLV 
                 305 
               
               
                   
               
               
                 P9-43 
                 RASQSVSSA 
                 202 
                 SASSLYS 
                 254 
                 VYFSPY 
                 306 
               
               
                   
               
               
                 P9-44 
                 RASQSVSSA 
                 203 
                 SASSLYS 
                 255 
                 GIDSPE 
                 307 
               
               
                   
               
               
                 P9-45 
                 RASQSVSSA 
                 204 
                 SASSLYS 
                 256 
                 GWDSLV 
                 308 
               
               
                   
               
               
                 P9-46 
                 RASQSVSSA 
                 205 
                 SASSLYS 
                 257 
                 YWWSPE 
                 309 
               
               
                   
               
               
                 P9-50 
                 RASQSVSSA 
                 207 
                 SASSLYS 
                 259 
                 FGSSLP 
                 311 
               
               
                   
               
               
                 P9-51 
                 RASQSVSSA 
                 208 
                 SASSLYS 
                 260 
                 WGSSLA 
                 312 
               
               
                   
               
               
                 P9-52 
                 RASQSVSSA 
                 209 
                 SASSLYS 
                 261 
                 LDYSLA 
                 313 
               
               
                   
               
               
                 P9-53 
                 RASQSVSSA 
                 210 
                 SASSLYS 
                 262 
                 GYPHPG 
                 314 
               
               
                   
               
               
                 P9-56 
                 RASQSVSSA 
                 212 
                 SASSLYS 
                 264 
                 YDYSLW 
                 316 
               
               
                   
               
               
                 P9-57 
                 RASQSVSSA 
                 213 
                 SASSLYS 
                 265 
                 SSSFLW 
                 317 
               
               
                   
               
            
           
         
       
     
     Table 5 presents the full CDR sequences for the human candidate inhibiting anti-GAL9 antibodies according to multiple art-accepted definitions. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 CDR definitions 
               
            
           
           
               
               
               
               
               
               
            
               
                 Region 
                 Definition 
                 Sequence 
                 Residues 
                 Length 
                 SEQ ID NO: 
               
               
                   
               
            
           
           
               
            
               
                 P9-01 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY 
                 26-32 
                 7 
                 318 
               
               
                   
                 AbM 
                 GFTFSSYWIH 
                 26-35 
                 10 
                 319 
               
               
                   
                 Kabat 
                 SYWIH 
                 31-35 
                 5 
                 320 
               
               
                   
                 Contact 
                 ----SSYWIH 
                 30-35 
                 6 
                 321 
               
               
                   
                 IMGT 
                 GFTFSSYW-- 
                 26-33 
                 8 
                 322 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 DPDYGT 
                 52-57 
                 6 
                 323 
               
               
                   
                 AbM 
                 ---WIDPDYGTTS 
                 50-59 
                 10 
                 324 
               
               
                   
                 Kabat 
                 ---WIDPDYGTTSYADSVKG 
                 50-66 
                 17 
                 325 
               
               
                   
                 Contact 
                 WVAWIDPDYGTTS 
                 47-59 
                 13 
                 326 
               
               
                   
                 IMGT 
                 IDPDYGTT 
                 51-58 
                 8 
                 327 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --AGISYVFDY 
                 99-107 
                 9 
                 328 
               
               
                   
                 AbM 
                 --AGISYVFDY 
                 99-107 
                 9 
                 329 
               
               
                   
                 Kabat 
                 --AGISYVFDY 
                 99-107 
                 9 
                 330 
               
               
                   
                 Contact 
                 ARAGISYVFD- 
                 97-106 
                 10 
                 331 
               
               
                   
                 IMGT 
                 ARAGISYVFDY 
                 97-107 
                 11 
                 332 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 333 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 334 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 335 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 336 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 337 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 338 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 339 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 340 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 341 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 342 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQQVSDLLT 
                 89-97 
                 9 
                 343 
               
               
                   
                 AbM 
                 QQQVSDLLT 
                 89-97 
                 9 
                 344 
               
               
                   
                 Kabat 
                 QQQVSDLLT 
                 89-97 
                 9 
                 345 
               
               
                   
                 Contact 
                 QQQVSDLL- 
                 89-96 
                 8 
                 346 
               
               
                   
                 IMGT 
                 QQQVSDLLT 
                 89-97 
                 9 
                 347 
               
               
                   
               
            
           
           
               
            
               
                 P9-02A 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY--- 
                 26-32 
                 7 
                 348 
               
               
                   
                 AbM 
                 GFTFSSYWIH 
                 26-35 
                 10 
                 349 
               
               
                   
                 Kabat 
                 SYWIH 
                 31-35 
                 5 
                 350 
               
               
                   
                 Contact 
                 SSYWIH 
                 30-35 
                 6 
                 351 
               
               
                   
                 IMGT 
                 GFTFSSYW-- 
                 26-33 
                 8 
                 352 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 DPDYGT 
                 52-57 
                 6 
                 353 
               
               
                   
                 AbM 
                 ---WIDPDYGTTS 
                 50-59 
                 10 
                 354 
               
               
                   
                 Kabat 
                 ---WIDPDYGTTSYADSVKG 
                 50-66 
                 17 
                 355 
               
               
                   
                 Contact 
                 WVAWIDPDYGTTS 
                 47-59 
                 13 
                 356 
               
               
                   
                 IMGT 
                 IDPDYGTT 
                 51-58 
                 8 
                 357 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --AQYVPGLDY 
                 99-107 
                 9 
                 358 
               
               
                   
                 AbM 
                 --AQYVPGLDY 
                 99-107 
                 9 
                 359 
               
               
                   
                 Kabat 
                 --AQYVPGLDY 
                 99-107 
                 9 
                 360 
               
               
                   
                 Contact 
                 ARAQYVPGLD- 
                 97-106 
                 10 
                 361 
               
               
                   
                 IMGT 
                 ARAQYVPGLDY 
                 97-107 
                 11 
                 362 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 363 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 364 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 365 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 366 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 367 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 368 
               
               
                   
                 AbM 
                 ----SASSLYS 
                 50-56 
                 7 
                 369 
               
               
                   
                 Kabat 
                 ----SASSLYS 
                 50-56 
                 7 
                 370 
               
               
                   
                 Contact 
                 LLTYSASSLY- 
                 46-55 
                 10 
                 371 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 372 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQSYPTLGT 
                 89-97 
                 9 
                 373 
               
               
                   
                 AbM 
                 QQSYPTLGT 
                 89-97 
                 9 
                 374 
               
               
                   
                 Kabat 
                 QQSYPTLGT 
                 89-97 
                 9 
                 375 
               
               
                   
                 Contact 
                 QQSYPTLG- 
                 89-96 
                 8 
                 376 
               
               
                   
                 IMGT 
                 QQSYPTLGT 
                 89-97 
                 9 
                 377 
               
               
                   
               
            
           
           
               
            
               
                 P9-03 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSGY 
                 26-32 
                 7 
                 378 
               
               
                   
                 AbM 
                 GFTFSGYYIH 
                 26-35 
                 10 
                 379 
               
               
                   
                 Kabat 
                 GYYIH 
                 31-35 
                 5 
                 380 
               
               
                   
                 Contact 
                 SGYYIH 
                 30-35 
                 6 
                 381 
               
               
                   
                 IMGT 
                 GFTFSGYY-- 
                 26-33 
                 8 
                 382 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 SPYSGY 
                 52-57 
                 6 
                 383 
               
               
                   
                 AbM 
                 ---VISPYSGYTS 
                 50-59 
                 10 
                 384 
               
               
                   
                 Kabat 
                 ---VISPYSGYTSYADSVKG 
                 50-66 
                 17 
                 385 
               
               
                   
                 Contact 
                 WVAVISPYSGYTS 
                 47-59 
                 13 
                 386 
               
               
                   
                 IMGT 
                 ----ISPYSGYT 
                 51-58 
                 8 
                 387 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --ATYMVPYGFDY 
                 99-109 
                 11 
                 388 
               
               
                   
                 AbM 
                 --ATYMVPYGFDY 
                 99-109 
                 11 
                 389 
               
               
                   
                 Kabat 
                 --ATYMVPYGFDY 
                 99-109 
                 11 
                 390 
               
               
                   
                 Contact 
                 ARATYMVPYGFD- 
                 97-108 
                 12 
                 391 
               
               
                   
                 IMGT 
                 ARATYMVPYGFDY 
                 97-109 
                 13 
                 392 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 393 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 394 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 395 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 396 
               
               
                   
                 IMGT 
                 ---QSVSSA---- 
                 27-32 
                 6 
                 397 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 398 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 399 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 400 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 401 
               
               
                   
                 IMGT 
                 ----SA 
                 50-51 
                 2 
                 402 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQGGSFPYT 
                 89-97 
                 9 
                 403 
               
               
                   
                 AbM 
                 QQGGSFPYT 
                 89-97 
                 9 
                 404 
               
               
                   
                 Kabat 
                 QQGGSFPYT 
                 89-97 
                 9 
                 405 
               
               
                   
                 Contact 
                 QQGGSFPY- 
                 89-96 
                 8 
                 406 
               
               
                   
                 IMGT 
                 QQGGSFPYT 
                 89-97 
                 9 
                 407 
               
               
                   
               
            
           
           
               
            
               
                 P9-06 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFAYY 
                 26-32 
                 7 
                 408 
               
               
                   
                 AbM 
                 GFTFAYYGIH 
                 26-35 
                 10 
                 409 
               
               
                   
                 Kabat 
                 YYGIH 
                 31-35 
                 5 
                 410 
               
               
                   
                 Contact 
                 AYYGIH 
                 30-35 
                 6 
                 411 
               
               
                   
                 IMGT 
                 GFTFAYYG-- 
                 26-33 
                 8 
                 412 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 YPHCYI 
                 52-57 
                 6 
                 413 
               
               
                   
                 AbM 
                 ---YIYPHGYITD 
                 50-59 
                 10 
                 414 
               
               
                   
                 Kabat 
                 ---YIYPHGYITDYADSVKG 
                 50-66 
                 17 
                 415 
               
               
                   
                 Contact 
                 WVAYIYPHGYITD 
                 47-59 
                 13 
                 416 
               
               
                   
                 IMGT 
                 IYPHGYIT 
                 51-58 
                 8 
                 417 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --DSGVPYYWAVLDY 
                 99-111 
                 13 
                 418 
               
               
                   
                 AbM 
                 --DSGVPYYWAVLDY 
                 99-111 
                 13 
                 419 
               
               
                   
                 Kabat 
                 --DSGVPYYWAVLDY 
                 99-111 
                 13 
                 420 
               
               
                   
                 Contact 
                 ARDSGVPYYWAVLD- 
                 97-110 
                 14 
                 421 
               
               
                   
                 IMGT 
                 ARDSGVPYYWAVLDY 
                 97-111 
                 15 
                 422 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 423 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 424 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 425 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 426 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 427 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 ----SASSLYS 
                 50-56 
                 7 
                 428 
               
               
                   
                 AbM 
                 ----SASSLYS 
                 50-56 
                 7 
                 429 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 430 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 431 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 432 
               
               
                 CDR-L3 
                 Chothia 
                 QQHFSSPGT 
                 89-97 
                 9 
                 433 
               
               
                   
               
               
                   
                 AbM 
                 QQHFSSPGT 
                 89-97 
                 9 
                 434 
               
               
                   
                 Kabat 
                 QQHFSSPGT 
                 89-97 
                 9 
                 435 
               
               
                   
                 Contact 
                 QQHFSSPG- 
                 89-96 
                 8 
                 436 
               
               
                   
                 IMGT 
                 QQHFSSPGT 
                 89-97 
                 9 
                 437 
               
               
                   
               
            
           
           
               
            
               
                 P9-07 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY 
                 26-32 
                 7 
                 438 
               
               
                   
                 AbM 
                 GFTFSSYYIH 
                 26-35 
                 10 
                 439 
               
               
                   
                 Kabat 
                 SYYIH 
                 31-35 
                 5 
                 440 
               
               
                   
                 Contact 
                 SSYYIH 
                 30-35 
                 6 
                 441 
               
               
                   
                 IMGT 
                 GFTFSSYY-- 
                 26-33 
                 8 
                 442 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 SPYGGD 
                 52-57 
                 6 
                 443 
               
               
                   
                 AbM 
                 ---YISPYGGDTS 
                 50-59 
                 10 
                 444 
               
               
                   
                 Kabat 
                 ---YISPYGGDTSYADSVKG 
                 50-66 
                 17 
                 445 
               
               
                   
                 Contact 
                 WVAYISPYGGDTS 
                 47-59 
                 13 
                 446 
               
               
                   
                 IMGT 
                 ----ISPYGGDT 
                 51-58 
                 8 
                 447 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --DSYMSYIDGFDY 
                 99-110 
                 12 
                 448 
               
               
                   
                 AbM 
                 --DSYMSYIDGFDY 
                 99-110 
                 12 
                 449 
               
               
                   
                 Kabat 
                 --DSYMSYIDGFDY 
                 99-110 
                 12 
                 450 
               
               
                   
                 Contact 
                 ARDSYMSYIDGFD- 
                 97-109 
                 13 
                 451 
               
               
                   
                 IMGT 
                 ARDSYMSYIDGFDY 
                 97-110 
                 14 
                 452 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 453 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 454 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 455 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 456 
               
               
                   
                 IMGT 
                 ---QSVSSA---- 
                 27-32 
                 6 
                 457 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 458 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 459 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 460 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 461 
               
               
                   
                 IMGT 
                 ----SA 
                 50-51 
                 2 
                 462 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQWTSTLWT 
                 89-97 
                 9 
                 463 
               
               
                   
                 AbM 
                 QQWTSTLWT 
                 89-97 
                 9 
                 464 
               
               
                   
                 Kabat 
                 QQWTSTLWT 
                 89-97 
                 9 
                 465 
               
               
                   
                 Contact 
                 QQWTSTLW- 
                 89-96 
                 8 
                 466 
               
               
                   
                 IMGT 
                 QQWTSTLWT 
                 89-97 
                 9 
                 467 
               
               
                   
               
            
           
           
               
            
               
                 P9-11 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY 
                 26-32 
                 7 
                 468 
               
               
                   
                 AbM 
                 GFTFSSYYIH 
                 26-35 
                 10 
                 469 
               
               
                   
                 Kabat 
                 SYYIH 
                 31-35 
                 5 
                 470 
               
               
                   
                 Contact 
                 SSYYIH 
                 30-35 
                 6 
                 471 
               
               
                   
                 IMGT 
                 GFTFSSYY-- 
                 26-33 
                 8 
                 472 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 SPSGGY 
                 52-57 
                 6 
                 473 
               
               
                   
                 AbM 
                 ---YISPSGGYTY 
                 50-59 
                 10 
                 474 
               
               
                   
                 Kabat 
                 ---YISPSGGYTYYADSVKG 
                 50-66 
                 17 
                 475 
               
               
                   
                 Contact 
                 WVAYISPSGGYTY 
                 47-59 
                 13 
                 476 
               
               
                   
                 IMGT 
                 ----ISPSGGYT 
                 51-58 
                 8 
                 477 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --GAVLYSSAMDY 
                 99-109 
                 11 
                 478 
               
               
                   
                 AbM 
                 --GAVLYSSAMDY 
                 99-109 
                 11 
                 479 
               
               
                   
                 Kabat 
                 --GAVLYSSAMDY 
                 99-109 
                 11 
                 480 
               
               
                   
                 Contact 
                 ARGAVLYSSAMD- 
                 97-108 
                 12 
                 481 
               
               
                   
                 IMGT 
                 ARGAVLYSSAMDY 
                 97-109 
                 13 
                 482 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 483 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 484 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 485 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 486 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 487 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 488 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 489 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 490 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 491 
               
               
                   
                 IMGT 
                 ----SA 
                 50-51 
                 2 
                 492 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQYYPSPST 
                 89-97 
                 9 
                 493 
               
               
                   
                 AbM 
                 QQYYPSPST 
                 89-97 
                 9 
                 494 
               
               
                   
                 Kabat 
                 QQYYPSPST 
                 89-97 
                 9 
                 495 
               
               
                   
                 Contact 
                 QQYYPSPS- 
                 89-96 
                 8 
                 496 
               
               
                   
                 IMGT 
                 QQYYPSPST 
                 89-97 
                 9 
                 497 
               
               
                   
               
            
           
           
               
            
               
                 P9-12 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY--- 
                 26-32 
                 7 
                 498 
               
               
                   
                 AbM 
                 GFTFSSYWTH 
                 26-35 
                 10 
                 499 
               
               
                   
                 Kabat 
                 SYWTH 
                 31-35 
                 5 
                 500 
               
               
                   
                 Contact 
                 SSYWIH 
                 30-35 
                 6 
                 501 
               
               
                   
                 IMGT 
                 GFTFSSYW-- 
                 26-33 
                 8 
                 502 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 ASYFGQ 
                 52-57 
                 6 
                 503 
               
               
                   
                 AbM 
                 ---SIASYFGQTY 
                 50-59 
                 10 
                 504 
               
               
                   
                 Kabat 
                 ---SIASYFGQTYYADSVKG 
                 50-66 
                 17 
                 505 
               
               
                   
                 Contact 
                 WVASIASYFGQTY 
                 47-59 
                 13 
                 506 
               
               
                   
                 IMGT 
                 ----IASYFGQT 
                 51-58 
                 8 
                 507 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --GFGYAAMDY 
                 99-107 
                 9 
                 508 
               
               
                   
                 AbM 
                 --GFGYAAMDY 
                 99-107 
                 9 
                 509 
               
               
                   
                 Kabat 
                 --GFGYAAMDY 
                 99-107 
                 9 
                 510 
               
               
                   
                 Contact 
                 ARGFGYAAMD- 
                 97-106 
                 10 
                 511 
               
               
                   
                 IMGT 
                 ARGFGYAAMDY 
                 97-107 
                 11 
                 512 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 513 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 514 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 515 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 516 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 517 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 518 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 519 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 520 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 521 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 522 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQEYGRPYT 
                 89-97 
                 9 
                 523 
               
               
                   
                 AbM 
                 QQEYGRPYT 
                 89-97 
                 9 
                 524 
               
               
                   
                 Kabat 
                 QQEYGRPYT 
                 89-97 
                 9 
                 525 
               
               
                   
                 Contact 
                 QQEYGRPY- 
                 89-96 
                 8 
                 526 
               
               
                   
                 IMGT 
                 QQEYGRPYT 
                 89-97 
                 9 
                 527 
               
            
           
           
               
            
               
                 P9-14 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFGSY 
                 26-32 
                 7 
                 528 
               
               
                   
                 AbM 
                 GFTFGSYYIH 
                 26-35 
                 10 
                 529 
               
               
                   
                 Kabat 
                 SYYIH 
                 31-35 
                 5 
                 530 
               
               
                   
                 Contact 
                 ----GSYYIH 
                 30-35 
                 6 
                 531 
               
               
                   
                 IMGT 
                 GFTFGSYY-- 
                 26-33 
                 8 
                 532 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 YPYFSS 
                 52-57 
                 6 
                 533 
               
               
                   
                 AbM 
                 ---DIYPYFSSTY 
                 50-59 
                 10 
                 534 
               
               
                   
                 Kabat 
                 ---DIYPYFSSTYYADSVKG 
                 50-66 
                 17 
                 535 
               
               
                   
                 Contact 
                 WVADIYPYFSSTY 
                 47-59 
                 13 
                 536 
               
               
                   
                 IMGT 
                 ----IYPYFSST 
                 51-58 
                 8 
                 537 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --GSHFGFDY 
                 99-106 
                 8 
                 538 
               
               
                   
                 AbM 
                 --GSHFGFDY 
                 99-106 
                 8 
                 539 
               
               
                   
                 Kabat 
                 --GSHFGFDY 
                 99-106 
                 8 
                 540 
               
               
                   
                 Contact 
                 ARGSHFGFD- 
                 97-105 
                 9 
                 541 
               
