Abstract:
Monoclonal antibodies that bind and inhibit activation of epidermal growth factor receptor related member ErbB3/HER3 are disclosed. The antibodies can be used to treat cell proliferative diseases and disorders, including certain forms of cancer, associated with activation of ErbB3/HER3.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims the benefit of and priority to U.S. provisional patent application Ser. No. 61/322,712, filed Apr. 9, 2010; the entire content of which is incorporated herein by reference. 
     
    
     SEQUENCE LISTING 
       [0002]    The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Apr. 7, 2011, is named AVO009.txt and is 232,685 bytes in size. 
       FIELD OF THE INVENTION 
       [0003]    The field of the invention is molecular biology, immunology and oncology. More particularly, the field is humanized antibodies that bind human ErbB3/HER3. 
       BACKGROUND 
       [0004]    HER3/c-ErbB3 (referred to herein as ErbB3) is a member of the epidermal growth factor receptor (EGFR) family. ErbB3 binds neuregulin/heregulin (NRG/HRG). Receptors in the EGFR family are single transmembrane receptors with an intracellular tyrosine kinase domain. While the other EGFR family members, i.e., EGFR/HER1/ErbB1, HER2/ErbB2, and HER4/ErbB4, each have tyrosine kinase activity, ErbB3 has little or no tyrosine kinase activity, and thus is “kinase-dead.” 
         [0005]    The extracellular domain (ECD) of the EGFR family contains four domains. Domains 1 and 3 (also known as domains L1 and L2) are responsible for ligand binding. Cysteine-rich domains 2 and 4 (also known as domains C1 and C2) are involved in dimerization with receptor partners. Upon ligand binding, the ECD undergoes conformational changes. The interaction of domains 2 and 4, which maintains the tethered (inactive) conformation of the receptor, is relieved, and an extended (active) conformation is adopted. The extended conformation favors dimerization with other receptor partners. HER2/ErbB2 is the only exception to this general rule, i.e., Her2-ECD is constitutively in the extended conformation. No ligand for HER2 has been identified thus far. 
         [0006]    Because ErbB3 lacks an intrinsic kinase activity, it must dimerize with another active tyrosine kinase receptor to be activated by tyrosine phosphorylation. Dimerization can occur between two different receptors (heterodimerization), e.g., ErbB3 and EGFR/HER1/ErbB1, HER2/ErbB2, or HER4/ErbB4. Recently, ErbB3 was also shown to dimerize with MET. Upon association with another tyrosine kinase receptor, ErbB3 is activated by phosphorylation of at least nine tyrosine residues in the ErbB3 intracellular domain, and then rapidly associates with adaptors or downstream signaling molecules. Six of the ErbB3 phosphorylated tyrosine residues associate directly with the p85 subunit of Phosphatidylinositol 3-Kinase (PIK3), which results in activation of the cellular survival pathway controlled by the PI3K/Akt axis. Constitutive activation of ErbB3 by unregulated dimerization and/or unregulated phosphorylation of ErbB3 can lead to certain cancers. 
         [0007]    Overexpression of ErbB3 is associated with poor prognosis in various carcinomas (e.g., breast, ovarian, prostate, colorectal, pancreatic, gastric, and head and neck cancers). Overexpression of ErbB3 also correlates with local to distal metastasis in lung, gastric, and colorectal cancers, and bone invasion in prostate cancer (Sithanandam et al., 2008, C ANCER  G ENE  T HERAPY  15:413). Overexpression of ErbB3 has been linked to resistance to several cancer treatments, including treatment with EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) and head and neck cancers, treatment with Her2 inhibitor in breast cancers, and treatment with radiotherapy in pancreatic cancers. Moreover, overexpression of NRG, a ligand for ErbB3, was also linked to resistance to EGFR tyrosine kinase inhibitor treatment. Chen et al. describe the use of anti-ErbB3 monoclonal antibodies that inhibit NRG function and show growth inhibitory activity against breast and ovarian cancer cells (Chen et al., 1996, J. B IOL . C HEM.  271: 7620). 
         [0008]    There is a need for improved anti-ErbB3 antibodies that can be used as therapeutic agents. 
       SUMMARY 
       [0009]    The invention is based on the discovery of a family of antibodies that specifically bind human ErbB3. The antibodies contain ErbB3 binding sites based on CDRs that specifically bind human ErbB3. When used as therapeutic agents, the antibodies are engineered, e.g., humanized, to reduce or eliminate an immune response when administered to a human patient. 