               
                   
                 IMGT 
                 ARGSHFGFDY 
                 97-106 
                 10 
                 542 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 543 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 544 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 545 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 546 
               
               
                   
                 IMGT 
                 ---QSVSSA---- 
                 27-32 
                 6 
                 547 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 ----SASSLYS 
                 50-56 
                 7 
                 548 
               
               
                   
                 AbM 
                 ----SASSLYS 
                 50-56 
                 7 
                 549 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 550 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 551 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 552 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQHASGPLT 
                 89-97 
                 9 
                 553 
               
               
                   
                 AbM 
                 QQHASGPLT 
                 89-97 
                 9 
                 554 
               
               
                   
                 Kabat 
                 QQHASGPLT 
                 89-97 
                 9 
                 555 
               
               
                   
                 Contact 
                 QQHASGPL- 
                 89-96 
                 8 
                 556 
               
               
                   
                 IMGT 
                 QQHASGPLT 
                 89-97 
                 9 
                 557 
               
               
                   
               
            
           
           
               
            
               
                 P9-23 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSQY--- 
                 26-32 
                 7 
                 558 
               
               
                   
                 AbM 
                 GFTFSQYYIH 
                 26-35 
                 10 
                 559 
               
               
                   
                 Kabat 
                 QYYIH 
                 31-35 
                 5 
                 560 
               
               
                   
                 Contact 
                 SQYYIH 
                 30-35 
                 6 
                 561 
               
               
                   
                 IMGT 
                 GFTFSQYY-- 
                 26-33 
                 8 
                 562 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 YPRGGY 
                 52-57 
                 6 
                 563 
               
               
                   
                 AbM 
                 ---TIYPRGGYTF 
                 50-59 
                 10 
                 564 
               
               
                   
                 Kabat 
                 ---TIYPRGGYTFYADSVKG 
                 50-66 
                 17 
                 565 
               
               
                   
                 Contact 
                 WVATIYPRGGYTF 
                 47-59 
                 13 
                 566 
               
               
                   
                 IMGT 
                 IYPRGGYT 
                 51-58 
                 8 
                 567 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --KSYWGMDY 
                 99-106 
                 8 
                 568 
               
               
                   
                 AbM 
                 --KSYWGMDY 
                 99-106 
                 8 
                 569 
               
               
                   
                 Kabat 
                 --KSYWGMDY 
                 99-106 
                 8 
                 570 
               
               
                   
                 Contact 
                 ARKSYWGMD- 
                 97-105 
                 9 
                 571 
               
               
                   
                 IMGT 
                 ARKSYWGMDY 
                 97-106 
                 10 
                 572 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 573 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 574 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 575 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 576 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 577 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 578 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 579 
               
               
                   
                 Kabat 
                 ----SASSLYS 
                 50-56 
                 7 
                 580 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 581 
               
               
                   
                 IMGT 
                 ----SA 
                 50-51 
                 2 
                 582 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQWSVYLET 
                 89-97 
                 9 
                 583 
               
               
                   
                 AbM 
                 QQWSVYLET 
                 89-97 
                 9 
                 584 
               
               
                   
                 Kabat 
                 QQWSVYLET 
                 89-97 
                 9 
                 585 
               
               
                   
                 Contact 
                 QQWSVYLE- 
                 89-96 
                 8 
                 586 
               
               
                   
                 IMGT 
                 QQWSVYLET 
                 89-97 
                 9 
                 587 
               
               
                   
               
            
           
           
               
            
               
                 P9-24 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY--- 
                 26-32 
                 7 
                 588 
               
               
                   
                 AbM 
                 GFTFSSYFIH 
                 26-35 
                 10 
                 589 
               
               
                   
                 Kabat 
                 SYFIH 
                 31-35 
                 5 
                 590 
               
               
                   
                 Contact 
                 SSYFIH 
                 30-35 
                 6 
                 591 
               
               
                   
                 IMGT 
                 GFTFSSYF-- 
                 26-33 
                 8 
                 592 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 YPTSHS 
                 52-57 
                 6 
                 593 
               
               
                   
                 AbM 
                 ---SIYPTSHSTS 
                 50-59 
                 10 
                 594 
               
               
                   
                 Kabat 
                 ---SIYPTSHSTSYADSVKG 
                 50-66 
                 17 
                 595 
               
               
                   
                 Contact 
                 WVASIYPTSHSTS 
                 47-59 
                 13 
                 596 
               
               
                   
                 IMGT 
                 IYPTSHST 
                 51-58 
                 8 
                 597 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --LGYPGVMDY 
                 99-107 
                 9 
                 598 
               
               
                   
                 AbM 
                 --LGYPGVMDY 
                 99-107 
                 9 
                 599 
               
               
                   
                 Kabat 
                 --LGYPGVMDY 
                 99-107 
                 9 
                 600 
               
               
                   
                 Contact 
                 ARLGYPGVMD- 
                 97-106 
                 10 
                 601 
               
               
                   
                 IMGT 
                 ARLGYPGVMDY 
                 97-107 
                 11 
                 602 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 603 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 604 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 605 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 606 
               
               
                   
                 IMGT 
                 ---QSVSSA---- 
                 27-32 
                 6 
                 607 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 ----SASSLYS 
                 50-56 
                 7 
                 608 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 609 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 610 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 611 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 612 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQVDSRLAT 
                 89-97 
                 9 
                 613 
               
               
                   
                 AbM 
                 QQVDSRLAT 
                 89-97 
                 9 
                 614 
               
               
                   
                 Kabat 
                 QQVDSRLAT 
                 89-97 
                 9 
                 615 
               
               
                   
                 Contact 
                 QQVDSRLA- 
                 89-96 
                 8 
                 616 
               
               
                   
                 IMGT 
                 QQVDSRLAT 
                 89-97 
                 9 
                 617 
               
               
                   
               
            
           
           
               
            
               
                 P9-25 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY 
                 26-32 
                 7 
                 618 
               
               
                   
                 AbM 
                 GFTFSSYYIH 
                 26-35 
                 10 
                 619 
               
               
                   
                 Kabat 
                 SYYIH 
                 31-35 
                 5 
                 620 
               
               
                   
                 Contact 
                 SSYYIH 
                 30-35 
                 6 
                 621 
               
               
                   
                 IMGT 
                 GFTFSSYY-- 
                 26-33 
                 8 
                 622 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 YPYGSY 
                 52-57 
                 6 
                 623 
               
               
                   
                 AbM 
                 ---SIYPYGSYTY 
                 50-59 
                 10 
                 624 
               
               
                   
                 Kabat 
                 ---SIYPYGSYTYYADSVKG 
                 50-66 
                 17 
                 625 
               
               
                   
                 Contact 
                 WVASIYPYGSYTY 
                 47-59 
                 13 
                 626 
               
               
                   
                 IMGT 
                 IYPYGSYT 
                 51-58 
                 8 
                 627 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --LGYSSGMDY 
                 99-107 
                 9 
                 628 
               
               
                   
                 AbM 
                 --LGYSSGMDY 
                 99-107 
                 9 
                 629 
               
               
                   
                 Kabat 
                 --LGYSSGMDY 
                 99-107 
                 9 
                 630 
               
               
                   
                 Contact 
                 ARLGYSSGMD- 
                 97-106 
                 10 
                 631 
               
               
                   
                 IMGT 
                 ARLGYSSGMDY 
                 97-107 
                 11 
                 632 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 633 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 634 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 635 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 636 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 637 
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 638 
               
               
                   
               
               
                   
                 AbM 
                 ----SASSLYS 
                 50-56 
                 7 
                 639 
               
               
                   
                 Kabat 
                 ----SASSLYS 
                 50-56 
                 7 
                 640 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 641 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 642 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQWAPDLTT 
                 89-97 
                 9 
                 643 
               
               
                   
                 AbM 
                 QQWAPDLTT 
                 89-97 
                 9 
                 644 
               
               
                   
                 Kabat 
                 QQWAPDLTT 
                 89-97 
                 9 
                 645 
               
               
                   
                 Contact 
                 QQWAPDLT- 
                 89-96 
                 8 
                 646 
               
               
                   
                 IMGT 
                 QQWAPDLTT 
                 89-97 
                 9 
                 647 
               
               
                   
               
            
           
           
               
            
               
                 P9-26 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY 
                 26-32 
                 7 
                 648 
               
               
                   
                 AbM 
                 GFTFSSYYIH 
                 26-35 
                 10 
                 649 
               
               
                   
                 Kabat 
                 SYYIH 
                 31-35 
                 5 
                 650 
               
               
                   
                 Contact 
                 SSYYIH 
                 30-35 
                 6 
                 651 
               
               
                   
                 IMGT 
                 GFTFSSYY-- 
                 26-33 
                 8 
                 652 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 ESSSSH 
                 52-57 
                 6 
                 653 
               
               
                   
                 AbM 
                 ---WIESSSSHTD 
                 50-59 
                 10 
                 654 
               
               
                   
                 Kabat 
                 ---WIESSSSHTDYADSVKG 
                 50-66 
                 17 
                 655 
               
               
                   
                 Contact 
                 WVAWIESSSSHTD 
                 47-59 
                 13 
                 656 
               
               
                   
                 IMGT 
                 ----IESSSSHT 
                 51-58 
                 8 
                 657 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --LPYKYYYLGVFDY 
                 99-111 
                 13 
                 658 
               
               
                   
                 AbM 
                 --LPYKYYYLGVFDY 
                 99-111 
                 13 
                 659 
               
               
                   
                 Kabat 
                 --LPYKYYYLGVFDY 
                 99-111 
                 13 
                 660 
               
               
                   
                 Contact 
                 ARLPYKYYYLGVFD- 
                 97-110 
                 14 
                 661 
               
               
                   
                 IMGT 
                 ARLPYKYYYLGVFDY 
                 97-111 
                 15 
                 662 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 663 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 664 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 665 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 666 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 667 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 668 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 669 
               
               
                   
                 Kabat 
                 ----SASSLYS 
                 50-56 
                 7 
                 670 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 671 
               
               
                   
                 IMGT 
                 ----SA 
                 50-51 
                 2 
                 672 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQYSSSLYT 
                 89-97 
                 9 
                 673 
               
               
                   
                 AbM 
                 QQYSSSLYT 
                 89-97 
                 9 
                 674 
               
               
                   
                 Kabat 
                 QQYSSSLYT 
                 89-97 
                 9 
                 675 
               
               
                   
                 Contact 
                 QQYSSSLY- 
                 89-96 
                 8 
                 676 
               
               
                   
                 IMGT 
                 QQYSSSLYT 
                 89-97 
                 9 
                 677 
               
               
                   
               
            
           
           
               
            
               
                 P9-29 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY 
                 26-32 
                 7 
                 678 
               
               
                   
                 AbM 
                 GFTFSSYAIH 
                 26-35 
                 10 
                 679 
               
               
                   
                 Kabat 
                 SYAIH 
                 31-35 
                 5 
                 680 
               
               
                   
                 Contact 
                 SSYAIH 
                 30-35 
                 6 
                 681 
               
               
                   
                 IMGT 
                 GFTFSSYA-- 
                 26-33 
                 8 
                 682 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 APGGSY 
                 52-57 
                 6 
                 683 
               
               
                   
                 AbM 
                 ---YIAPGGSYTY 
                 50-59 
                 10 
                 684 
               
               
                   
                 Kabat 
                 ---YIAPGGSYTYYADSVKG 
                 50-66 
                 17 
                 685 
               
               
                   
                 Contact 
                 WVAYIAPGGSYTY 
                 47-59 
                 13 
                 686 
               
               
                   
                 IMGT 
                 IAPGGSYT 
                 51-58 
                 8 
                 687 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --LSYPGVMDY 
                 99-107 
                 9 
                 688 
               
               
                   
                 AbM 
                 --LSYPGVMDY 
                 99-107 
                 9 
                 689 
               
               
                   
                 Kabat 
                 --LSYPGVMDY 
                 99-107 
                 9 
                 690 
               
               
                   
                 Contact 
                 ARLSYPGVMD- 
                 97-106 
                 10 
                 691 
               
               
                   
                 IMGT 
                 ARLSYPGVMDY 
                 97-107 
                 11 
                 692 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 693 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 694 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 695 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 696 
               
               
                   
                 IMGT 
                 ---QSVSSA---- 
                 27-32 
                 6 
                 697 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 698 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 699 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 700 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 701 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 702 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQGYSSLLT 
                 89-97 
                 9 
                 703 
               
               
                   
                 AbM 
                 QQGYSSLLT 
                 89-97 
                 9 
                 704 
               
               
                   
                 Kabat 
                 QQGYSSLLT 
                 89-97 
                 9 
                 705 
               
               
                   
                 Contact 
                 QQGYSSLL- 
                 89-96 
                 8 
                 706 
               
               
                   
                 IMGT 
                 QQGYSSLLT 
                 89-97 
                 9 
                 707 
               
               
                   
               
            
           
           
               
            
               
                 P9-30 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSTY--- 
                 26-32 
                 7 
                 708 
               
               
                   
                 AbM 
                 GFTFSTYTIH 
                 26-35 
                 10 
                 709 
               
               
                   
                 Kabat 
                 TYTIH 
                 31-35 
                 5 
                 710 
               
               
                   
                 Contact 
                 STYTIH 
                 30-35 
                 6 
                 711 
               
               
                   
                 IMGT 
                 GFTFSTYT-- 
                 26-33 
                 8 
                 712 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 YPKGGS 
                 52-57 
                 6 
                 713 
               
               
                   
                 AbM 
                 ---WIYPKGGSTD 
                 50-59 
                 10 
                 714 
               
               
                   
                 Kabat 
                 ---WIYPKGGSTDYADSVKG 
                 50-66 
                 17 
                 715 
               
               
                   
                 Contact 
                 WVAWIYPKGGSTD 
                 47-59 
                 13 
                 716 
               
               
                   
                 IMGT 
                 ----IYPKGGST 
                 51-58 
                 8 
                 717 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --PSGYGFDY 
                 99-106 
                 8 
                 718 
               
               
                   
                 AbM 
                 --PSGYGFDY 
                 99-106 
                 8 
                 719 
               
               
                   
                 Kabat 
                 --PSGYGFDY 
                 99-106 
                 8 
                 720 
               
               
                   
                 Contact 
                 ARPSGYGFD- 
                 97-105 
                 9 
                 721 
               
               
                   
                 IMGT 
                 ARPSGYGFDY 
                 97-106 
                 10 
                 722 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 723 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 724 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 725 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 726 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 727 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 728 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 729 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 730 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 731 
               
               
                   
                 IMGT 
                 ----SA 
                 50-51 
                 2 
                 732 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQYLSSPYT 
                 89-97 
                 9 
                 733 
               
               
                   
                 AbM 
                 QQYLSSPYT 
                 89-97 
                 9 
                 734 
               
               
                   
                 Kabat 
                 QQYLSSPYT 
                 89-97 
                 9 
                 735 
               
               
                   
                 Contact 
                 QQYLSSPY- 
                 89-96 
                 8 
                 736 
               
               
                   
                 IMGT 
                 QQYLSSPYT 
                 89-97 
                 9 
                 737 
               
               
                   
               
            
           
           
               
            
               
                 P9-34 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSTY 
                 26-32 
                 7 
                 738 
               
               
                   
                 AbM 
                 GFTFSTYFIH 
                 26-35 
                 10 
                 739 
               
               
                   
                 Kabat 
                 TYFIH 
                 31-35 
                 5 
                 740 
               
               
                   
                 Contact 
                 ----STYFIH 
                 30-35 
                 6 
                 741 
               
               
                   
                 IMGT 
                 GFTFSTYF-- 
                 26-33 
                 8 
                 742 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 YPQGGY 
                 52-57 
                 6 
                 743 
               
               
                   
                 AbM 
                 ---YIYPQGGYTY 
                 50-59 
                 10 
                 744 
               
               
                   
                 Kabat 
                 ---YIYPQGGYTYYADSVKG 
                 50-66 
                 17 
                 745 
               
               
                   
                 Contact 
                 WVAYIYPQGGYTY 
                 47-59 
                 13 
                 746 
               
               
                   
                 IMGT 
                 IYPQGGYT 
                 51-58 
                 8 
                 747 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --QSYPGVFDY 
                 99-107 
                 9 
                 748 
               
               
                   
                 AbM 
                 --QSYPCVFDY 
                 99-107 
                 9 
                 749 
               
               
                   
                 Kabat 
                 --QSYPGVFDY 
                 99-107 
                 9 
                 750 
               
               
                   
                 Contact 
                 ARQSYPGVFD- 
                 97-106 
                 10 
                 751 
               
               
                   
                 IMGT 
                 ARQSYPGVFDY 
                 97-107 
                 11 
                 752 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 753 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 754 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 755 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 756 
               
               
                   
                 IMGT 
                 ---QSVSSA---- 
                 27-32 
                 6 
                 757 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 ----SASSLYS 
                 50-56 
                 7 
                 758 
               
               
                   
                 AbM 
                 ----SASSLYS 
                 50-56 
                 7 
                 759 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 760 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 761 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 762 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQWTIALTT 
                 89-97 
                 9 
                 763 
               
               
                   
                 AbM 
                 QQWTIALTT 
                 89-97 
                 9 
                 764 
               
               
                   
                 Kabat 
                 QQWTIALTT 
                 89-97 
                 9 
                 765 
               
               
                   
                 Contact 
                 QQWTIALT- 
                 89-96 
                 8 
                 766 
               
               
                   
                 IMGT 
                 QQWTIALTT 
                 89-97 
                 9 
                 767 
               
               
                   
               
            
           
           
               
            
               
                 P9-37 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY--- 
                 26-32 
                 7 
                 768 
               
               
                   
                 AbM 
                 GFTFSSYWIH 
                 26-35 
                 10 
                 769 
               
               
                   
                 Kabat 
                 SYWIH 
                 31-35 
                 5 
                 770 
               
               
                   
                 Contact 
                 SSYWIH 
                 30-35 
                 6 
                 771 
               
               
                   
                 IMGT 
                 GFTFSSYW-- 
                 26-33 
                 8 
                 772 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 DPDYGT 
                 52-57 
                 6 
                 773 
               
               
                   
                 AbM 
                 ---WIDPDYGTTS 
                 50-59 
                 10 
                 774 
               
               
                   
                 Kabat 
                 ---WIDPDYGTTSYADSVKG 
                 50-66 
                 17 
                 775 
               
               
                   
                 Contact 
                 WVAWIDPDYGTTS 
                 47-59 
                 13 
                 776 
               
               
                   
                 IMGT 
                 IDPDYGTT 
                 51-58 
                 8 
                 777 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --SETGAAMDY 
                 99-107 
                 9 
                 778 
               
               
                   
                 AbM 
                 --SETGAAMDY 
                 99-107 
                 9 
                 779 
               
               
                   
                 Kabat 
                 --SETGAAMDY 
                 99-107 
                 9 
                 780 
               
               
                   
                 Contact 
                 ARSETGAAMD- 
                 97-106 
                 10 
                 781 
               
               
                   
                 IMGT 
                 ARSETGAAMDY 
                 97-107 
                 11 
                 782 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 783 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 784 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 785 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 786 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 787 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 788 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 789 
               
               
                   
                 Kabat 
                 ----SASSLYS 
                 50-56 
                 7 
                 790 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 791 
               
               
                   
                 IMGT 
                 ----SA 
                 50-51 
                 2 
                 792 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQGSYFLQT 
                 89-97 
                 9 
                 793 
               
               
                   
                 AbM 
                 QQGSYFLQT 
                 89-97 
                 9 
                 794 
               
               
                   
                 Kabat 
                 QQGSYFLQT 
                 89-97 
                 9 
                 795 
               
               
                   
                 Contact 
                 QQGSYFLQ- 
                 89-96 
                 8 
                 796 
               
               
                   
                 IMGT 
                 QQGSYFLQT 
                 89-97 
                 9 
                 797 
               
               
                   
               
            
           
           
               
            
               
                 P9-40 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFRWY 
                 26-32 
                 7 
                 798 
               
               
                   
                 AbM 
                 GFTFRWYYIH 
                 26-35 
                 10 
                 799 
               
               
                   
                 Kabat 
                 WYYIH 
                 31-35 
                 5 
                 800 
               
               
                   
                 Contact 
                 ----RWYYIH 
                 30-35 
                 6 
                 801 
               
               
                   
                 IMGT 
                 GFTFRWYY-- 
                 26-33 
                 8 
                 802 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 YPDWDY 
                 52-57 
                 6 
                 803 
               
               
                   
                 AbM 
                 ---TIYPDWDYTT 
                 50-59 
                 10 
                 804 
               
               
                   
                 Kabat 
                 ---TIYPDWDYTTYADSVKG 
                 50-66 
                 17 
                 805 
               
               
                   
                 Contact 
                 WVATIYPDWDYTT 
                 47-59 
                 13 
                 806 
               
               
                   
                 IMGT 
                 IYPDWDYT 
                 51-58 
                 8 
                 807 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --SPVTGPYGFDY 
                 99-109 
                 11 
                 808 
               
               
                   
                 AbM 
                 --SPVTGPYGFDY 
                 99-109 
                 11 
                 809 
               
               
                   
                 Kabat 
                 --SPVTGPYGFDY 
                 99-109 
                 11 
                 810 
               
               
                   
                 Contact 
                 ARSPVTGPYGFD- 
                 97-108 
                 12 
                 811 
               
               
                   
                 IMGT 
                 ARSPVTGPYGFDY 
                 97-109 
                 13 
                 812 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 813 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 814 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 815 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 816 
               
               
                   
                 IMGT 
                 ---QSVSSA---- 
                 27-32 
                 6 
                 817 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 ----SASSLYS 
                 50-56 
                 7 
                 818 
               
               
                   
                 AbM 
                 ----SASSLYS 
                 50-56 
                 7 
                 819 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 820 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 821 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 822 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQPTYSLWT 
                 89-97 
                 9 
                 823 
               
               
                   
                 AbM 
                 QQPTYSLWT 
                 89-97 
                 9 
                 824 
               
               
                   
                 Kabat 
                 QQPTYSLWT 
                 89-97 
                 9 
                 825 
               
               
                   
                 Contact 
                 QQPTYSLW- 
                 89-96 
                 8 
                 826 
               
               
                   
                 IMGT 
                 QQPTYSLWT 
                 89-97 
                 9 
                 827 
               
               
                   
               
            
           
           
               
            
               
                 P9-41 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFRYY 
                 26-32 
                 7 
                 828 
               
               
                   
                 AbM 
                 GFTFRYYWIH 
                 26-35 
                 10 
                 829 
               
               
                   
                 Kabat 
                 YYWIH 
                 31-35 
                 5 
                 830 
               
               
                   
                 Contact 
                 RYYWIH 
                 30-35 
                 6 
                 831 
               
               
                   
                 IMGT 
                 GFTFRYYW-- 
                 26-33 
                 8 
                 832 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 YPSSDS 
                 52-57 
                 6 
                 833 
               
               
                   
                 AbM 
                 ---AIYPSSDSTY 
                 50-59 
                 10 
                 834 
               
               
                   
                 Kabat 
                 ---AIYPSSDSTYYADSVKG 
                 50-66 
                 17 
                 835 
               
               
                   
                 Contact 
                 WVAAIYPSSDSTY 
                 47-59 
                 13 
                 836 
               
               
                   
                 IMGT 
                 ----IYPSSDST 
                 51-58 
                 8 
                 837 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --SSPYPYGQGVFDY 
                 99-111 
                 13 
                 838 
               
               
                   
                 AbM 
                 --SSPYPYGQGVFDY 
                 99-111 
                 13 
                 839 
               
               
                   
                 Kabat 
                 --SSPYPYGQGVFDY 
                 99-111 
                 13 
                 840 
               
               
                   
                 Contact 
                 ARSSPYPYGQGVFD- 
                 97-110 
                 14 
                 841 
               
               
                   
                 IMGT 
                 ARSSPYPYGQGVFDY 
                 97-111 
                 15 
                 842 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 843 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 844 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 845 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 846 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 847 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 848 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 849 
               
               
                   
                 Kabat 
                 ----SASSLYS 
                 50-56 
                 7 
                 850 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 851 
               
               
                   
                 IMGT 
                 ----SA 
                 50-51 
                 2 
                 852 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQWYSSLWT 
                 89-97 
                 9 
                 853 
               
               
                   
                 AbM 
                 QQWYSSLWT 
                 89-97 
                 9 
                 854 
               
               
                   
                 Kabat 
                 QQWYSSLWT 
                 89-97 
                 9 
                 855 
               
               
                   
                 Contact 
                 QQWYSSLW- 
                 89-96 
                 8 
                 856 
               
               
                   
                 IMGT 
                 QQWYSSLWT 
                 89-97 
                 9 
                 857 
               
               
                   
               
            
           
           
               
            
               
                 P9-42 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY 
                 26-32 
                 7 
                 858 
               
               
                   
                 AbM 
                 GFTFSSYYIH 
                 26-35 
                 10 
                 859 
               
               
                   
                 Kabat 
                 SYYIH 
                 31-35 
                 5 
                 860 
               
               
                   
                 Contact 
                 ----SSYYTH 
                 30-35 
                 6 
                 861 
               
               
                   
                 IMGT 
                 GFTFSSYY-- 
                 26-33 
                 8 
                 862 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 YSAWGT 
                 52-57 
                 6 
                 863 
               
               
                   
                 AbM 
                 ---AIYSAWGTTY 
                 50-59 
                 10 
                 864 
               
               
                   
                 Kabat 
                 ---AIYSAWGTTYYADSVKG 
                 50-66 
                 17 
                 865 
               
               
                   
                 Contact 
                 WVAAIYSAWGTTY 
                 47-59 
                 13 
                 866 
               
               
                   
                 IMGT 
                 ----IYSAWGTT 
                 51-58 
                 8 
                 867 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --SYGYVFGYYSGMDY 
                 99-112 
                 14 
                 868 
               
               
                   
                 AbM 
                 --SYGYVFGYYSGMDY 
                 99-112 
                 14 
                 869 
               
               
                   
                 Kabat 
                 --SYGYVFGYYSGMDY 
                 99-112 
                 14 
                 870 
               
               
                   
                 Contact 
                 ARSYGYVFGYYSGMD- 
                 97-111 
                 15 
                 871 
               
               
                   
                 IMGT 
                 ARSYGYVFGYYSGMDY 
                 97-112 
                 16 
                 872 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 873 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 874 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 875 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 876 
               
               
                   
                 IMGT 
                 ---QSVSSA---- 
                 27-32 
                 6 
                 877 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 878 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 879 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 880 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 881 
               
               
                   
                 IMGT 
                 ----SA 
                 50-51 
                 2 
                 882 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQWSSDLVT 
                 89-97 
                 9 
                 883 
               
               
                   
                 AbM 
                 QQWSSDLVT 
                 89-97 
                 9 
                 884 
               
               
                   
                 Kabat 
                 QQWSSDLVT 
                 89-97 
                 9 
                 885 
               
               
                   
                 Contact 
                 QQWSSDLV- 
                 89-96 
                 8 
                 886 
               
               
                   
                 IMGT 
                 QQWSSDLVT 
                 89-97 
                 9 
                 887 
               
               
                   
               
            
           
           
               
            
               
                 P9-43 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFHSY--- 
                 26-32 
                 7 
                 888 
               
               
                   
                 AbM 
                 GFTFHSYWIH 
                 26-35 
                 10 
                 889 
               
               
                   
                 Kabat 
                 SYWIH 
                 31-35 
                 5 
                 890 
               
               
                   
                 Contact 
                 HSYWIH 
                 30-35 
                 6 
                 891 
               
               
                   
                 IMGT 
                 GFTFHSYW-- 
                 26-33 
                 8 
                 892 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 DSSKFG 
                 52-57 
                 6 
                 893 
               
               
                   
                 AbM 
                 ---RIDSSKFGTY 
                 50-59 
                 10 
                 894 
               
               
                   
                 Kabat 
                 ---RIDSSKFGTYYADSVKG 
                 50-66 
                 17 
                 895 
               
               
                   
                 Contact 
                 WVARIDSSKFGTY 
                 47-59 
                 13 
                 896 
               
               
                   
                 IMGT 
                 IDSSKFGT 
                 51-58 
                 8 
                 897 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --SYIDYPVSPAVFDY 
                 99-112 
                 14 
                 898 
               
               
                   
                 AbM 
                 --SYIDYPVSPAVFDY 
                 99-112 
                 14 
                 899 
               
               
                   
                 Kabat 
                 --SYIDYPVSPAVFDY 
                 99-112 
                 14 
                 900 
               
               
                   
                 Contact 
                 ARSYIDYPVSPAVFD- 
                 97-111 
                 15 
                 901 
               
               
                   
                 IMGT 
                 ARSYIDYPVSPAVFDY 
                 97-112 
                 16 
                 902 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 903 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 904 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 905 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 906 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 907 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 ----SASSLYS 
                 50-56 
                 7 
                 908 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 909 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 910 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 911 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 912 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQVYFSPYT 
                 89-97 
                 9 
                 913 
               
               
                   
                 AbM 
                 QQVYFSPYT 
                 89-97 
                 9 
                 914 
               
               
                   
                 Kabat 
                 QQVYFSPYT 
                 89-97 
                 9 
                 915 
               
               
                   
                 Contact 
                 QQVYFSPY- 
                 89-96 
                 8 
                 916 
               
               
                   
                 IMGT 
                 QQVYFSPYT 
                 89-97 
                 9 
                 917 
               
               
                   
               
            
           
           
               
            
               
                 P9-44 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSYY 
                 26-32 
                 7 
                 918 
               
               
                   
                 AbM 
                 GFTFSYYWIH 
                 26-35 
                 10 
                 919 
               
               
                   
                 Kabat 
                 YYWIH 
                 31-35 
                 5 
                 920 
               
               
                   
                 Contact 
                 ----SYYWIH 
                 30-35 
                 6 
                 921 
               
               
                   
                 IMGT 
                 GFTFSYYW-- 
                 26-33 
                 8 
                 922 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 SPSGSY 
                 52-57 
                 6 
                 923 
               
               
                   
                 AbM 
                 ---AISPSGSYTS 
                 50-59 
                 10 
                 924 
               
               
                   
                 Kabat 
                 ---AISPSGSYTSYADSVKG 
                 50-66 
                 17 
                 925 
               
               
                   
                 Contact 
                 WVAAISPSGSYTS 
                 47-59 
                 13 
                 926 
               
               
                   
                 IMGT 
                 ----ISPSGSYT 
                 51-58 
                 8 
                 927 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --SYYRFRTPYTVMDY 
                 99-112 
                 14 
                 928 
               
               
                   
                 AbM 
                 --SYYRFRTPYTVMDY 
                 99-112 
                 14 
                 929 
               
               
                   
                 Kabat 
                 --SYYRFRTPYTVMDY 
                 99-112 
                 14 
                 930 
               
               
                   
                 Contact 
                 ARSYYRFRTPYTVMD- 
                 97-111 
                 15 
                 931 
               
               
                   
                 IMGT 
                 ARSYYRFRTPYTVMDY 
                 97-112 
                 16 
                 932 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 933 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 934 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 935 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 936 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 937 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 938 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 939 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 940 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 941 
               
               
                   
                 IMGT 
                 ----SA 
                 50-51 
                 2 
                 942 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQGIDSPET 
                 89-97 
                 9 
                 943 
               
               
                   
                 AbM 
                 QQGIDSPET 
                 89-97 
                 9 
                 944 
               
               
                   
                 Kabat 
                 QQGIDSPET 
                 89-97 
                 9 
                 945 
               
               
                   
                 Contact 
                 QQGIDSPE- 
                 89-96 
                 8 
                 946 
               
               
                   
                 IMGT 
                 QQGIDSPET 
                 89-97 
                 9 
                 947 
               
               
                   
               
            
           
           
               
            
               
                 P9-45 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFFSY--- 
                 26-32 
                 7 
                 948 
               
               
                   
                 AbM 
                 GFTFFSYVIH 
                 26-35 
                 10 
                 949 
               
               
                   
                 Kabat 
                 SYVIH 
                 31-35 
                 5 
                 950 
               
               
                   
                 Contact 
                 FSYVIH 
                 30-35 
                 6 
                 951 
               
               
                   
                 IMGT 
                 GFTFFSYV-- 
                 26-33 
                 8 
                 952 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 YPYSGY 
                 52-57 
                 6 
                 953 
               
               
                   
                 AbM 
                 ---AIYPYSGYTT 
                 50-59 
                 10 
                 954 
               
               
                   
                 Kabat 
                 ---AIYPYSGYTTYADSVKG 
                 50-66 
                 17 
                 955 
               
               
                   
                 Contact 
                 WVAAIYPYSGYTT 
                 47-59 
                 13 
                 956 
               
               
                   
                 IMGT 
                 IYPYSGYT 
                 51-58 
                 8 
                 957 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --TKYYDYHVFDY 
                 99-109 
                 11 
                 958 
               
               
                   
                 AbM 
                 --TKYYDYHVFDY 
                 99-109 
                 11 
                 959 
               
               
                   
                 Kabat 
                 --TKYYDYHVFDY 
                 99-109 
                 11 
                 960 
               
               
                   
                 Contact 
                 ARTKYYDYHVFD- 
                 97-108 
                 12 
                 961 
               
               
                   
                 IMGT 
                 ARTKYYDYHVFDY 
                 97-109 
                 13 
                 962 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 963 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 964 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 965 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 966 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 967 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 ----SASSLYS 
                 50-56 
                 7 
                 968 
               
               
                   
                 AbM 
                 ----SASSLYS 
                 50-56 
                 7 
                 969 
               
               
                   
                 Kabat 
                 ----SASSLYS 
                 50-56 
                 7 
                 970 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 971 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 972 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQGWDSLVT 
                 89-97 
                 9 
                 973 
               
               
                   
                 AbM 
                 QQGWDSLVT 
                 89-97 
                 9 
                 974 
               
               
                   
                 Kabat 
                 QQGWDSLVT 
                 89-97 
                 9 
                 975 
               
               
                   
                 Contact 
                 QQGWDSLV- 
                 89-96 
                 8 
                 976 
               
               
                   
                 IMGT 
                 QQGWDSLVT 
                 89-97 
                 9 
                 977 
               
               
                   
               
            
           
           
               
            
               
                 P9-46 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSRY 
                 26-32 
                 7 
                 978 
               
               
                   
                 AbM 
                 GFTFSRYYIH 
                 26-35 
                 10 
                 979 
               
               
                   
                 Kabat 
                 RYYIH 
                 31-35 
                 5 
                 980 
               
               
                   
                 Contact 
                 ----SRYYIH 
                 30-35 
                 6 
                 981 
               
               
                   
                 IMGT 
                 GFTFSRYY-- 
                 26-33 
                 8 
                 982 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 SSDSGY 
                 52-57 
                 6 
                 983 
               
               
                   
                 AbM 
                 ---FISSDSGYTQ 
                 50-59 
                 10 
                 984 
               
               
                   
                 Kabat 
                 ---FISSDSGYTQYADSVKG 
                 50-66 
                 17 
                 985 
               
               
                   
                 Contact 
                 WVAFISSDSGYTQ 
                 47-59 
                 13 
                 986 
               
               
                   
                 IMGT 
                 ISSDSGYT 
                 51-58 
                 8 
                 987 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --TMSYSALDY 
                 99-107 
                 9 
                 988 
               
               
                   
                 AbM 
                 --TMSYSALDY 
                 99-107 
                 9 
                 989 
               
               
                   
                 Kabat 
                 --TMSYSALDY 
                 99-107 
                 9 
                 990 
               
               
                   
                 Contact 
                 ARTMSYSALD- 
                 97-106 
                 10 
                 991 
               
               
                   
                 IMGT 
                 ARTMSYSALDY 
                 97-107 
                 11 
                 992 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 993 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 994 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 995 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 996 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 997 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 998 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 999 
               
               
                   
                 Kabat 
                 ----SASSLYS 
                 50-56 
                 7 
                 1000 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 1001 
               
               
                   
                 IMGT 
                 ----SA 
                 50-51 
                 2 
                 1002 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQYWWSPET 
                 89-97 
                 9 
                 1003 
               
               
                   
                 AbM 
                 QQYWWSPET 
                 89-97 
                 9 
                 1004 
               
               
                   
                 Kabat 
                 QQYWWSPET 
                 89-97 
                 9 
                 1005 
               
               
                   
                 Contact 
                 QQYWWSPE- 
                 89-96 
                 8 
                 1006 
               
               
                   
                 IMGT 
                 QQYWWSPET 
                 89-97 
                 9 
                 1007 
               
               
                   
               
            
           
           
               
            
               
                 P9-50 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY 
                 26-32 
                 7 
                 1008 
               
               
                   
                 AbM 
                 GFTFSSYVIH 
                 26-35 
                 10 
                 1009 
               
               
                   
                 Kabat 
                 SYVIH 
                 31-35 
                 5 
                 1010 
               
               
                   
                 Contact 
                 ----SSYVIH 
                 30-35 
                 6 
                 1011 
               
               
                   
                 IMGT 
                 GFTFSSYV-- 
                 26-33 
                 8 
                 1012 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 YSSGGY 
                 52-57 
                 6 
                 1013 
               
               
                   
                 AbM 
                 ---LIYSSGGYTQ 
                 50-59 
                 10 
                 1014 
               
               
                   
                 Kabat 
                 ---LIYSSGGYTQYADSVKG 
                 50-66 
                 17 
                 1015 
               
               
                   
                 Contact 
                 WVALIYSSGGYTQ 
                 47-59 
                 13 
                 1016 
               
               
                   
                 IMGT 
                 IYSSGGYT 
                 51-58 
                 8 
                 1017 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --VGTTYPSRYLEALDY 
                 99-113 
                 15 
                 1018 
               
               
                   
                 AbM 
                 --VGTTYPSRYLEALDY 
                 99-113 
                 15 
                 1019 
               
               
                   
                 Kabat 
                 --VGTTYPSRYLEALDY 
                 99-113 
                 15 
                 1020 
               
               
                   
                 Contact 
                 ARVGTTYPSRYLEALD- 
                 97-112 
                 16 
                 1021 
               
               
                   
                 IMGT 
                 ARVGTTYPSRYLEALDY 
                 97-113 
                 17 
                 1022 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1023 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1024 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1025 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 1026 
               
               
                   
                 IMGT 
                 ---QSVSSA---- 
                 27-32 
                 6 
                 1027 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 ----SASSLYS 
                 50-56 
                 7 
                 1028 
               
               
                   
                 AbM 
                 ----SASSLYS 
                 50-56 
                 7 
                 1029 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 1030 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 1031 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 1032 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQFGSSLPT 
                 89-97 
                 9 
                 1033 
               
               
                   
                 AbM 
                 QQFGSSLPT 
                 89-97 
                 9 
                 1034 
               
               
                   
                 Kabat 
                 QQFGSSLPT 
                 89-97 
                 9 
                 1035 
               
               
                   
                 Contact 
                 QQFGSSLP- 
                 89-96 
                 8 
                 1036 
               
               
                   
                 IMGT 
                 QQFGSSLPT 
                 89-97 
                 9 
                 1037 
               
               
                   
               
            
           
           
               
            
               
                 P9-51 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY 
                 26-32 
                 7 
                 1038 
               
               
                   
                 AbM 
                 GFTFSSYYIH 
                 26-35 
                 10 
                 1039 
               
               
                   
                 Kabat 
                 SYYIH 
                 31-35 
                 5 
                 1040 
               
               
                   
                 Contact 
                 SSYYIH 
                 30-35 
                 6 
                 1041 
               
               
                   