         [0010]    The antibodies disclosed herein prevent or inhibit the activation of human ErbB3. In some embodiments, the antibodies prevent ErbB3 from binding to a ligand, e.g., NRG/HRG, thereby neutralizing the biological activity of ErbB3. In other embodiments, the anti-ErbB3 antibodies inhibit ErbB3 dimerization, thereby neutralizing the biological activity of ErbB3. The antibodies disclosed herein can be used to inhibit the proliferation of tumor cells in vitro or in vivo. When administered to a human cancer patient (or an animal model such as a mouse model), the antibodies inhibit or reduce tumor growth in the human patient (or animal model). 
         [0011]    These and other aspects and advantages of the invention are illustrated by the following figures, detailed description and claims. As used herein, “including” means without limitation, and examples cited are non-limiting. 
     
    
     
       DESCRIPTION OF THE DRAWINGS 
         [0012]    The invention can be more completely understood with reference to the following drawings. 
           [0013]      FIG. 1  (prior art) is a schematic representation of a typical antibody. 
           [0014]      FIG. 2  is a schematic diagram showing the amino acid sequence of the complete immunoglobulin heavy chain variable region of the antibodies denoted as 04D01, 09D03, 11G01, 12A07, 18H02, 22A02, and 24C05. The amino acid sequences for each antibody are aligned against one another, and Complementary Determining Sequences (CDR) (Kabat definition), CDR 1 , CDR 2 , and CDR 3 , are identified in boxes. The unboxed sequences represent framework (FR) sequences. 
           [0015]      FIG. 3  is a schematic diagram showing the CDR 1 , CDR 2 , and CDR 3  sequences (Kabat definition) for each of the immunoglobulin heavy chain variable region sequences in  FIG. 2 . 
           [0016]      FIG. 4  is a schematic diagram showing the amino acid sequence of the complete immunoglobulin light chain variable region of antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02, and 24C05. The amino acid sequences for each antibody are aligned against one another, and CDR 1 , CDR 2 , and CDR 3  sequences (Kabat definition) are identified in boxes. The unboxed sequences represent framework (FR) sequences. 
           [0017]      FIG. 5  is a schematic diagram showing the CDR 1 , CDR 2 , and CDR 3  sequences (Kabat definition) for each of the immunoglobulin light chain variable region sequences in  FIG. 4 . 
           [0018]      FIGS. 6A and 6B  are graphs summarizing results from an experiment to measure the neutralization activity of negative control (murine IgG (Δ)) and anti-ErbB3 monoclonal antibodies 04D01 (▪), 12A07 (◯), 18H02 (⋄), 22A02 () and 24C05 (□) to inhibit NRG1-β1 binding to hErbB3 ( FIG. 6A ) and to measure the enhanced binding of NRG1-β1 to rhErbB3 by the anti-ErbB3 mAb 09D03 (▴) and 11G01 (*) ( FIG. 6B ). 
           [0019]      FIG. 7  is a graph summarizing results from an experiment to measure the neutralization activity of negative control (murine IgG) and anti-ErbB3 monoclonal antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05 to inhibit NRG1-α1 binding to rhErbB3. 
           [0020]      FIG. 8  is a graph summarizing results from an experiment to measure the cell surface recognition of the anti-ErbB3 antibodies of the chimeric protein Her2/3d2 expressed at the surface of CHO cells. 
           [0021]      FIG. 9  is a graph summarizing results from an experiment to measure the anti-proliferation activity of negative control IgG (murine IgG (Δ)) and anti-ErbB3 monoclonal antibodies 04D01 (▪), 09D03 (▾), 11G01 (♦), 12A07 (◯), 18H02 (⋄), 22A02 () and 24C05 (□) in BaF/3 cells expressing Her2 and ErbB3 in presence of NRG1-β1. 
           [0022]      FIG. 10  is a graph summarizing results from an experiment to measure the anti-proliferation activity of anti-ErbB3 monoclonal antibodies 04D01 (▪), 09D03 (▾), 11G01 (♦), 12A07 (◯), 18H02 (⋄), 22A02 () and 24C05 (□) in MCF7 cells in the presence of NRG1-β1. 
           [0023]      FIG. 11  is a graph summarizing results from an experiment to measure the anti-proliferation activity of negative control (murine IgG) and anti-ErbB3 monoclonal antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05 in SKBR-3 cells treated with 5 μg/ml of antibodies in the presence of serum. 
           [0024]      FIG. 12  is graph summarizing results from an experiment to measure the inhibitory activity of negative control IgG and anti-ErbB3 monoclonal antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05 on the phosphorylation of ErbB3 induced by NRG in SKBR-3 cells. No antibody/no ligand and no antibody controls are also shown. 