                 IMGT 
                 GFTFSSYY-- 
                 26-33 
                 8 
                 1042 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 YPEGSY 
                 52-57 
                 6 
                 1043 
               
               
                   
                 AbM 
                 ---GIYPEGSYTY 
                 50-59 
                 10 
                 1044 
               
               
                   
                 Kabat 
                 ---GIYPEGSYTYYADSVKG 
                 50-66 
                 17 
                 1045 
               
               
                   
                 Contact 
                 WVAGIYPEGSYTY 
                 47-59 
                 13 
                 1046 
               
               
                   
                 IMGT 
                 IYPEGSYT 
                 51-58 
                 8 
                 1047 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --VGYPGVMDY 
                 99-107 
                 9 
                 1048 
               
               
                   
                 AbM 
                 --VGYPGVMDY 
                 99-107 
                 9 
                 1049 
               
               
                   
                 Kabat 
                 --VGYPGVMDY 
                 99-107 
                 9 
                 1050 
               
               
                   
                 Contact 
                 ARVGYPGVMD- 
                 97-106 
                 10 
                 1051 
               
               
                   
                 IMGT 
                 ARVGYPGVMDY 
                 97-107 
                 11 
                 1052 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1053 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1054 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1055 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 1056 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 1057 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 1058 
               
               
                   
                 AbM 
                 ----SASSLYS 
                 50-56 
                 7 
                 1059 
               
               
                   
                 Kabat 
                 ----SASSLYS 
                 50-56 
                 7 
                 1060 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 1061 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 1062 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQWGSSLAT 
                 89-97 
                 9 
                 1063 
               
               
                   
                 AbM 
                 QQWGSSLAT 
                 89-97 
                 9 
                 1064 
               
               
                   
                 Kabat 
                 QQWGSSLAT 
                 89-97 
                 9 
                 1065 
               
               
                   
                 Contact 
                 QQWGSSLA- 
                 89-96 
                 8 
                 1066 
               
               
                   
                 IMGT 
                 QQWGSSLAT 
                 89-97 
                 9 
                 1067 
               
               
                   
               
            
           
           
               
            
               
                 P9-52 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSTY 
                 26-32 
                 7 
                 1068 
               
               
                   
                 AbM 
                 GFTFSTYLIH 
                 26-35 
                 10 
                 1069 
               
               
                   
                 Kabat 
                 TYLIH 
                 31-35 
                 5 
                 1070 
               
               
                   
                 Contact 
                 ----STYLIH 
                 30-35 
                 6 
                 1071 
               
               
                   
                 IMGT 
                 GFTFSTYL-- 
                 26-33 
                 8 
                 1072 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 TPYSGY 
                 52-57 
                 6 
                 1073 
               
               
                   
                 AbM 
                 ---AITPYSGYTS 
                 50-59 
                 10 
                 1074 
               
               
                   
                 Kabat 
                 ---AITPYSGYTSYADSVKG 
                 50-66 
                 17 
                 1075 
               
               
                   
                 Contact 
                 WVAAITPYSGYTS 
                 47-59 
                 13 
                 1076 
               
               
                   
                 IMGT 
                 ----ITPYSGYT 
                 51-58 
                 8 
                 1077 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --VGYPMVMDY 
                 99-107 
                 9 
                 1078 
               
               
                   
                 AbM 
                 --VGYPMVMDY 
                 99-107 
                 9 
                 1079 
               
               
                   
                 Kabat 
                 --VGYPMVMDY 
                 99-107 
                 9 
                 1080 
               
               
                   
                 Contact 
                 ARVGYPMVMD- 
                 97-106 
                 10 
                 1081 
               
               
                   
                 IMGT 
                 ARVGYPMVMDY 
                 97-107 
                 11 
                 1082 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1083 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1084 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1085 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 1086 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 1087 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 1088 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 1089 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 1090 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 1091 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 1092 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQLDYSLAT 
                 89-97 
                 9 
                 1093 
               
               
                   
                 AbM 
                 QQLDYSLAT 
                 89-97 
                 9 
                 1094 
               
               
                   
                 Kabat 
                 QQLDYSLAT 
                 89-97 
                 9 
                 1095 
               
               
                   
                 Contact 
                 QQLDYSLA- 
                 89-96 
                 8 
                 1096 
               
               
                   
                 IMGT 
                 QQLDYSLAT 
                 89-97 
                 9 
                 1097 
               
               
                   
               
            
           
           
               
            
               
                 P9-53 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSRY--- 
                 26-32 
                 7 
                 1098 
               
               
                   
                 AbM 
                 GFTFSRYQIH 
                 26-35 
                 10 
                 1099 
               
               
                   
                 Kabat 
                 RYQIH 
                 31-35 
                 5 
                 1100 
               
               
                   
                 Contact 
                 SRYQIH 
                 30-35 
                 6 
                 1101 
               
               
                   
                 IMGT 
                 GFTFSRYQ-- 
                 26-33 
                 8 
                 1102 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 ASASGT 
                 52-57 
                 6 
                 1103 
               
               
                   
                 AbM 
                 ---YIASASGTTS 
                 50-59 
                 10 
                 1104 
               
               
                   
                 Kabat 
                 ---YIASASGTTSYADSVKG 
                 50-66 
                 17 
                 1105 
               
               
                   
                 Contact 
                 WVAYIASASGTTS 
                 47-59 
                 13 
                 1106 
               
               
                   
                 IMGT 
                 ----IASASGTT 
                 51-58 
                 8 
                 1107 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --VPYVAMDY 
                 99-106 
                 8 
                 1108 
               
               
                   
                 AbM 
                 --VPYVAMDY 
                 99-106 
                 8 
                 1109 
               
               
                   
                 Kabat 
                 --VPYVAMDY 
                 99-106 
                 8 
                 1110 
               
               
                   
                 Contact 
                 ARVPYVAMD- 
                 97-105 
                 9 
                 1111 
               
               
                   
                 IMGT 
                 ARVPYVAMDY 
                 97-106 
                 10 
                 1112 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1113 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1114 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1115 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 1116 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 1117 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 1118 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 1119 
               
               
                   
                 Kabat 
                 SASSLYS 
                 50-56 
                 7 
                 1120 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 1121 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 1122 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQGYPHPGT 
                 89-97 
                 9 
                 1123 
               
               
                   
                 AbM 
                 QQGYPHPGT 
                 89-97 
                 9 
                 1124 
               
               
                   
                 Kabat 
                 QQGYPHPGT 
                 89-97 
                 9 
                 1125 
               
               
                   
                 Contact 
                 QQGYPHPG- 
                 89-96 
                 8 
                 1126 
               
               
                   
                 IMGT 
                 QQGYPHPGT 
                 89-97 
                 9 
                 1127 
               
               
                   
               
            
           
           
               
            
               
                 P9-56 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY--- 
                 26-32 
                 7 
                 1128 
               
               
                   
                 AbM 
                 GFTFSSYYIH 
                 26-35 
                 10 
                 1129 
               
               
                   
                 Kabat 
                 SYYIH 
                 31-35 
                 5 
                 1130 
               
               
                   
                 Contact 
                 SSYYIH 
                 30-35 
                 6 
                 1131 
               
               
                   
                 IMGT 
                 GFTFSSYY-- 
                 26-33 
                 8 
                 1132 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 DSSGKY 
                 52-57 
                 6 
                 1133 
               
               
                   
                 AbM 
                 ---YIDSSGKYTD 
                 50-59 
                 10 
                 1134 
               
               
                   
                 Kabat 
                 ---YIDSSGKYTDYADSVKG 
                 50-66 
                 17 
                 1135 
               
               
                   
                 Contact 
                 WVAYIDSSGKYTD 
                 47-59 
                 13 
                 1136 
               
               
                   
                 IMGT 
                 ----IDSSGKYT 
                 51-58 
                 8 
                 1137 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --YAYPGVMDY 
                 99-107 
                 9 
                 1138 
               
               
                   
                 AbM 
                 --YAYPGVMDY 
                 99-107 
                 9 
                 1139 
               
               
                   
                 Kabat 
                 --YAYPGVMDY 
                 99-107 
                 9 
                 1140 
               
               
                   
                 Contact 
                 ARYAYPGVMD- 
                 97-106 
                 10 
                 1141 
               
               
                   
                 IMGT 
                 ARYAYPGVMDY 
                 97-107 
                 11 
                 1142 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1143 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1144 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1145 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 1146 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 1147 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 ----SASSLYS 
                 50-56 
                 7 
                 1148 
               
               
                   
                 AbM 
                 ----SASSLYS 
                 50-56 
                 7 
                 1149 
               
               
                   
                 Kabat 
                 ----SASSLYS 
                 50-56 
                 7 
                 1150 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 1151 
               
               
                   
                 IMGT 
                 SA 
                 50-51 
                 2 
                 1152 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQYDYSLWT 
                 89-97 
                 9 
                 1153 
               
               
                   
                 AbM 
                 QQYDYSLWT 
                 89-97 
                 9 
                 1154 
               
               
                   
                 Kabat 
                 QQYDYSLWT 
                 89-97 
                 9 
                 1155 
               
               
                   
                 Contact 
                 QQYDYSLW- 
                 89-96 
                 8 
                 1156 
               
               
                   
                 IMGT 
                 QQYDYSLWT 
                 89-97 
                 9 
                 1157 
               
               
                   
               
            
           
           
               
            
               
                 P9-57 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR-H1 
                 Chothia 
                 GFTFSSY 
                 26-32 
                 7 
                 1158 
               
               
                   
                 AbM 
                 GFTFSSYYIH 
                 26-35 
                 10 
                 1159 
               
               
                   
                 Kabat 
                 SYYIH 
                 31-35 
                 5 
                 1160 
               
               
                   
                 Contact 
                 ----SSYYIH 
                 30-35 
                 6 
                 1161 
               
               
                   
                 IMGT 
                 GFTFSSYY-- 
                 26-33 
                 8 
                 1162 
               
               
                   
               
               
                 CDR-H2 
                 Chothia 
                 YPSGGY 
                 52-57 
                 6 
                 1163 
               
               
                   
                 AbM 
                 ---TIYPSGGYTY 
                 50-59 
                 10 
                 1164 
               
               
                   
                 Kabat 
                 ---TIYPSGGYTYYADSVKG 
                 50-66 
                 17 
                 1165 
               
               
                   
                 Contact 
                 WVATIYPSGGYTY 
                 47-59 
                 13 
                 1166 
               
               
                   
                 IMGT 
                 IYPSGGYT 
                 51-58 
                 8 
                 1167 
               
               
                   
               
               
                 CDR-H3 
                 Chothia 
                 --YSYPGVLDY 
                 99-107 
                 9 
                 1168 
               
               
                   
                 AbM 
                 --YSYPGVLDY 
                 99-107 
                 9 
                 1169 
               
               
                   
                 Kabat 
                 --YSYPGVLDY 
                 99-107 
                 9 
                 1170 
               
               
                   
                 Contact 
                 ARYSYPGVLD- 
                 97-106 
                 10 
                 1171 
               
               
                   
                 IMGT 
                 ARYSYPGVLDY 
                 97-107 
                 11 
                 1172 
               
               
                   
               
               
                 CDR-L1 
                 Chothia 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1173 
               
               
                   
                 AbM 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1174 
               
               
                   
                 Kabat 
                 RASQSVSSAVA-- 
                 24-34 
                 11 
                 1175 
               
               
                   
                 Contact 
                 SSAVAWY 
                 30-36 
                 7 
                 1176 
               
               
                   
                 IMGT 
                 QSVSSA 
                 27-32 
                 6 
                 1177 
               
               
                   
               
               
                 CDR-L2 
                 Chothia 
                 SASSLYS 
                 50-56 
                 7 
                 1178 
               
               
                   
                 AbM 
                 SASSLYS 
                 50-56 
                 7 
                 1179 
               
               
                   
                 Kabat 
                 ----SASSLYS 
                 50-56 
                 7 
                 1180 
               
               
                   
                 Contact 
                 LLIYSASSLY- 
                 46-55 
                 10 
                 1181 
               
               
                   
                 IMGT 
                 ----SA 
                 50-51 
                 2 
                 1182 
               
               
                   
               
               
                 CDR-L3 
                 Chothia 
                 QQSSSFLWT 
                 89-97 
                 9 
                 1183 
               
               
                   
                 AbM 
                 QQSSSFLWT 
                 89-97 
                 9 
                 1184 
               
               
                   
                 Kabat 
                 QQSSSFLWT 
                 89-97 
                 9 
                 1185 
               
               
                   
                 Contact 
                 QQSSSFLW- 
                 89-96 
                 8 
                 1186 
               
               
                   
                 IMGT 
                 QQSSSFLWT 
                 89-97 
                 9 
                 1187 
               
               
                   
               
            
           
         
       
     
     Table 6 presents full immunoglobulin heavy and full immunoglobulin light chain sequences, and the VH and VL sequences, of various ABS candidates formatted into a bivalent monospecific human full-length IgG1 architecture. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Full chain sequences and VH/VL sequences of candidate GAL9 ABS clones and IgG 
               
               
                 formatted antibodies comprising GAL9 ABSs 
               
            
           
           
               
               
               
               
               
            
               
                 ABS 
                   
                   
                   
                   
               
               
                 clone 
                 Full IgG Light Chain 
                 Full IgG Heavy Chain 
                 VH sequence 
                 VL sequence 
               
               
                   
               
               
                 P9-01 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSSYWIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAWI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYWI 
                 TITCRASQSV 
               
               
                   
                 DPDYGTTSYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQQVSDL 
                 LEWVAWIDPD 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARAGIS 
                 LTFGQGTKVEIKRTVAAPS 
                 YGTTSYADSVK 
                 YSASSLYSGV 
               
               
                   
                 YVFDYWGQGTLVTVSS 
                 VFIFPPSDSQLKSGTASVVC 
                 GRFTISADTSKN 
                 PSRFSGSRSG 
               
               
                   
                 ASTKGPSVFPLAPSSKST 
                 LLNNFYPREAKVQWKVDN 
                 TAYLQMNSLRA 
                 TDFTLTISSLQ 
               
               
                   
                 SGGTAALGCLVKDYFPE 
                 ALQSGNSQESVTEQDSKDS 
                 EDTAVYYCAR 
                 PEDFATYYC 
               
               
                   
                 PVTVSWNSGALTSGVHT 
                 TYSLSSTLTLSKADYEKHK 
                 AGISYVFDYWG 
                 QQQVSDLLT 
               
               
                   
                 FPAVLQSSGLYSLSSVVT 
                 VYACEVTHQGLSSPVTKSF 
                 QGTLVTVSS 
                 FGQGTKVEIK 
               
               
                   
                 VPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 RTV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSLS 
                   
                   
                   
               
               
                   
                 PGK 
                   
                   
                   
               
               
                   
               
               
                 P9-02A 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSSYWIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAWI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYWI 
                 TITCRASQSV 
               
               
                   
                 DPDYGTTSYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQSYPTLG 
                 LEWVAWIDPD 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARAQY 
                 TFGQGTKVEIKRTVAAPSV 
                 YGTTSYADSVK 
                 YSASSLYSGV 
               
               
                   
                 VPGLDYWGQGTLVTVS 
                 FIFPPSDSQLKSGTASVVCL 
                 GRFTISADTSKN 
                 PSRFSGSRSG 
               
               
                   
                 SASTKGPSVFPLAPSSKS 
                 LNNFYPREAKVQWKVDN 
                 TAYLQMNSLRA 
                 TDFTLTISSLQ 
               
               
                   
                 TSGGTAALGCLVKDYFP 
                 ALQSGNSQESVTEQDSKDS 
                 EDTAVYYCAR 
                 PEDFATYYC 
               
               
                   
                 EPVTVSWNSGALTSGVH 
                 TYSLSSTLTLSKADYEKHK 
                 AQYVPGLDYW 
                 QQSYPTLGTF 
               
               
                   
                 TFPAVLQSSGLYSLSSVV 
                 VYACEVTHQGLSSPVTKSF 
                 GQGTLVTVSS 
                 GQGTKVEIKR 
               
               
                   
                 TVPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 TV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSLS 
                   
                   
                   
               
               
                   
                 PGK 
                   
                   
                   
               
               
                   
               
               
                 P9-03 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSGYYIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAVI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSGYYI 
                 TITCRASQSV 
               
               
                   
                 SPYSGYTSYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQGGSFPY 
                 LEWVAVISPYS 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARATY 
                 TFGQGTKVEIKRTVAAPSV 
                 GYTSYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 MVPYGFDYWGQGTLVT 
                 FIFPPSDSQLKSGTASVVCL 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 VSSASTKGPSVFPLAPSS 
                 LNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 KSTSGGTAALGCLVKDY 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARA 
                 PEDFATYYC 
               
               
                   
                 FPEPVTVSWNSGALTSG 
                 TYSLSSTLTLSKADYEKHK 
                 TYMVPYGFDY 
                 QQGGSFPYTF 
               
               
                   
                 VHTFPAVLQSSGLYSLSS 
                 VYACEVTHQGLSSPVTKSF 
                 WGQGTLVTVSS 
                 GQGTKVEIKR 
               
               
                   
                 VVTVPSSSLGTQTYICNV 
                 NRGEC 
                   
                 TV 
               
               
                   
                 NHKPSNTKVDKKVEPKS 
                   
                   
                   
               
               
                   
                 CDKTHTCPPCPAPELLG 
                   
                   
                   
               
               
                   
                 GPSVFLFPPKPKDTLMIS 
                   
                   
                   
               
               
                   
                 RTPEVTCVVVDVSHEDP 
                   
                   
                   
               
               
                   
                 EVKFNWYVDGVEVHNA 
                   
                   
                   
               
               
                   
                 KTKPREEQYNSTYRVVS 
                   
                   
                   
               
               
                   
                 VLTVLHQDWLNGKEYK 
                   
                   
                   
               
               
                   
                 CKVSNKALPAPIEKTISK 
                   
                   
                   
               
               
                   
                 AKGQPREPQVYTLPPSR 
                   
                   
                   
               
               
                   
                 DELTKNQVSLTCLVKGF 
                   
                   
                   
               
               
                   
                 YPSDIAVEWESNGQPEN 
                   
                   
                   
               
               
                   
                 NYKTTPPVLDSDGSFFL 
                   
                   
                   
               
               
                   
                 YSKLTVDKSRWQQGNV 
                   
                   
                   
               
               
                   
                 FSCSVMHEALHNHYTQ 
                   
                   
                   
               
               
                   
                 KSLSLSPGK 
                   
                   
                   
               
               
                   
               
               
                 P9-06 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 ′EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFAYYGIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAYI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFAYYG 
                 TITCRASQSV 
               
               
                   
                 YPHGYITDYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 IHWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQHFSSPG 
                 LEWVAYIYPHG 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARDSG 
                 TFGQGTKVEIKRTVAAPSV 
                 YITDYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 VPYYWAVLDYWGQGTL 
                 FIFPPSDSQLKSGTASVVCL 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 VTVSSASTKGPSVFPLAP 
                 LNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 SSKSTSGGTAALGCLVK 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARDS 
                 PEDFATYYC 
               
               
                   
                 DYFPEPVTVSWNSGALT 
                 TYSLSSTLTLSKADYEKHK 
                 GVPYYWAVLD 
                 QQHFSSPGTF 
               
               
                   
                 SGVHTFPAVLQSSGLYS 
                 VYACEVTHQGLSSPVTKSF 
                 YWGQGTLVTV 
                 GQGTKVEIKR 
               
               
                   
                 LSSVVTVPSSSLGTQTYI 
                 NRGEC 
                 SS 
                 TV 
               
               
                   
                 CNVNHKPSNTKVDKKV 
                   
                   
                   
               
               
                   
                 EPKSCDKTHTCPPCPAPE 
                   
                   
                   
               
               
                   
                 LLGGPSVFLFPPKPKDTL 
                   
                   
                   
               
               
                   
                 MISRTPEVTCVVVDVSH 
                   
                   
                   
               
               
                   
                 EDPEVKFNWYVDGVEV 
                   
                   
                   
               
               
                   
                 HNAKTKPREEQYNSTYR 
                   
                   
                   
               
               
                   
                 VVSVLTVLHQDWLNGK 
                   
                   
                   
               
               
                   
                 EYKCKVSNKALPAPIEK 
                   
                   
                   
               
               
                   
                 TISKAKGQPREPQVYTLP 
                   
                   
                   
               
               
                   
                 PSRDELTKNQVSLTCLV 
                   
                   
                   
               
               
                   
                 KGFYPSDIAVEWESNGQ 
                   
                   
                   
               
               
                   
                 PENNYKTTPPVLDSDGS 
                   
                   
                   
               
               
                   
                 FFLYSKLTVDKSRWQQG 
                   
                   
                   
               
               
                   
                 NVFSCSVMHEALHNHY 
                   
                   
                   
               
               
                   
                 TQKSLSLSPGK 
                   
                   
                   
               
               
                   
               
               
                 P9-07 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSSYYIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAYI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYYI 
                 TITCRASQSV 
               
               
                   
                 SPYGGDTSYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQWTSTL 
                 LEWVAYISPYG 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARDSY 
                 WTFGQGTKVEIKRTVAAPS 
                 GDTSYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 MSYIDGFDYWGQGTLV 
                 VFIFPPSDSQLKSGTASVVC 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 TVSSASTKGPSVFPLAPS 
                 LLNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 SKSTSGGTTALGCLVKD 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARDS 
                 PEDFATYYC 
               
               
                   
                 YFPEPVTVSWNSGALTS 
                 TYSLSSTLTLSKADYEKHK 
                 YMSYIDGFDY 
                 QQWTSTLWT 
               
               
                   
                 GVHTFPAVLQSSGLYSL 
                 VYACEVTHQGLSSPVTKSF 
                 WGQGTLVTVSS 
                 FGQGTKVEIK 
               
               
                   
                 SSVVTVPSSSLGTQTYIC 
                 NRGEC 
                   
                 RTV 
               
               
                   
                 NVNHKPSNTKVDKKVE 
                   
                   
                   
               
               
                   
                 PKSCDKTHTCPPCPAPEL 
                   
                   
                   
               
               
                   
                 LGGPSVFLFPPKPKDTL 
                   
                   
                   
               
               
                   
                 MISRTPEVTCVVVDVSH 
                   
                   
                   
               
               
                   
                 EDPEVKFNWYVDGVEV 
                   
                   
                   
               
               
                   
                 HNAKTKPREEQYNSTYR 
                   
                   
                   
               
               
                   
                 VVSVLTVLHQDWLNGK 
                   
                   
                   
               
               
                   
                 EYKCKVSNKALPAPIEK 
                   
                   
                   
               
               
                   
                 TISKAKGQPREPQVYTLP 
                   
                   
                   
               
               
                   
                 PSRDELTKNQVSLTCLV 
                   
                   
                   
               
               
                   
                 KGFYPSDIAVEWESNGQ 
                   
                   
                   
               
               
                   
                 PENNYKTTPPVLDSDGS 
                   
                   
                   
               
               
                   
                 FFLYSKLTVDKSRWQQG 
                   
                   
                   
               
               
                   
                 NVFSCSVMHEALHNHY 
                   
                   
                   
               
               
                   
                 TQKSLSLSPGK 
                   
                   
                   
               
               
                   
               
               
                 P9-11 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSSYYIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAYI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYYI 
                 TITCRASQSV 
               
               
                   
                 SPSGGYTYYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQYYPSPS 
                 LEWVAYISPSG 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARGAV 
                 TFGQGTKVEIKRTVAAPSV 
                 GYTYYADSVK 
                 YSASSLYSGV 
               
               
                   
                 LYSSAMDYWGQGTLVT 
                 FIFPPSDSQLKSGTASVVCL 
                 GRFTISADTSKN 
                 PSRFSGSRSG 
               
               
                   
                 VSSASTKGPSVFPLAPSS 
                 LNNFYPREAKVQWKVDN 
                 TAYLQMNSLRA 
                 TDFTLTISSLQ 
               
               
                   
                 KSTSGGTAALGCLVKDY 
                 ALQSGNSQESVTEQDSKDS 
                 EDTAVYYCAR 
                 PEDFATYYC 
               
               
                   
                 FPEPVTVSWNSGALTSG 
                 TYSLSSTLTLSKADYEKHK 
                 GAVLYSSAMD 
                 QQYYPSPSTF 
               
               
                   
                 VHTFPAVLQSSGLYSLSS 
                 VYACEVTHQGLSSPVTKSF 
                 YWGQGTLVTV 
                 GQGTKVEIKR 
               
               
                   
                 VVTVPSSSLGTQTYICNV 
                 NRGEC 
                 SS 
                 TV 
               
               
                   
                 NHKPSNTKVDKKVEPKS 
                   
                   
                   
               
               
                   
                 CDKTHTCPPCPAPELLG 
                   
                   
                   
               
               
                   
                 GPSVFLFPPKPKDTLMIS 
                   
                   
                   
               
               
                   
                 RTPEVTCVVVDVSHEDP 
                   
                   
                   
               
               
                   
                 EVKFNWYVDGVEVHNA 
                   
                   
                   
               
               
                   
                 KTKPREEQYNSTYRVVS 
                   
                   
                   
               
               
                   
                 VLTVLHQDWLNGKEYK 
                   
                   
                   
               
               
                   
                 CKVSNKALPAPIEKTISK 
                   
                   
                   
               
               
                   
                 AKGQPREPQVYTLPPSR 
                   
                   
                   
               
               
                   
                 DELTKNQVSLTCLVKGF 
                   
                   
                   
               
               
                   
                 YPSDIAVEWESNGQPEN 
                   
                   
                   
               
               
                   
                 NYKTTPPVLDSDGSFFL 
                   
                   
                   
               
               
                   
                 YSKLTVDKSRWQQGNV 
                   
                   
                   
               
               
                   
                 FSCSVMHEALHNHYTQ 
                   
                   
                   
               
               
                   
                 KSLSLSPGK 
                   
                   
                   
               
               
                   
               
               
                 P9-12 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSSYWIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVASI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYWI 
                 TITCRASQSV 
               
               
                   
                 ASYFGQTYYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQEYGRP 
                 LEWVASIASYF 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARGFG 
                 YTFGQGTKVEIKRTVAAPS 
                 GQTYYADSVK 
                 YSASSLYSGV 
               
               
                   
                 YAAMDYWGQGTLVTVS 
                 VFIFPPSDSQLKSGTASVVC 
                 GRFTISADTSKN 
                 PSRFSGSRSG 
               
               
                   
                 SASTKGPSVFPLAPSSKS 
                 LLNNFYPREAKVQWKVDN 
                 TAYLQMNSLRA 
                 TDFTLTISSLQ 
               
               
                   
                 TSGGTAALGCLVKDYFP 
                 ALQSGNSQESVTEQDSKDS 
                 EDTAVYYCAR 
                 PEDFATYYC 
               
               
                   
                 EPVTVSWNSGALTSGVH 
                 TYSLSSTLTLSKADYEKHK 
                 GFGYAAMDYW 
                 QQEYGRPYT 
               
               
                   
                 TFPAVLQSSGLYSLSSVV 
                 VYACEVTHQGLSSPVTKSF 
                 GQGTLVTVSS 
                 FGQGTKVEIK 
               
               
                   
                 TVPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 RTV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSLS 
                   
                   
                   
               
               
                   
                 PGK 
                   
                   
                   
               
               
                   
               
               
                 P9-14 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFGSYYIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVADI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFGSYYI 
                 TITCRASQSV 
               
               
                   
                 YPYFSSTYYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQHASGPL 
                 LEWVADIYPYF 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARGSHF 
                 TFGQGTKVEIKRTVAAPSV 
                 SSTYYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 GFDYWGQGTLVTVSSAS 
                 FIFPPSDSQLKSGTASVVCL 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 TKGPSVFPLAPSSKSTSG 
                 LNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 GTAALGCLVKDYFPEPV 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARGS 
                 PEDFATYYC 
               
               
                   
                 TVSWNSGALTSGVHTFP 
                 TYSLSSTLTLSKADYEKHK 
                 HFGFDYWGQG 
                 QQHASGPLTF 
               
               
                   
                 AVLQSSGLYSLSSVVTV 
                 VYACEVTHQGLSSPVTKSF 
                 TLVTVSS 
                 GQGTKVEIKR 
               
               
                   
                 PSSSLGTQTYICNVNHKP 
                 NRGEC 
                   
                 TV 
               
               
                   
                 SNTKVDKKVEPKSCDKT 
                   
                   
                   
               
               
                   
                 HTCPPCPAPELLGGPSVF 
                   
                   
                   
               
               
                   
                 LFPPKPKDTLMISRTPEV 
                   
                   
                   
               
               
                   
                 TCVVVDVSHEDPEVKFN 
                   
                   
                   
               
               
                   
                 WYVDGVEVHNAKTKPR 
                   
                   
                   
               
               
                   
                 EEQYNSTYRVVSVLTVL 
                   
                   
                   
               
               
                   
                 HQDWLNGKEYKCKVSN 
                   
                   
                   
               
               
                   
                 KALPAPIEKTISKAKGQP 
                   
                   
                   
               
               
                   
                 REPQVYTLPPSRDELTK 
                   
                   
                   
               
               
                   
                 NQVSLTCLVKGFYPSDI 
                   
                   
                   
               
               
                   
                 AVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSL 
                   
                   
                   
               
               
                   
               
               
                 P9-23 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSQYYIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVATI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSQYYI 
                 TITCRASQSV 
               
               
                   
                 YPRGGYTFYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQWSVYL 
                 LEWVATIYPRG 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARKSY 
                 ETFGQGTKVEIKRTVAAPS 
                 GYTFYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 WGMDYWGQGTLVTVSS 
                 VFIFPPSDSQLKSGTASVVC 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 ASTKGPSVFPLAPSSKST 
                 LLNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 SGGTAALGCLVKDYFPE 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARKS 
                 PEDFATYYC 
               
               
                   
                 PVTVSWNSGALTSGVHT 
                 TYSLSSTLTLSKADYEKHK 
                 YWGMDYWGQ 
                 QQWSVYLET 
               
               
                   
                 FPAVLQSSGLYSLSSVVT 
                 VYACEVTHQGLSSPVTKSF 
                 GTLVTVSS 
                 FGQGTKVEIK 
               
               
                   
                 VPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 RTV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSLS 
                   
                   
                   
               
               
                   
                 PGK 
                   
                   
                   
               
               
                   
               
               
                 P9-24 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSSYFIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVASI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYFI 
                 TITCRASQSV 
               
               
                   
                 YPTSHSTSYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQVDSRL 
                 LEWVASIYPTS 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARLGYP 
                 ATFGQGTKVEIKRTVAAPS 
                 HSTSYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 GVMDYWGQGTLVTVSS 
                 VFIFPPSDSQLKSGTASVVC 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 ASTKGPSVFPLAPSSKST 
                 LLNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 SGGTAALGCLVKDYFPE 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARL 
                 PEDFATYYC 
               
               
                   
                 PVTVSWNSGALTSGVHT 
                 TYSLSSTLTLSKADYEKHK 
                 GYPGVMDYWG 
                 QQVDSRLAT 
               
               
                   
                 FPAVLQSSGLYSLSSVVT 
                 VYACEVTHQGLSSPVTKSF 
                 QGTLVTVSS 
                 FGQGTKVEIK 
               
               
                   
                 VPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 RTV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSLS 
                   
                   
                   
               
               
                   
                 PGK 
                   
                   
                   
               
               
                   
               
               
                 P9-25 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSSYYIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVASI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYYI 
                 TITCRASQSV 
               
               
                   
                 YPYGSYTYYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQWAPDL 
                 LEWVASIYPYG 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARLGYS 
                 TTFGQGTKVEIKRTVAAPS 
                 SYTYYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 SGMDYWGQGTLVTVSS 
                 VFIFPPSDSQLKSGTASVVC 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 ASTKGPSVFPLAPSSKST 
                 LLNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 SGGTAALGCLVKDYFPE 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARL 
                 PEDFATYYC 
               
               
                   
                 PVTVSWNSGALTSGVHT 
                 TYSLSSTLTLSKADYEKHK 
                 GYSSGMDYWG 
                 QQWAPDLTT 
               
               
                   
                 FPAVLQSSGLYSLSSVVT 
                 VYACEVTHQGLSSPVTKSF 
                 QGTLVTVSS 
                 FGQGTKVEIK 
               
               
                   
                 VPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 RTV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSLS 
                   
                   
                   
               
               
                   
                 PGK 
                   
                   
                   
               
               
                   
               
               
                 P9-26 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                 NEG. 
                 LRLSCAASGFTFSSYYIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                 CON 
                 WVRQAPGKGLEWVAWI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYYI 
                 TITCRASQSV 
               
               
                   
                 ESSSSHTDYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQYSSSLY 
                 LEWVAWIESSS 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARLPYK 
                 TFGQGTKVEIKRTVAAPSV 
                 SHTDYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 YYYLGVFDYWGQGTLV 
                 FIFPPSDSQLKSGTASVVCL 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 TVSSASTKGPSVFPLAPS 
                 LNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 SKSTSGGTAALGCLVKD 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARLP 
                 PEDFATYYC 
               
               
                   
                 YFPEPVTVSWNSGALTS 
                 TYSLSSTLTLSKADYEKHK 
                 YKYYYLGVFD 
                 QQYSSSLYTF 
               
               
                   
                 GVHTFPAVLQSSGLYSL 
                 VYACEVTHQGLSSPVTKSF 
                 YWGQGTLVTV 
                 GQGTKVEIKR 
               
               
                   
                 SSVVTVPSSSLGTQTYIC 
                 NRGEC 
                 SS 
                 TVA 
               
               
                   
                 NVNHKPSNTKVDKKVE 
                   
                   
                   
               
               
                   
                 PKSCDKTHTCPPCPAPEL 
                   
                   
                   
               
               
                   
                 LGGPSVFLFPPKPKDTL 
                   
                   
                   
               
               
                   
                 MISRTPEVTCVVVDVSH 
                   
                   
                   
               
               
                   
                 EDPEVKFNWYVDGVEV 
                   
                   
                   
               
               
                   
                 HNAKTKPREEQYNSTYR 
                   
                   
                   
               
               
                   
                 VVSVLTVLHQDWLNGK 
                   
                   
                   
               
               
                   
                 EYKCKVSNKALPAPIEK 
                   
                   
                   
               
               
                   
                 TISKAKGQPREPQVYTLP 
                   
                   
                   
               
               
                   
                 PSRDELTKNQVSLTCLV 
                   
                   
                   
               
               
                   
                 KGFYPSDIAVEWESNGQ 
                   
                   
                   
               
               
                   
                 PENNYKTTPPVLDSDGS 
                   
                   
                   
               
               
                   
                 FFLYSKLTVDKSRWQQG 
                   
                   
                   
               
               
                   
                 NVFSCSVMHEALHNHY 
                   
                   
                   
               
               
                   
                 TQKSLSLSPGK 
                   
                   
                   
               
               
                   
               
               
                 P9-29 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSSYAIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAYI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYAI 
                 TITCRASQSV 
               
               
                   
                 APGGSYTYYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQGYSSLL 
                 LEWVAYIAPGG 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARLSYP 
                 TFGQGTKVEIKRTVAAPSV 
                 SYTYYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 GVMDYWGQGTLVTVSS 
                 FIFPPSDSQLKSGTASVVCL 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 ASTKGPSVFPLAPSSKST 
                 LNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 SGGTAALGCLVKDYFPE 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARLS 
                 PEDFATYYC 
               
               
                   
                 PVTVSWNSGALTSGVHT 
                 TYSLSSTLTLSKADYEKHK 
                 YPGVMDYWGQ 
                 QQGYSSLLTF 
               
               
                   
                 FPAVLQSSGLYSLSSVVT 
                 VYACEVTHQGLSSPVTKSF 
                 GTLVTVSS 
                 GQGTKVEIKR 
               
               
                   
                 VPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 TV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSLS 
                   
                   
                   
               
               
                   
                 PGK 
                   
                   
                   
               
               
                   
               
               
                 P9-30 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSTYTIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAWI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSTYTI 
                 TITCRASQSV 
               
               
                   
                 YPKGGSTDYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQYLSSPY 
                 LEWVAWIYPK 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARPSGY 
                 TFGQGTKVEIKRTVAAPSV 
                 GGSTDYADSVK 
                 YSASSLYSGV 
               
               
                   
                 GFDYWGQGTLVTVSSAS 
                 FIFPPSDSQLKSGTASVVCL 
                 GRFTISADTSKN 
                 PSRFSGSRSG 
               
               
                   
                 TKGPSVFPLAPSSKSTSG 
                 LNNFYPREAKVQWKVDN 
                 TAYLQMNSLRA 
                 TDFTLTISSLQ 
               
               
                   
                 GTAALGCLVKDYFPEPV 
                 ALQSGNSQESVTEQDSKDS 
                 EDTAVYYCARP 
                 PEDFATYYC 
               
               
                   
                 TVSWNSGALTSGVHTFP 
                 TYSLSSTLTLSKADYEKHK 
                 SGYGFDYWGQ 
                 QQYLSSPYTF 
               
               
                   
                 AVLQSSGLYSLSSVVTV 
                 VYACEVTHQGLSSPVTKSF 
                 GTLVTVSS 
                 GQGTKVEIKR 
               
               
                   
                 PSSSLGTQTYICNVNHKP 
                 NRGEC 
                   
                 TV 
               
               
                   
                 SNTKVDKKVEPKSCDKT 
                   
                   
                   
               
               
                   
                 HTCPPCPAPELLGGPSVF 
                   
                   
                   
               
               
                   
                 LFPPKPKDTLMISRTPEV 
                   
                   
                   
               
               
                   
                 TCVVVDVSHEDPEVKFN 
                   
                   
                   
               
               
                   
                 WYVDGVEVHNAKTKPR 
                   
                   
                   
               
               
                   
                 EEQYNSTYRVVSVLTVL 
                   
                   
                   
               
               
                   
                 HQDWLNGKEYKCKVSN 
                   
                   
                   
               
               
                   
                 KALPAPIEKTISKAKGQP 
                   
                   
                   
               
               
                   
                 REPQVYTLPPSRDELTK 
                   
                   
                   
               
               
                   
                 NQVSLTCLVKGFYPSDI 
                   
                   
                   
               
               
                   
                 AVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSQSLS 
                   
                   
                   
               
               
                   
                 PGK 
                   
                   
                   
               
               
                   
               
               
                 P9-34 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSTYFIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAYI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSTYFI 
                 TITCRASQSV 
               
               
                   
                 YPQGGYTYYADSVKGR 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 FTISADTSKNTAYLQMN 
                 LQPEDFATYYCQQWTIALT 
                 LEWVAYIYPQG 
                 KPGKAPKLLI 
               
               
                   
                 SLRAEDTAVYYCARQSY 
                 TFGQGTKVEIKRTVAAPSV 
                 GYTYYADSVK 
                 YSASSLYSGV 
               
               
                   
                 PGVFDYWGQGTLVTVSS 
                 FIFPPSDSQLKSGTASVVCL 
                 GRFTISADTSKN 
                 PSRFSGSRSG 
               
               
                   
                 ASTKGPSVFPLAPSSKST 
                 LNNFYPREAKVQWKVDN 
                 TAYLQMNSLRA 
                 TDFTLTISSLQ 
               
               
                   
                 SGGTAALGCLVKDYFPE 
                 ALQSGNSQESVTEQDSKDS 
                 EDTAVYYCAR 
                 PEDFATYYC 
               
               
                   
                 PVTVSWNSGALTSGVHT 
                 TYSLSSTLTLSKADYEKHK 
                 QSYPGVFDYW 
                 QQWTIALTTF 
               
               
                   