           [0025]      FIGS. 13A and 13B  are graphs representing results from an experiment to measure the inhibitory activity of anti-ErbB3 monoclonal antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05 on the phosphorylation of Akt in response to NRG1-β1 in MCF7 cells (FIG.  13 A) and in DU145 cells ( FIG. 13B ) as determined by ELISA. No antibody/no ligand and no antibody controls are also shown. 
           [0026]      FIG. 14  is a graph summarizing results from an experiment to measure the tumor inhibitory activity of the anti-ErbB3 antibodies 04D01 (Δ), 09D03 (*), 11G01 (□), 12A07 (▴), 18H02 (), 22A02 (▪), 24C05 (◯) and a human IgG control (--▪--) dosed at 20 mg/kg in a B×PC3 pancreatic tumor xenograft model in CB17 SCID mice (vehicle control, PBS (♦)). 
           [0027]      FIG. 15  is a schematic diagram showing the amino acid sequences of the complete heavy chain variable region of 24C05 and the complete humanized heavy chain variable regions denoted as Sh24C05 Hv3-7, Sh24C05 Hv3-11, Sh24C05 Hv3-11 N62S, Sh24C05 Hv3-21, Sh24C05 Hv3-23, Sh24C05 Hv3-30, and Hu24C05 HvA. The amino acid sequences for each heavy chain variable regions are aligned against one another, and Complementary Determining Sequences (CDR) (Kabat definition), CDR 1 , CDR 2 , and CDR 3 , are identified in boxes. The unboxed sequences represent framework (FR) sequences. 
           [0028]      FIG. 16  is a schematic diagram showing the amino acid sequences of the complete light chain variable region of 24C05 and the complete humanized light chain variable regions denoted as Sh24C05 Kv1-9, Sh24C05 Kv1-16, Sh24C05 Kv1-17, Sh24C05 Kv1-33, Sh24C05 Kv1-39, and Hu24C05 KvA. The amino acid sequences for each light chain variable regions are aligned against one another, and CDR 1 , CDR 2 , and CDR 3  sequences (Kabat definition) are identified in boxes. The unboxed sequences represent framework (FR) sequences. 
           [0029]      FIG. 17  are Biacore sensorgrams representing results from an experiment to measure the kinetic values of anti-ErbB3 monoclonal antibodies, Sh24C05-31 N62S-IgG1, Ab#6, U1-53, and U1-59. 
           [0030]      FIG. 18A  is a graph summarizing results from an experiment to measure the neutralization activity of negative control (human IgG (Δ)) and anti-ErbB3 monoclonal antibodies Sh24C05-25 N62S-IgG1 (▴), Sh24C05-25 N62S-IgG2 (Δ), Sh24C05-31 N625-IgG1 () and Sh24C05-31 N62S-IgG2 (◯).  FIG. 18B  is a graph summarizing results from an experiment to measure the neutralization activity of human IgG (□) and anti-ErbB3 monoclonal antibodies Ab#6 IgG2 (▾), U1-53 (⋄) and U1-59 (▪). 
           [0031]      FIG. 19A  is a graph summarizing results from an experiment to measure the inhibitory activity of negative control (human IgG (□)) and anti-ErbB3 monoclonal antibodies Sh24C05-25 N62S-IgG1 (▾), Sh24C05-25 N62S-IgG2 (Δ), Sh24C05-31 N62S-IgG1 () and Sh24C05-31 N62S-IgG2 (◯) in BaF/3 cells expressing Her2 and ErbB3 in the presence of NRG1-β1.  FIG. 19B  is a graph summarizing results from an experiment to measure the inhibitory activity of human IgG (□) and anti-ErbB3 monoclonal antibodies Sh24C05-31 N62S-IgG1 (), Ab#6 IgG2 (∇), U1-53 (⋄) and U1-59 (▪) in BaF/3 cells expressing Her2 and ErbB3 in the presence of NRG1-β1. 
           [0032]      FIG. 20  is a graph summarizing results from an experiment to measure the inhibitory activity of negative control (human IgG) and anti-ErbB3 monoclonal antibodies Sh24C05-25 N62S-IgG1, Sh24C05-25 N62S-IgG2, Sh24C05-31 N62S-IgG1, and Sh24C05-31 N62S-IgG2 on the steady state phosphorylation of ErbB3 in growing SKBR-3 cells. 
           [0033]      FIG. 21  is a graph summarizing results from an experiment to measure the degradation of ErbB3 receptor by negative control (human IgG) and anti-ErbB3 monoclonal antibodies Sh24C05-25 N62S-IgG1, Sh24C05-25 N62S-IgG2, Sh24C05-31 N62S-IgG1, and Sh24C05-31 N62S-IgG2 in growing SKBR-3 cells. 