                 FPAVLQSSGLYSLSSVVT 
                 VYACEVTHQGLSSPVTKSF 
                 GQGTLVTVSS 
                 GQGTKVEIKR 
               
               
                   
                 VPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 TV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSLS 
                   
                   
                   
               
               
                   
                 PGK 
                   
                   
                   
               
               
                   
               
               
                 P9-37 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFWKYGI 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 HWVRQAPGKGLEWVA 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFWKYG 
                 TITCRASQSV 
               
               
                   
                 YIYPAGGITSYADSVKG 
                 VPSRFSGSRSGTDFTLTISS 
                 IHWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 RFTISADTSKNTAYLQM 
                 LQPEDFATYYCQQYYPSPS 
                 LEWVAYIYPAG 
                 KPGKAPKLLI 
               
               
                   
                 NSLRAEDTAVYYCARSD 
                 TFGQGTKVEIKRTVAAPSV 
                 GITSYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 YYSGMGMDYWGQGTL 
                 FIFPPSDSQLKSGTASVVCL 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 VTVSSASTKGPSVFPLAP 
                 LNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 SSKSTSGGTAALGCLVK 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARSD 
                 PEDFATYYC 
               
               
                   
                 DYFPEPVTVSWNSGALT 
                 TYSLSSTLTLSKADYEKHK 
                 YYSGMGMDY 
                 QQYYPSPSTF 
               
               
                   
                 SGVHTFPAVLQSSGLYS 
                 VYACEVTHQGLSSPVTKSF 
                 WGQGTLVTVSS 
                 GQGTKVEIKR 
               
               
                   
                 LSSVVTVPSSSLGTQTYI 
                 NRGEC 
                   
                 TV 
               
               
                   
                 CNVNHKPSNTKVDKKV 
                   
                   
                   
               
               
                   
                 EPKSCDKTHTCPPCPAPE 
                   
                   
                   
               
               
                   
                 LLGGPSVFLFPPKPKDTL 
                   
                   
                   
               
               
                   
                 MISRTPEVTCVVVDVSH 
                   
                   
                   
               
               
                   
                 EDPEVKFNWYVDGVEV 
                   
                   
                   
               
               
                   
                 HNAKTKPREEQYNSTYR 
                   
                   
                   
               
               
                   
                 VVSVLTVLHQDWLNGK 
                   
                   
                   
               
               
                   
                 EYKCKVSNKALPAPIEK 
                   
                   
                   
               
               
                   
                 TISKAKGQPREPQVYTLP 
                   
                   
                   
               
               
                   
                 PSRDELTKNQVSLTCLV 
                   
                   
                   
               
               
                   
                 KGFYPSDIAVEWESNGQ 
                   
                   
                   
               
               
                   
                 PENNYKTTPPVLDSDGS 
                   
                   
                   
               
               
                   
                 FFLYSKLTVDKSRWQQG 
                   
                   
                   
               
               
                   
                 NVFSCSVMHEALHNHY 
                   
                   
                   
               
               
                   
                 TQKSLSLSPGK 
                   
                   
                   
               
               
                   
               
               
                 P9-38 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSSYWIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAWI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYWI 
                 TITCRASQSV 
               
               
                   
                 DPDYGTTSYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQGSYFLQ 
                 LEWVAWIDPD 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARSETG 
                 TFGQGTKVEIKRTVAAPSV 
                 YGTTSYADSVK 
                 YSASSLYSGV 
               
               
                   
                 AAMDYWGQGTLVTVSS 
                 FIFPPSDSQLKSGTASVVCL 
                 GRFTISADTSKN 
                 PSRFSGSRSG 
               
               
                   
                 ASTKGPSVFPLAPSSKST 
                 LNNFYPREAKVQWKVDN 
                 TAYLQMNSLRA 
                 TDFTLTISSLQ 
               
               
                   
                 SGGTAALGCLVKDYFPE 
                 ALQSGNSQESVTEQDSKDS 
                 EDTAVYYCARS 
                 PEDFATYYC 
               
               
                   
                 PVTVSWNSGALTSGVHT 
                 TYSLSSTLTLSKADYEKHK 
                 ETGAAMDYWG 
                 QQGSYFLQTF 
               
               
                   
                 FPAVLQSSGLYSLSSVVT 
                 VYACEVTHQGLSSPVTKSF 
                 QGTLVTVSS 
                 GQGTKVEIKR 
               
               
                   
                 VPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 TV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MetHEALHNHYTQKSLS 
                   
                   
                   
               
               
                   
                 LSPGK 
                   
                   
                   
               
               
                   
               
               
                 P9-40 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFRWYYI 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 HWVRQAPGKGLEWVAT 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFRWYY 
                 TITCRASQSV 
               
               
                   
                 IYPDWDYTTYADSVKGR 
                 VPSRFSGSRSGTDFTLTISS 
                 IHWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 FTISADTSKNTAYLQMN 
                 LQPEDFATYYCQQPTYSL 
                 LEWVATIYPDW 
                 KPGKAPKLLI 
               
               
                   
                 SLRAEDTAVYYCARSPV 
                 WTFGQGTKVEIKRTVAAPS 
                 DYTTYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 TGPYGFDYWGQGTLVT 
                 VFIFPPSDSQLKSGTASVVC 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 VSSASTKGPSVFPLAPSS 
                 LLNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 KSTSGGTAALGCLVKDY 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARSP 
                 PEDFATYYC 
               
               
                   
                 FPEPVTVSWNSGALTSG 
                 TYSLSSTLTLSKADYEKHK 
                 VTGPYGFDYW 
                 QQPTYSLWT 
               
               
                   
                 VHTFPAVLQSSGLYSLSS 
                 VYACEVTHQGLSSPVTKSF 
                 GQGTLVTVSS 
                 FGQGTKVEIK 
               
               
                   
                 VVTVPSSSLGTQTYICNV 
                 NRGEC 
                   
                 RTV 
               
               
                   
                 NHKPSNTKVDKKVEPKS 
                   
                   
                   
               
               
                   
                 CDKTHTCPPCPAPELLG 
                   
                   
                   
               
               
                   
                 GPSVFLFPPKPKDTLMIS 
                   
                   
                   
               
               
                   
                 RTPEVTCVVVDVSHEDP 
                   
                   
                   
               
               
                   
                 EVKFNWYVDGVEVHNA 
                   
                   
                   
               
               
                   
                 KTKPREEQYNSTYRVVS 
                   
                   
                   
               
               
                   
                 VLTVLHQDWLNGKEYK 
                   
                   
                   
               
               
                   
                 CKVSNKALPAPIEKTISK 
                   
                   
                   
               
               
                   
                 AKGQPREPQVYTLPPSR 
                   
                   
                   
               
               
                   
                 DELTKNQVSLTCLVKGF 
                   
                   
                   
               
               
                   
                 YPSDIAVEWESNGQPEN 
                   
                   
                   
               
               
                   
                 NYKTTPPVLDSDGSFFL 
                   
                   
                   
               
               
                   
                 YSKLTVDKSRWQQGNV 
                   
                   
                   
               
               
                   
                 FSCSVMHEALHNHYTQ 
                   
                   
                   
               
               
                   
                 KSLSLSPGK 
                   
                   
                   
               
               
                   
               
               
                 P9-41 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 ′EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFRYYWI 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 HWVRQAPGKGLEWVA 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFRYYW 
                 TITCRASQSV 
               
               
                   
                 AIYPSSDSTYYADSVKG 
                 VPSRFSGSRSGTDFTLTISS 
                 IHWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 RFTISADTSKNTAYLQM 
                 LQPEDFATYYCQQWYSSL 
                 LEWVAAIYPSS 
                 KPGKAPKLLI 
               
               
                   
                 NSLRAEDTAVYYCARSS 
                 WTFGQGTKVEIKRTVAAPS 
                 DSTYYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 PYPYGQGVFDYWGQGT 
                 VFIFPPSDSQLKSGTASVVC 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 LVTVSSASTKGPSVFPLA 
                 LLNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 PSSKSTSGGTAALGCLV 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARSS 
                 PEDFATYYC 
               
               
                   
                 KDYFPEPVTVSWNSGAL 
                 TYSLSSTLTLSKADYEKHK 
                 PYPYGQGVFDY 
                 QQWYSSLWT 
               
               
                   
                 TSGVHTFPAVLQSSGLY 
                 VYACEVTHQGLSSPVTKSF 
                 WGQGTLVTVSS 
                 FGQGTKVEIK 
               
               
                   
                 SLSSVVTVPSSSLGTQTY 
                 NRGEC 
                   
                 RTV 
               
               
                   
                 ICNVNHKPSNTKVDKKV 
                   
                   
                   
               
               
                   
                 EPKSCDKTHTCPPCPAPE 
                   
                   
                   
               
               
                   
                 LLGGPSVFLFPPKPKDTL 
                   
                   
                   
               
               
                   
                 MISRTPEVTCVVVDVSH 
                   
                   
                   
               
               
                   
                 EDPEVKFNWYVDGVEV 
                   
                   
                   
               
               
                   
                 HNAKTKPREEQYNSTYR 
                   
                   
                   
               
               
                   
                 VVSVLTVLHQDWLNGK 
                   
                   
                   
               
               
                   
                 EYKCKVSNKALPAPIEK 
                   
                   
                   
               
               
                   
                 TISKAKGQPREPQVYTLP 
                   
                   
                   
               
               
                   
                 PSRDELTKNQVSLTCLV 
                   
                   
                   
               
               
                   
                 KGFYPSDIAVEWESNGQ 
                   
                   
                   
               
               
                   
                 PENNYKTTPPVLDSDGS 
                   
                   
                   
               
               
                   
                 FFLYSKLTVDKSRWQQG 
                   
                   
                   
               
               
                   
                 NVFSCSVMHEALHNHY 
                   
                   
                   
               
               
                   
                 TQKSLSLSPGK 
                   
                   
                   
               
               
                   
               
               
                 P9-42 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSSYYIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAAI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYYI 
                 TITCRASQSV 
               
               
                   
                 YSAWGTTYYADSVKGR 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 FTISADTSKNTAYLQMN 
                 LQPEDFATYYCQQWSSDL 
                 LEWVAAIYSA 
                 KPGKAPKLLI 
               
               
                   
                 SLRAEDTAVYYCARSYG 
                 VTFGQGTKVEIKRTVAAPS 
                 WGTTYYADSV 
                 YSASSLYSGV 
               
               
                   
                 YVFGYYSGMDYWGQGT 
                 VFIFPPSDSQLKSGTASVVC 
                 KGRFTISADTSK 
                 PSRFSGSRSG 
               
               
                   
                 LVTVSSASTKGPSVFPLA 
                 LLNNFYPREAKVQWKVDN 
                 NTAYLQMNSLR 
                 TDFTLTISSLQ 
               
               
                   
                 PSSKSTSGGTAALGCLV 
                 ALQSGNSQESVTEQDSKDS 
                 AEDTAVYYCA 
                 PEDFATYYC 
               
               
                   
                 KDYFPEPVTVSWNSGAL 
                 TYSLSSTLTLSKADYEKHK 
                 RSYGYVFGYYS 
                 QQWSSDLVT 
               
               
                   
                 TSGVHTFPAVLQSSGLY 
                 VYACEVTHQGLSSPVTKSF 
                 GMDYWGQGTL 
                 FGQGTKVEIK 
               
               
                   
                 SLSSVVTVPSSSLGTQTY 
                 NRGEC 
                 VTVSS 
                 RTV 
               
               
                   
                 ICNVNHKPSNTKVDKKV 
                   
                   
                   
               
               
                   
                 EPKSCDKTHTCPPCPAPE 
                   
                   
                   
               
               
                   
                 LLGGPSVFLFPPKPKDTL 
                   
                   
                   
               
               
                   
                 MISRTPEVTCVVVDVSH 
                   
                   
                   
               
               
                   
                 EDPEVKFNWYVDGVEV 
                   
                   
                   
               
               
                   
                 HNAKTKPREEQYNSTYR 
                   
                   
                   
               
               
                   
                 VVSVLTVLHQDWLNGK 
                   
                   
                   
               
               
                   
                 EYKCKVSNKALPAPIEK 
                   
                   
                   
               
               
                   
                 TISKAKGQPREPQVYTLP 
                   
                   
                   
               
               
                   
                 PSRDELTKNQVSLTCLV 
                   
                   
                   
               
               
                   
                 KGFYPSDIAVEWESNGQ 
                   
                   
                   
               
               
                   
                 PENNYKTTPPVLDSDGS 
                   
                   
                   
               
               
                   
                 FFLYSKLTVDKSRWQQG 
                   
                   
                   
               
               
                   
                 NVFSCSVMHEALHNHY 
                   
                   
                   
               
               
                   
                 TQKSLSLSPGK 
                   
                   
                   
               
               
                   
               
               
                 P9-43 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFHSYWI 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 HWVRQAPGKGLEWVAR 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFHSYW 
                 TITCRASQSV 
               
               
                   
                 IDSSKFGTYYADSVKGR 
                 VPSRFSGSRSGTDFTLTISS 
                 IHWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 FTISADTSKNTAYLQMN 
                 LQPEDFATYYCQQVYFSPY 
                 LEWVARIDSSK 
                 KPGKAPKLLI 
               
               
                   
                 SLRAEDTAVYYCARSYI 
                 TFGQGTKVEIKRTVAAPSV 
                 FGTYYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 DYPVSPAVFDYWGQGT 
                 FIFPPSDSQLKSGTASVVCL 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 LVTVSSASTKGPSVFPLA 
                 LNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 PSSKSTSGGTAALGCLV 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARSY 
                 PEDFATYYC 
               
               
                   
                 KDYFPEPVTVSWNSGAL 
                 TYSLSSTLTLSKADYEKHK 
                 IDYPVSPAVFD 
                 QQVYFSPYTF 
               
               
                   
                 TSGVHTFPAVLQSSGLY 
                 VYACEVTHQGLSSPVTKSF 
                 YWGQGTLVTV 
                 GQGTKVEIKR 
               
               
                   
                 SLSSVVTVPSSSLGTQTY 
                 NRGEC 
                 SS 
                 TV 
               
               
                   
                 ICNVNHKPSNTKVDKKV 
                   
                   
                   
               
               
                   
                 EPKSCDKTHTCPPCPAPE 
                   
                   
                   
               
               
                   
                 LLGGPSVFLFPPKPKDTL 
                   
                   
                   
               
               
                   
                 MISRTPEVTCVVVDVSH 
                   
                   
                   
               
               
                   
                 EDPEVKFNWYVDGVEV 
                   
                   
                   
               
               
                   
                 HNAKTKPREEQYNSTYR 
                   
                   
                   
               
               
                   
                 VVSVLTVLHQDWLNGK 
                   
                   
                   
               
               
                   
                 EYKCKVSNKALPAPIEK 
                   
                   
                   
               
               
                   
                 TISKAKGQPREPQVYTLP 
                   
                   
                   
               
               
                   
                 PSRDELTKNQVSLTCLV 
                   
                   
                   
               
               
                   
                 KGFYPSDIAVEWESNGQ 
                   
                   
                   
               
               
                   
                 PENNYKTTPPVLDSDGS 
                   
                   
                   
               
               
                   
                 FFLYSKLTVDKSRWQQG 
                   
                   
                   
               
               
                   
                 NVFSCSVMHEALHNHY 
                   
                   
                   
               
               
                   
                 TQKSLSLSPGK 
                   
                   
                   
               
               
                   
               
               
                 P9-44 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSYYWI 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 HWVRQAPGKGLEWVA 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSYYW 
                 TITCRASQSV 
               
               
                   
                 AISPSGSYTSYADSVKGR 
                 VPSRFSGSRSGTDFTLTISS 
                 IHWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 FTISADTSKNTAYLQMN 
                 LQPEDFATYYCQQGIDSPE 
                 LEWVAAISPSG 
                 KPGKAPKLLI 
               
               
                   
                 SLRAEDTAVYYCARSYY 
                 TFGQGTKVEIKRTVAAPSV 
                 SYTSYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 RFRTPYTVMDYWGQGT 
                 FIFPPSDSQLKSGTASVVCL 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 LVTVSSASTKGPSVFPLA 
                 LNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 PSSKSTSGGTAALGCLV 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARSY 
                 PEDFATYYC 
               
               
                   
                 KDYFPEPVTVSWNSGAL 
                 TYSLSSTLTLSKADYEKHK 
                 YRFRTPYTVMD 
                 QQGIDSPETF 
               
               
                   
                 TSGVHTFPAVLQSSGLY 
                 VYACEVTHQGLSSPVTKSF 
                 YWGQGTLVTV 
                 GQGTKVEIKR 
               
               
                   
                 SLSSVVTVPSSSLGTQTY 
                 NRGEC 
                 SS 
                 TV 
               
               
                   
                 ICNVNHKPSNTKVDKKV 
                   
                   
                   
               
               
                   
                 EPKSCDKTHTCPPCPAPE 
                   
                   
                   
               
               
                   
                 LLGGPSVFLFPPKPKDTL 
                   
                   
                   
               
               
                   
                 MISRTPEVTCVVVDVSH 
                   
                   
                   
               
               
                   
                 EDPEVKFNWYVDGVEV 
                   
                   
                   
               
               
                   
                 HNAKTKPREEQYNSTYR 
                   
                   
                   
               
               
                   
                 VVSVLTVLHQDWLNGK 
                   
                   
                   
               
               
                   
                 EYKCKVSNKALPAPIEK 
                   
                   
                   
               
               
                   
                 TISKAKGQPREPQVYTLP 
                   
                   
                   
               
               
                   
                 PSRDELTKNQVSLTCLV 
                   
                   
                   
               
               
                   
                 KGFYPSDIAVEWESNGQ 
                   
                   
                   
               
               
                   
                 PENNYKTTPPVLDSDGS 
                   
                   
                   
               
               
                   
                 FFLYSKLTVDKSRWQQG 
                   
                   
                   
               
               
                   
                 NVFSCSVMHEALHNHY 
                   
                   
                   
               
               
                   
                 TQKSLSLSPGK 
                   
                   
                   
               
               
                   
               
               
                 P9-45 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFFSYVIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAAI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFFSYVI 
                 TITCRASQSV 
               
               
                   
                 YPYSGYTTYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQGWDSL 
                 LEWVAAIYPYS 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARTKY 
                 VTFGQGTKVEIKRTVAAPS 
                 GYTTYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 YDYHVFDYWGQGTLVT 
                 VFIFPPSDSQLKSGTASVVC 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 VSSASTKGPSVFPLAPSS 
                 LLNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 KSTSGGTAALGCLVKDY 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCART 
                 PEDFATYYC 
               
               
                   
                 FPEPVTVSWNSGALTSG 
                 TYSLSSTLTLSKADYEKHK 
                 KYYDYHVFDY 
                 QQGWDSLVT 
               
               
                   
                 VHTFPAVLQSSGLYSLSS 
                 VYACEVTHQGLSSPVTKSF 
                 WGQGTLVTVSS 
                 FGQGTKVEIK 
               
               
                   
                 VVTVPSSSLGTQTYICNV 
                 NRGEC 
                   
                 RTV 
               
               
                   
                 NHKPSNTKVDKKVEPKS 
                   
                   
                   
               
               
                   
                 CDKTHTCPPCPAPELLG 
                   
                   
                   
               
               
                   
                 GPSVFLFPPKPKDTLMIS 
                   
                   
                   
               
               
                   
                 RTPEVTCVVVDVSHEDP 
                   
                   
                   
               
               
                   
                 EVKFNWYVDGVEVHNA 
                   
                   
                   
               
               
                   
                 KTKPREEQYNSTYRVVS 
                   
                   
                   
               
               
                   
                 VLTVLHQDWLNGKEYK 
                   
                   
                   
               
               
                   
                 CKVSNKALPAPIEKTISK 
                   
                   
                   
               
               
                   
                 AKGQPREPQVYTLPPSR 
                   
                   
                   
               
               
                   
                 DELTKNQVSLTCLVKGF 
                   
                   
                   
               
               
                   
                 YPSDIAVEWESNGQPEN 
                   
                   
                   
               
               
                   
                 NYKTTPPVLDSDGSFFL 
                   
                   
                   
               
               
                   
                 YSKLTVDKSRWQQGNV 
                   
                   
                   
               
               
                   
                 FSCSVMHEALHNHYTQ 
                   
                   
                   
               
               
                   
                 KSLSLSPGK 
                   
                   
                   
               
               
                   
               
               
                 P9-46 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSRYYIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAFI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSRYYI 
                 TITCRASQSV 
               
               
                   
                 SSDSGYTQYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQYWWSP 
                 LEWVAFISSDS 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARTMS 
                 ETFGQGTKVEIKRTVAAPS 
                 GYTQYADSVK 
                 YSASSLYSGV 
               
               
                   
                 YSALDYWGQGTLVTVS 
                 VFIFPPSDSQLKSGTASVVC 
                 GRFTISADTSKN 
                 PSRFSGSRSG 
               
               
                   
                 SASTKGPSVFPLAPSSKS 
                 LLNNFYPREAKVQWKVDN 
                 TAYLQMNSLRA 
                 TDFTLTISSLQ 
               
               
                   
                 TSGGTAALGCLVKDYFP 
                 ALQSGNSQESVTEQDSKDS 
                 EDTAVYYCART 
                 PEDFATYYC 
               
               
                   
                 EPVTVSWNSGALTSGVH 
                 TYSLSSTLTLSKADYEKHK 
                 MSYSALDYWG 
                 QQYWWSPET 
               
               
                   
                 TFPAVLQSSGLYSLSSVV 
                 VYACEVTHQGLSSPVTKSF 
                 QGTLVTVSS 
                 FGQGTKVEIK 
               
               
                   
                 TVPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 RTV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSLS 
                   
                   
                   
               
               
                   
                 PGK 
                   
                   
                   
               
               
                   
               
               
                 P9-50 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSSYVIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVALI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYVI 
                 TITCRASQSV 
               
               
                   
                 YSSGGYTQYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQFGSSLP 
                 LEWVALIYSSG 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARVGT 
                 TFGQGTKVEIKRTVAAPSV 
                 GYTQYADSVK 
                 YSASSLYSGV 
               
               
                   
                 TYPSRYLEALDYWGQG 
                 FIFPPSDSQLKSGTASVVCL 
                 GRFTISADTSKN 
                 PSRFSGSRSG 
               
               
                   
                 TLVTVSSASTKGPSVFPL 
                 LNNFYPREAKVQWKVDN 
                 TAYLQMNSLRA 
                 TDFTLTISSLQ 
               
               
                   
                 APSSKSTSGGTAALGCL 
                 ALQSGNSQESVTEQDSKDS 
                 EDTAVYYCAR 
                 PEDFATYYC 
               
               
                   
                 VKDYFPEPVTVSWNSGA 
                 TYSLSSTLTLSKADYEKHK 
                 VGTTYPSRYLE 
                 QQFGSSLPTF 
               
               
                   
                 LTSGVHTFPAVLQSSGL 
                 VYACEVTHQGLSSPVTKSF 
                 ALDYWGQGTL 
                 GQGTKVEIKR 
               
               
                   
                 YSLSSVVTVPSSSLGTQT 
                 NRGEC 
                 VTVSS 
                 TV 
               
               
                   
                 YICNVNHKPSNTKVDKK 
                   
                   
                   
               
               
                   
                 VEPKSCDKTHTCPPCPAP 
                   
                   
                   
               
               
                   
                 ELLGGPSVFLFPPKPKDT 
                   
                   
                   
               
               
                   
                 LMISRTPEVTCVVVDVS 
                   
                   
                   
               
               
                   
                 HEDPEVKFNWYVDGVE 
                   
                   
                   
               
               
                   
                 VHNAKTKPREEQYNSTY 
                   
                   
                   
               
               
                   
                 RVVSVLTVLHQDWLNG 
                   
                   
                   
               
               
                   
                 KEYKCKVSNKALPAPIE 
                   
                   
                   
               
               
                   
                 KTISKAKGQPREPQVYT 
                   
                   
                   
               
               
                   
                 LPPSRDELTKNQVSLTCL 
                   
                   
                   
               
               
                   
                 VKGFYPSDIAVEWESNG 
                   
                   
                   
               
               
                   
                 QPENNYKTTPPVLDSDG 
                   
                   
                   
               
               
                   
                 SFFLYSKLTVDKSRWQQ 
                   
                   
                   
               
               
                   
                 GNVFSCSVMHEALHNH 
                   
                   
                   
               
               
                   
                 YTQKSLSLSPG 
                   
                   
                   
               
               
                   
               
               
                 P9-51 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSSYYIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAGI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYYI 
                 TITCRASQSV 
               
               
                   
                 YPEGSYTYYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQWGSSL 
                 LEWVAGIYPEG 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARVGY 
                 ATFGQGTKVEIKRTVAAPS 
                 SYTYYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 PGVMDYWGQGTLVTVS 
                 VFIFPPSDSQLKSGTASVVC 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 SASTKGPSVFPLAPSSKS 
                 LLNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 TSGGTAALGCLVKDYFP 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARV 
                 PEDFATYYC 
               
               
                   
                 EPVTVSWNSGALTSGVH 
                 TYSLSSTLTLSKADYEKHK 
                 GYPGVMDYWG 
                 QQWGSSLAT 
               
               
                   
                 TFPAVLQSSGLYSLSSVV 
                 VYACEVTHQGLSSPVTKSF 
                 QGTLVTVSS 
                 FGQGTKVEIK 
               
               
                   
                 TVPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 RTV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSLS 
                   
                   
                   
               
               
                   
                 PGK 
                   
                   
                   
               
               
                   
               
               
                 P9-52 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSTYLIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAAI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSTYLI 
                 TITCRASQSV 
               
               
                   
                 TPYSGYTSYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQLDYSL 
                 LEWVAAITPYS 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARVGY 
                 ATFGQGTKVEIKRTVAAPS 
                 GYTSYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 PMVMDYWGQGTLVTVS 
                 VFIFPPSDSQLKSGTASVVC 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 SASTKGPSVFPLAPSSKS 
                 LLNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 TSGGTAALGCLVKDYFP 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARV 
                 PEDFATYYC 
               
               
                   
                 EPVTVSWNSGALTSGVH 
                 TYSLSSTLTLSKADYEKHK 
                 GYPMVMDYW 
                 QQLDYSLAT 
               
               
                   
                 TFPAVLQSSGLYSLSSVV 
                 VYACEVTHQGLSSPVTKSF 
                 GQGTLVTVSS 
                 FGQGTKVEIK 
               
               
                   
                 TVPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 RTV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSLS 
                   
                   
                   
               
               
                   
                 PGK 
                   
                   
                   
               
               
                   
               
               
                 P9-53 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSRYQIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAYI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSRYQI 
                 TITCRASQSV 
               
               
                   
                 ASASGTTSYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQGYPHP 
                 LEWVAYIASAS 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARVPY 
                 GTFGQGTKVEIKRTVAAPS 
                 GTTSYADSVKG 
                 YSASSLYSGV 
               
               
                   
                 VAMDYWGQGTLVTVSS 
                 VFIFPPSDSQLKSGTASVVC 
                 RFTISADTSKNT 
                 PSRFSGSRSG 
               
               
                   
                 ASTKGPSVFPLAPSSKST 
                 LLNNFYPREAKVQWKVDN 
                 AYLQMNSLRAE 
                 TDFTLTISSLQ 
               
               
                   
                 SGGTAALGCLVKDYFPE 
                 ALQSGNSQESVTEQDSKDS 
                 DTAVYYCARVP 
                 PEDFATYYC 
               
               
                   
                 PVTVSWNSGALTSGVHT 
                 TYSLSSTLTLSKADYEKHK 
                 YVAMDYWGQ 
                 QQGYPHPGT 
               
               
                   
                 FPAVLQSSGLYSLSSVVT 
                 VYACEVTHQGLSSPVTKSF 
                 GTLVTVSS 
                 FGQGTKVEIK 
               
               
                   
                 VPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 RTV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSLS 
                   
                   
                   
               
               
                   
                 PG 
                   
                   
                   
               
               
                   
               
               
                 P9-55 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                 NEG. 
                 LRLSCAASGFTFATYYIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                 CON. 
                 WVRQAPGKGLEWVAYI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFATYYI 
                 TITCRASQSV 
               
               
                   
                 DSESGYTYYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQRYSSLL 
                 LEWVAYIDSES 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARVSR 
                 TFGQGTKVEIKRTVAAPSV 
                 GYTYYADSVK 
                 YSASSLYSGV 
               
               
                   
                 GSSGTHVMDYWGQGTL 
                 FIFPPSDSQLKSGTASVVCL 
                 GRFTISADTSKN 
                 PSRFSGSRSG 
               
               
                   
                 VTVSSASTKGPSVFPLAP 
                 LNNFYPREAKVQWKVDN 
                 TAYLQMNSLRA 
                 TDFTLTISSLQ 
               
               
                   
                 SSKSTSGGTAALGCLVK 
                 ALQSGNSQESVTEQDSKDS 
                 EDTAVYYCAR 
                 PEDFATYYC 
               
               
                   
                 DYFPEPVTVSWNSGALT 
                 TYSLSSTLTLSKADYEKHK 
                 VSRGSSGTHVM 
                 QQRYSSLLTF 
               
               
                   
                 SGVHTFPAVLQSSGLYS 
                 VYACEVTHQGLSSPVTKSF 
                 DYWGQGTLVT 
                 GQGTKVEIKR 
               
               
                   
                 LSSVVTVPSSSLGTQTYI 
                 NRGEC 
                 VSS 
                 TV 
               
               
                   
                 CNVNHKPSNTKVDKKV 
                   
                   
                   
               
               
                   
                 EPKSCDKTHTCPPCPAPE 
                   
                   
                   
               
               
                   
                 LLGGPSVFLFPPKPKDTL 
                   
                   
                   
               
               
                   
                 MISRTPEVTCVVVDVSH 
                   
                   
                   
               
               
                   
                 EDPEVKFNWYVDGVEV 
                   
                   
                   
               
               
                   
                 HNAKTKPREEQYNSTYR 
                   
                   
                   
               
               
                   
                 VVSVLTVLHQDWLNGK 
                   
                   
                   
               
               
                   
                 EYKCKVSNKALPAPIEK 
                   
                   
                   
               
               
                   
                 TISKAKGQPREPQVYTLP 
                   
                   
                   
               
               
                   
                 PSRDELTKNQVSLTCLV 
                   
                   
                   
               
               
                   
                 KGFYPSDIAVEWESNGQ 
                   
                   
                   
               
               
                   
                 PENNYKTTPPVLDSDGS 
                   
                   
                   
               
               
                   
                 FFLYSKLTVDKSRWQQG 
                   
                   
                   
               
               
                   
                 NVFSCSVMHEALHNHY 
                   
                   
                   
               
               
                   
                 TQKSLSLSPGK 
                   
                   
                   
               
               
                   
               
               
                 P9-56 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSSYYIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVAYI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYYI 
                 TITCRASQSV 
               
               
                   
                 DSSGKYTDYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQYDYSL 
                 LEWVAYIDSSG 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARYAY 
                 WTFGQGTKVEIKRTVAAPS 
                 KYTDYADSVK 
                 YSASSLYSGV 
               
               
                   
                 PGVMDYWGQGTLVTVS 
                 VFIFPPSDSQLKSGTASVVC 
                 GRFTISADTSKN 
                 PSRFSGSRSG 
               
               
                   
                 SASTKGPSVFPLAPSSKS 
                 LLNNFYPREAKVQWKVDN 
                 TAYLQMNSLRA 
                 TDFTLTISSLQ 
               
               
                   
                 TSGGTAALGCLVKDYFP 
                 ALQSGNSQESVTEQDSKDS 
                 EDTAVYYCAR 
                 PEDFATYYC 
               
               
                   
                 EPVTVSWNSGALTSGVH 
                 TYSLSSTLTLSKADYEKHK 
                 YAYPGVMDYW 
                 QQYDYSLWT 
               
               
                   
                 TFPAVLQSSGLYSLSSVV 
                 VYACEVTHQGLSSPVTKSF 
                 GQGTLVTVSS 
                 FGQGTKVEIK 
               
               
                   
                 TVPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 RTV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDRDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSLS 
                   
                   
                   
               
               
                   
                 PGK 
                   
                   
                   
               
               
                   
               
               
                 P9-57 
                 EVQLVESGGGLVQPGGS 
                 DIQMTQSPSSLSASVGDRV 
                 EVQLVESGGGL 
                 DIQMTQSPSS 
               
               
                   
                 LRLSCAASGFTFSSYYIH 
                 TITCRASQSVSSAVAWYQQ 
                 VQPGGSLRLSC 
                 LSASVGDRV 
               
               
                   
                 WVRQAPGKGLEWVATI 
                 KPGKAPKLLIYSASSLYSG 
                 AASGFTFSSYYI 
                 TITCRASQSV 
               
               
                   
                 YPSGGYTYYADSVKGRF 
                 VPSRFSGSRSGTDFTLTISS 
                 HWVRQAPGKG 
                 SSAVAWYQQ 
               
               
                   
                 TISADTSKNTAYLQMNS 
                 LQPEDFATYYCQQSSSFLW 
                 LEWVATIYPSG 
                 KPGKAPKLLI 
               
               
                   
                 LRAEDTAVYYCARYSYP 
                 TFGQGTKVEIKRTVAAPSV 
                 GYTYYADSVK 
                 YSASSLYSGV 
               
               
                   
                 GVLDYWGQGTLVTVSS 
                 FIFPPSDSQLKSGTASVVCL 
                 GRFTISADTSKN 
                 PSRFSGSRSG 
               
               
                   
                 ASTKGPSVFPLAPSSKST 
                 LNNFYPREAKVQWKVDN 
                 TAYLQMNSLRA 
                 TDFTLTISSLQ 
               
               
                   
                 SGGTAALGCLVKDYFPE 
                 ALQSGNSQESVTEQDSKDS 
                 EDTAVYYCAR 
                 PEDFATYYC 
               
               
                   
                 PVTVSWNSGALTSGVHT 
                 TYSLSSTLTLSKADYEKHK 
                 YSYPGVLDYW 
                 QQSSSFLWTF 
               
               
                   
                 FPAVLQSSGLYSLSSVVT 
                 VYACEVTHQGLSSPVTKSF 
                 GQGTLVTVSS 
                 GQGTKVEIKR 
               
               
                   
                 VPSSSLGTQTYICNVNH 
                 NRGEC 
                   
                 TV 
               
               
                   
                 KPSNTKVDKKVEPKSCD 
                   
                   
                   
               
               
                   
                 KTHTCPPCPAPELLGGPS 
                   
                   
                   
               
               
                   
                 VFLFPPKPKDTLMISRTP 
                   
                   
                   
               
               
                   
                 EVTCVVVDVSHEDPEVK 
                   
                   
                   
               
               
                   
                 FNWYVDGVEVHNAKTK 
                   
                   
                   
               
               
                   
                 PREEQYNSTYRVVSVLT 
                   
                   
                   
               
               
                   
                 VLHQDWLNGKEYKCKV 
                   
                   
                   
               
               
                   
                 SNKALPAPIEKTISKAKG 
                   
                   
                   
               
               
                   
                 QPREPQVYTLPPSRDELT 
                   
                   
                   
               
               
                   
                 KNQVSLTCLVKGFYPSD 
                   
                   
                   
               
               
                   
                 IAVEWESNGQPENNYKT 
                   
                   
                   
               
               
                   
                 TPPVLDSDGSFFLYSKLT 
                   
                   
                   
               
               
                   
                 VDKSRWQQGNVFSCSV 
                   
                   
                   
               
               
                   
                 MHEALHNHYTQKSLSLS 
                   
                   
                   
               
               
                   
                 PGK 
               
               
                   
               
            
           
         
       
     
     Select GAL9 binding candidates were analyzed for binding properties: cross-reactive binding with murine GAL9; qualitative binding; epitope binning (Bin 2—candidates bin with Commercial antibody Clone ECA8 from LS Bio [LS-C179448]; Bin 3—candidates Bins with Commercial antibody Clone ECA42 from LS Bio [LS-C179449], which is the “tool antibody” referenced in  FIG. 10 ), and monovalent affinity binding. Analysis results are presented in Table 7. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Candidate anti-human GAL9 Binding Properties 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Mouse 
                 Binding Off-Rate 
                   
                   
               
               
                   
                 Cross- 
                 ( ++  = moderate;  
                   
                 Calculated  
               
               
                 ABS 
                 reactivity 
                   +++  = slow) 
                 Bin 
                 K D  (M) 
               
               
                   
               
               
                 P9-01 
                 Y 
                 
                   +++ 
                 
                 1 
                   
               
               
                 P9-02A 
                 Y 
                 
                   +++ 
                 
                 1 
                   
               
               
                 P9-03 
                   
                 
                   +++ 
                 
                 1 
                   
               
               
                 P9-06 
                   
                 
                   ++ 
                 
                 1 
                   
               
               
                 P9-07 
                 Y 
                 
                   ++ 
                 
                 3 
                   
               
               
                 P9-11 
                 Y 
                 
                   +++ 
                 
                 1 
                 6.554 × 10 −9   
               
               
                 P9-12 
                   
                 
                   ++ 
                 
                 3 
                   
               
               
                 P9-14 
                   
                 
                   +++ 
                 
                 2 
                   
               
               
                 P9-24 
                   
                 
                   +++ 
                 
                 1 
                 5.409 × 10 −9   
               
               
                 P9-25 
                   
                 
                   +++ 
                 
                 1 
                  3.48 × 10 −9   
               
               
                 P9-26 
                   
                 Negative Control (NC) 
                   
                   
               
               
                 P9-29 
                   
                 
                   +++ 
                 
                 1 
                   
               
               
                 P9-30 
                   
                 
                   +++ 
                 
                 1 
                   
               
               
                 P9-34 
                   
                 
                   +++ 
                 
                 1 
                   
               
               
                 P9-37 
                 Y 
                 
                   +++ 
                 
                 1 
                 4.543 × 10 −9   
               
               
                 P9-38 
                   
                 
                   ++ 
                 
                 1 
                   
               
               
                 P9-40 
                 Y 
                 
                   +++ 
                 
                 1 
                   
               
               
                 P9-41 
                   
                 
                   ++ 
                 
                 1 
                   
               
               
                 P9-42 
                 Y 
                 
                   ++ 
                 
                 1 
                   
               
               
                 P9-43 
                 Y 
                 
                   +++ 
                 
                 1 
                   
               
               
                 P9-45 
                   
                 
                   ++ 
                 
                 3 
                   
               
               
                 P9-46 
                   
                 
                   +++ 
                 
                 2 
                   
               
               
                 P9-50 
                 Y 
                 
                   +++ 
                 
                 3 
                 1.206 × 10 −9   
               
               
                 P9-51 
                   
                 
                   +++ 
                 
                 1 
                   
               
               
                 P9-52 
                   
                 
                   +++ 
                 
                 1 
                   
               
               
                 P9-53 
                   
                 
                   +++ 
                 
                 1 
                   
               
               
                 P9-55 
                   
                 Negative Control (NC) 
                   
                   
               
               
                 P9-56 
                 Y 
                 
                   +++ 
                 
                 1 
                   
               
               
                 P9-57 
                 Y 
                 
                   +++ 
                 
                 1 
                 2.557 × 10 −9   
               
               
                   
               
            
           
         
       
     
     Select GALS binding candidates were further analyzed for sequence motifs that could adversely affect antibody properties that are relevant to clinical development, such as stability, mutability, and immunogenicity. Computational analysis was performed according to Kumar and Singh ( Developability of biotherapeutics: computational approaches . Boca Raton: CRC Press, Taylor &amp; Francis Group, 2016). Analysis results are presented in Table 8, and demonstrate a limited number of adverse sequence motifs are present in the listed clones, indicating the potential for further clinical development. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Candidate anti-human GAL9 Antibody Properties 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 CDR3 
                   
                   
                   
                 Number 
                 Number 
                 Number 
                 Number 
                   
                 Number 
                 Number 
               
               
                   
                 Loop 
                 Yield 
                 Mol Weight 
                 Isoelectric 
                 Deamidation 
                 Isomerization 
                 Fragmentation 
                 N-linked 
                 Cys in 
                 Other 
                 T-cell 
               
               
                 ABS 
                 Length 
                 (ug/mL) 
                 (kDa) 
                 Point 
                 Sites 1   
                 Sites 2   
                 Sites 3   
                 Glycosylation Sites 4   
                 CDR 
                 Sites 5   
                 Epitopes 6   
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 P9-07 
                 15 
                 45 
                 1.453 × 10 5   
                 8.08 
                 0 
                 3 
                 1 
                 0 
                 No 
                 0 
                 1 
               
               
                 P9-11 
                 14 
                 68.85 
                 1.446 × 10 5   
                 8.42 
                 0 
                 1 
                 1 
                 0 
                 No 
                 0 
                 2 
               
               
                 P9-24 
                 12 
                 72.15 
                 1.438 × 10 5   
                 8.43 
                 0 
                 2 
                 2 
                 0 
                 No 
                 0 
                 0 
               
               
                 P9-25 
                 12 
                 163.5 
                 1.444 × 10 5   
                 8.32 
                 0 
                 1 
                 1 
                 0 
                 No 
                 0 
                 0 
               
               
                 P9-37 
                 14 
                 108.45 
                 1.447 × 10 5   
                 8.42 
                 0 
                 1 
                 2 
                 0 
                 No 
                 0 
                 1 
               
               
                 P9-50 
                 18 
                 78.6 
                 1.453 × 10 5   
                 8.22 
                 0 
                 1 
                 1 
                 0 
                 No 
                 0 
                 0 
               
               
                 P9-55 
                 — 
                 — 
                 1.452 × 10 5   
                 8.42 
                 0 
                 2 
                 1 
                 0 
                 No 
                 0 
                 0 
               
               
                 P9-57 
                 12 
                 30 
                 1.442 × 10 5   
                 8.42 
                 0 
                 1 
                 1 
                 0 
                 No 
                 0 
                 0 
               
               
                   
               
               
                   1 (NG, NS, NA, NH, ND) 
               
               
                   2 (DG, DP, DS) 
               
               
                   3 (DP, DY, HS, KT, HXS, SXH) 
               
               
                   4 (NXS/T) 
               
               
                   5 (LLQG, HPQ, FHENSP, LPRWG, HHH) 
               
               
                   6 3% in at least 2 of DRB1_0101, DRB1_0301, DRB1_0401, DRB1_0701, DRB1_1101, DRB1_1301, DRB1_1501, DRB1_0801 
               
            
           
         
       
     
     6.11.9. Example 8: Anti-Human GAL9 Candidates&#39; Effect on Cytokine Production in Peripheral Blood Mononuclear Cells (PBMCs) 
     Candidate anti-human GAL9 antigen binding sites (ABSs) were formatted into a bivalent monospecific native human full-length IgG1 heavy chain and light chain architecture (SEQ ID NO:5 and SEQ ID NO:3, respectively) and were tested for their effect on cytokine production by human PBMCs following peptide stimulation. PBMCs were stimulated essentially as described in Section 6.11.1 above. Briefly, PBMCs were harvested from human donors known to be responsive to human CMV virus (HCMV) placed in culture, and stimulated with HCMV PepMix to prime an antigen specific response, and treated with one of: control IgG, a comparator anti-human GAL9 tool activating mAb (clone ECA42, murine IgG2a), α-PD1 (Nivolumab), or candidate anti-GAL9 antibodies formatted as bivalent monospecific full-length human IgG1 antibodies. Cytokine secretion was measured at 24 and 72 hrs post-treatment by bead cytokine array. Results for INF-γ and TNF-α are depicted in  FIGS. 10A and 10B . The data shown in  FIG. 10  is described in more detail in Table 9 and Table 10 provided below. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 INF-γ 72 hr 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Average/donor 
                   
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Donor 19 
                 Donor 25 
                 Donor 27 
                 Average 
                 as % 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 IgG 
                 pg/ml 
                 5922 
                 43775 
                 1657 
                   
                   
               
               
                 P9-11 
                 pg/ml 
                 5891 
                 22998 
                 891 
                   
                   
               
               
                   
                 Fold change 
                 0.99 
                 0.52 
                 0.53 
                 0.68 
                 68.2 
               
               
                 P9-24 
                 pg/ml 
                 NT 
                 35748 
                 1258 
                   
                   
               
               
                   
                 Fold change 
                   
                 0.82 
                 0.78 
                 0.80 
                 87.6 
               
               
                 P9-34 
                 pg/ml 
                 NT 
                 44378 
                 1048 
                   
                   
               
               
                   
                 Fold change 
                   
                 1.01 
                 0.74 
                 0.88 
                 87.6 
               
               
                 P9-37 
                 pg/ml 
                 3231 
                 NT 
                 NT 
                   
                   
               
               
                   
                 Fold change 
                 0.55 
                   
                   
                 0.55 
                 54.56 
               
               
                 P9-57 
                 pg/ml 
                 4939 
                 NT 
                 NT 
                   
                   
               
               
                   
                 Fold change 
                 0.83 
                   
                   
                 0.83 
                 83.4 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 TNF-α 72 hr 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Average/donor 
                   
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Donor 19 
                 Donor 25 
                 Donor 27 
                 Average 
                 as % 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 IgG 
                 pg/ml 
                 777 
                 1284 
                 929 
                   
                   
               
               
                 P9-11 
                 pg/ml 
                 607 
                 982 
                 374 
                   
                   
               
               
                   
                 Fold change 
                 0.78 
                 0.76 
                 0.40 
                 0.64 
                 64.7 
               
               
                 P9-24 
                 pg/ml 
                 NT 
                 962 
                 299 
                   
                   
               
               
                   
                 Fold change 
                   
                 0.75 
                 0.32 
                 0.54 
                 53.5 
               
               
                 P9-34 
                 pg/ml 
                 NT 
                 874 
                 596 
                   
                   
               
               
                   
                 Fold change 
                   
                 0.68 
                 0.79 
                 0.74 
                 73.7 
               
               
                 P9-37 
                 pg/ml 
                 429 
                 NT 
                 NT 
                   
                   
               
               
                   
                 Fold change 
                 0.55 
                   
                   
                 0.55 
                 55.2 
               
               
                 P9-57 
                 pg/ml 
                 417 
                 NT 
                 NT 
                   
                   
               
               
                   
                 Fold change 
                 0.54 
                   
                   
                 0.54 
                 53.66 
               
               
                   
               
            
           
         
       
     
     6.11.10. Example 9: Treating with Anti-Human GAL9 IgG1 Antibodies P9-11, P9-37, or P9-57 Decreases Production of TNF-α and IFN-γ in Activated PBMCs 
     Selected inhibitory anti-human GAL9 candidates from Example 7, formatted as bivalent monospecific human IgG1 antibodies, were further tested on PBMCs from three additional human donors for their ability to inhibit cytokine production in PBMCs. 
     Stimulation of PBMCs 
     Human primary PBMC were collected from donor 19, donor RCB, and donor RG, which are known to have strong responses to human CMV virus (HCMV). PBMCs were stimulated essentially as described in Section 6.11.1 above. Briefly, PBMCs were harvested from human donors known to be responsive to human CMV virus (HCMV), placed in culture, stimulated with HCMV PepMix to prime an antigen specific response, and treated with P9-41, P9-42, P9-53, P9-11, P9-37, or P9-57, formatted as bivalent monospecific full length human IgG1 antibodies, or a human IgG control. 
     Cytokine Assay 
     Secretion of TNF-α and IFN-γ was measured at 24 hrs and 72 hrs post-treatment using BD™ Cytometric Bead Array (CBA) following the manufacturer&#39;s instructions. Assays were performed in quadruplicate. 
     Results/Conclusion 
     Representative data from 72 hrs of treatment are shown in  FIGS. 11A-11C . The average is indicated as a horizontal bar on the scatter plots. Error bars show standard deviation. 
       FIGS. 11A-11B  show scatter plots of TNF-α levels after with treatment with human IgG control (hIgG) and inhibitory anti-human GAL9 candidates. Treatment with P9-11, P9-37, or P9-57 formatted as human IgG1 antibodies, decreased TNF-α levels in PBMCs from all three human donors compared to IgG control.  FIG. 11C  show scatter plots of IFN-γ levels after treatment with a human control IgG (hIgG) or the anti-human GAL9 candidates. Treatment with either P9-11, P9-37, or P9-57 decreased IFN-γ levels in PBMCs as compared to control. 
     Treatment with either P9-41, P9-42, or P9-53 gave neutral or weak TNF-α and IFN-γ secretion (data not shown). 
     6.11.11. Example 10: Treating with Anti-Human GAL9 P9-11, P9-24, or P9-34 Decreases TNF-α and INF-γ Production and Increases IL-10 Production in Activated PBMCs 
     This study was conducted to determine the effect of select inhibitory anti-human GAL9 candidates from Example 7 on secretion of TNF-α, INF-γ, and IL-10 in activated human PBMCs. 
     Stimulation of PBMCs 
     PBMCs were stimulated essentially as described in Section 6.11.1 above. Briefly, PBMCs were harvested from human donors known to be highly responsive to human CMV virus (HCMV), placed in culture, stimulated with HCMV PepMix to prime an antigen specific response, and treated with one of P9-11, P9-24, and P9-34, formatted as a bivalent, monospecific, human IgG1 antibody, or a human IgG control. 
     Cytokine Assay 
     Cytokine secretion of TNF-α, INF-γ, and IL-10 was measured 72 hrs post-treatment using BD™ Cytometric Bead Array (CBA) following manufacturer&#39;s instructions. 
     Results/Conclusion 
       FIG. 12A  shows bar graphs of TNF-α levels after treatment with control IgG (hIgG) or inhibitory anti-human GAL9 candidates. Treatment with anti-human IgG1 P9-11, P9-24, or P9-34 resulted in a decrease of TNF-α secretion from PBMCs compared to IgG control.  FIG. 12B  shows bar graphs of INF-γ levels after with treatment with control IgG (hIgG) or inhibitory anti-GAL9 candidates. Treatment with anti-human GAL9 antibodies P9-11, P9-24, or P9-34 resulted in a decrease of INF-γ secretion from PBMCs compared to IgG control.  FIG. 12C  shows bar graphs of IL-10 levels after with treatment inhibitory anti-human GAL9 candidates or IgG control. Treatment with P9-11, P9-24, or P9-34 antibodies increased IL-10 secretion in PBMCs as compared to control. 
     6.11.12. Example 11: Treating Activated CD3 +  T-Cells with Anti-Human GAL9 Antibodies P9-11, P9-24, or P9-34 Improves the Cytokine Profile, while Anti-Mouse GAL9 (108A2) Results in a Complete Block of Cytokine Secretion 
     We measured INF-γ, TNF-α, or IL-10 cytokine secretion to determine the effect of anti-mouse GAL9 (clone 108A2) and anti-human GAL9 antibodies P9-11, P9-24, or P9-34, formatted as human IgG1 antibodies, on the cytokine profile in activated CD3 +  T-cells from mice. 
     Animals and Isolation of CD3 +  T-Cells 
     Five mice were used for each treatment group. All animals used in the study were housed and cared for in accordance with the NHMRC Guidelines for Animal Use. 
     Antibodies 
     Antibodies P9-11, P9-24, and P9-34, formatted as bivalent monospecific human IgG1 antibodies, and a human IgG control were used. In addition, the inhibitory anti-mouse GAL9 clone 108A2 “mGAL9” (BioLegend® San Diego, Calif.) was used. 
     Simulation of CD3 +  T-Cells 
     CD3 +  T-cells (CD90.2±CD3±) were isolated from the spleens of naïve mice. Mouse CD3 +  T cells were stimulated with anti-CD3 clone 145.2C11 (Aviva Systems Biology Corp. San Diego, Calif.) at 5 μg/ml. Next, the stimulated CD3 +  T cells were treated either with IgG control or one of the inhibitory antibodies at 20 μg/ml and cultured for 72 hours. 
     Cytokine Assays 
     After 72 hrs of treatment, the concentration of INF-γ, TNF-α, or IL-10 was measured using BD™ Cytometric Bead Array (CBA) following the manufacturer&#39;s instructions. 
     Statistical Analyses 
     Non-parametric unpaired t-test was conducted using GraphPad Prism (GraphPad Software). 
     Results/Conclusion 
     The results are shown in  FIGS. 13A and 13B . A reduced ratio of TNF-α:IL-10 or INF-γ:IL:10 indicates a reduction in pro-inflammatory cytokines with an increase in the inhibitory cytokine, IL-10. Treatment with the anti-mouse GAL9 (108A2) antibody significantly reduced secretion of TNF-α, INF-γ, and IL-10. See  FIG. 13A . In contrast, treatment with either anti-human GAL9 antibody P9-11, P9-24, or P9-34 (human IgG1 Fc) did not reduce TNF-α or INF-γ secretion, and IL-10 secretion was significantly increased. See  FIG. 13B . The asterisk “*” indicates a statistical significance of p-value &lt;0.05 compared to control. 
     Treatment with anti-human P9-11 and P9-24 antibodies, formatted as human IgG1 antibodies, resulted in an improved inflammatory environment, decreasing secretion of TNF-α, INF-γ, an increasing IL-10 secretion. Notably, treatment with anti-mouse GAL9 (108A2) resulted in a complete block of cytokine response, including IL-10 secretion. The differences in the cytokine profiles generated by anti-human GAL9 and anti-murine GAL9 (108A2) suggest that anti-human GAL9 and anti-mouse GAL9 (108A2) antibodies have a different mechanism of action. 
     6.11.13. Example 12: Treating with Anti-Human GAL9 does not Substantially Change the Expression of Immune Checkpoint Molecules in Stimulated CD4 +  and CD8 +  T Cells, and Decreases 4-1BB, CD40L, and OX40 Costimulatory Molecules in CD8 +  T Cells 
     This study was conducted to determine the effect of anti-human GAL9 candidates P9-11, P9-24, and P9-34 on the expression of select checkpoint molecules in stimulated CD8 +  and CD4 +  T cells and the effect of anti-human GAL9 P9-11 on select costimulatory molecules in stimulated CD8 +  T cells. 
     Stimulation &amp; Treatment 
     PBMCs, which include the population of CD8 +  or CD4 +  T-cells, were stimulated as described above and treated with anti-human GAL9 P9-11, P9-24, P9-34, formatted as bivalent monospecific human IgG1 antibodies, or a human IgG control. 
     Immunolabelling 
     PMBCs were resuspended at 5×10 6  cells/mL in 10% FBS in RPMI. 200 μL of resuspended cells were aliquoted to 96 well plates, then stained with Fixable Viability Dye eFluor® 780 for 30 minutes at 2-8° C. to irreversibly label dead cells. Cells were then washed and incubated with human Fc Block solution (Cat. No. 14-9161-73, eBiosciences) for 10 minutes at room temperature. The surface expression of PD-L1, PD-1, CTLA-4, TIM3, LAGS, 4-1BB, CD27, CD40L, ICOS, or OX40 was assessed by flow cytometry. 
     Flow Cytometry 
     Flow cytometry analysis was performed using a BD LSR Fortessa flow cytometer and BD FACSDiva software (Becton, Dickinson and Company, Franklin Lakes, N.J., USA). For each sample, at least 5×10 5  events were collected. 
     Representative data for the percentage of CD4 +  or CD8 +  T-cells that stained positive for immune checkpoint molecules are presented in Table 11 and Table 12 below. Data for the percentage of CD8 +  T-cells that stained positive for costimulatory molecules are presented in Table 13 below. 
     The “% value” represents the % of cells with detectable levels of the indicated marker. “(x)” indicates the fold change after treatment with the selected α-GAL9 antibody candidates as compared to a human IgG control. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Percent CD4 +  cells positive for selected immune checkpoint molecules 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Marker 
                 PD-L1 
                 PD-1 
                 GAL9 
                 CTLA-4 
                 TIM3 
                 LAG3 
               
               
                   
               
               
                 hIgG 
                 43.6% 
                 14.2% 
                 3.02% 
                 0.67% 
                 0.99% 
                 1.00% 
               
               
                 Control 
                   
                   
                   
                   
                   
                   
               
               
                 P9-11  
                 37.3% (0.9x) 
                 14.2% (1.0x) 
                 2.21% (0.7x) 
                 0.71% (1.0x) 
                 1.14 % (1.1x) 
                 0.93% (0.9x) 
               
               
                 P9-24 
                 40.2% (0.9x) 
                 15.0% (1.0x) 
                 2.05% (0.6x) 
                 0.67% (1.0x) 
                 0.93% (0.9x) 
                 1.03% (1.0x) 
               
               
                 P9-34 
                 42.3% (0.9x) 
                 16.0% (1.1x) 
                 2.63% (0.8x) 
                 0.71% (1.0x) 
                 1.03% (1.0x) 
                 1.12% (1.1x) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Percent CD8 +  cells positive for selected immune checkpoint molecules 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Marker 
                 PD-L1 
                 PD-1 
                 GAL9 
                 CTLA-4 
                 TIM3 
                 LAG3 
               
               
                   
               
               
                 hIgG 
                 29.1% 
                 16.1% 
                 4.35% 
                 18.7% 
                 0.81% 
                 2.25% 
               
               
                 Control 
                   
                   
                   
                   
                   
                   
               
               
                 P9-11 
                 26.7% (0.9x) 
                 16.5% (1.0x) 
                 1.63% (0.3x) 
                 15.2% (0.8x) 
                 0.95% (1.1x) 
                 2.00% (0.9x) 
               
               
                 P9-24 
                 24.5% (0.8x) 
                 16.7% (1.0x) 
                 1.82% (0.4x) 
                 15.1% (0.8x) 
                 0.88% (1.0x) 
                 1.88% (0.8x) 
               
               
                 P9-34 
                 26.3% (0.9x) 
                 17.0% (1.0x) 
                 2.79% (0.6x) 
                 15.0% (0.8x) 
                 0.82% (1.0x) 
                 2.40% (1.0x) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Percent CD8 +  cells positive for selected costimulatory molecules 
               
            
           
           
               
               
               
               
               
               
            
               
                 Marker 
                 4-1BB 
                 CD27 
                 CD40L 
                 ICOS 
                 OX40 
               
               
                   
               
               
                 hIgG 
                 5.64% 
                 53.5% 
                 2.57% 
                 6.39% 
                 9.95% 
               
               
                 control 
                   
                   
                   
                   
                   
               
               
                 P9-11 
                 3.03%  
                 52.6%  
                 1.85%  
                 5.56%  
                 5.2%  
               
               
                   
                 (0.53×) 
                 (0.98×) 
                 (0.72×) 
                 (0.87×) 
                 (0.5×) 
               
               
                   
               
            
           
         
       
     
     Results/Conclusion 
     There was no substantial change in the expression of any of the immune checkpoint molecules in stimulated CD8 +  or CD4 +  T-cells. However, we observed a decrease in the costimulatory molecules 4-1BB, CD40L, and OX40 in stimulated CD8 +  T-cells. These results suggest that the effects of the anti-human GAL9 candidates on cytokine response is driven by the inhibition of GAL9, and not through PD-1/PD-L1 immune checkpoint pathway or other checkpoint molecules such as CTLA-4, TIM3, or LAGS. 
     7. EQUIVALENTS 
     While various specific embodiments have been illustrated and described, the above specification is not restrictive. It will be appreciated that various changes can be made without departing from the spirit and scope of the invention(s). Many variations will become apparent to those skilled in the art upon review of this specification.