           [0034]      FIG. 22  is a graph summarizing the results from an experiment to measure tumor inhibitory activity of a human IgG, murine IgG, or anti-ErbB3 monoclonal antibodies dosed at 2 mg/kg in a B×PC3 pancreatic tumor xenograft model in CB17 SCID mice (murine 24C05 (Δ), Sh24C05-31 N62S IgG1 (), Sh24C05-31 N62S IgG2 (♦), Sh24C05-25 N62S IgG1 (▴), Sh24C05-25 N62S IgG2 (▪), vehicle control (□), murine IgG (x), and human IgG (⋄)). 
           [0035]      FIG. 23A  is a graph summarizing the results from an experiment to measure tumor inhibitory activity of a murine IgG or anti-ErbB3 monoclonal antibodies dosed at 5 mg/kg in a Calu-3 non-small cell lung cancer xenograft model in NCR nude mice (vehicle control (□), murine IgG (x), Sh24C05-31 N62S IgG1 (▴), Ab#6 IgG2 (), and U1-59 (▪)). 
           [0036]      FIG. 23B  is a graph summarizing the results from an experiment to measure tumor inhibitory activity of a murine IgG or anti-ErbB3 monoclonal antibodies dosed at 10 mg/kg in a Calu-3 non-small cell lung cancer xenograft model in NCR nude mice (vehicle control (□), murine IgG (x), Sh24C05-31 N62S IgG1 (▴), Ab#6 IgG2 (), and U1-59 (▪)). 
           [0037]      FIG. 23C  is a graph summarizing the results from an experiment to measure tumor inhibitory activity of a murine IgG or anti-ErbB3 monoclonal antibodies dosed at 20 mg/kg in a Calu-3 non-small cell lung cancer xenograft model in NCR nude mice (vehicle control (□), murine IgG (x), Sh24C05-31 N62S IgG1 (▴), Ab#6 IgG2 (), and U1-59 (▪)). 
           [0038]      FIG. 24  is a graph summarizing the results from an experiment to measure tumor inhibitory activity of a human IgG, murine or anti-ErbB3 monoclonal antibodies in a MDA-MB-453 breast cancer xenograft model in NOD SCID mice (vehicle control (□), human IgG (x), Sh24C05-31 N62S IgG1 dosed at 5 mg/kg (⋄), Sh24C05-31 N62S IgG1 dosed at 10 mg/kg (Δ), Sh24C05-31 N62S IgG1 dosed at 20 mg/kg (▴), Ab#6 IgG2 dosed at 10 mg/kg (), and U1-59 dosed at 10 mg/kg (▪)). 
       
    
    
     DETAILED DESCRIPTION 
       [0039]    The ErbB3 antibodies disclosed herein are based on the antigen binding sites of certain monoclonal antibodies selected for their ability to neutralize the biological activity of human ErbB3 polypeptides. The antibodies contain immunoglobulin variable region CDR sequences that define a binding site for ErbB3. In some embodiments, the antibodies prevent ErbB3 from binding to a ligand, e.g., NRG/HRG, thereby neutralizing the biological activity of ErbB3. In other embodiments, the anti-ErbB3 antibodies inhibit ErbB3 dimerization, thereby neutralizing the biological activity of ErbB3. In still other embodiments, the anti-ErbB3 antibodies inhibit phosphorylation of ErbB3 and downstream signaling. 
         [0040]    Because of the neutralizing activity of these antibodies, they are useful for inhibiting the growth and/or proliferation of certain cancer cells and tumors. The antibodies can be engineered to minimize or eliminate an immune response when administered to a human patient. In some embodiments, the antibodies are fused or conjugated to other moieties, such as detectable labels or effector molecules such as small molecule toxins. 
         [0000]    I. Antibodies that Bind ErbB3 
         [0041]    In some embodiments, the antibody comprises: (a) an immunoglobulin heavy chain variable region comprising the structure CDR H1 -CDR H2 -CDR H3  and (b) immunoglobulin light chain variable region, wherein the heavy chain variable region and the light chain variable region together define a single binding site for binding human ErbB3. A CDR H1  comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 5 (04D01), SEQ ID NO:15 (09D03), SEQ ID NO: 25 (11G01), SEQ ID NO: 34 (12A07), SEQ ID NO: 41 (18H02), SEQ ID NO: 51 (22A02), SEQ ID NO: 57 (24C05), and SEQ ID NO: 75 (24C05); a CDR H2  comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 6 (04D01), SEQ ID NO:16 (09D03), SEQ ID NO: 26 (11G01), SEQ ID NO: 35 (12A07), SEQ ID NO: 42 (18H02), SEQ ID NO: 52 (22A02), SEQ ID NO: 58 (24C05), and SEQ ID NO: 148 (Sh24C05 Hv3-11 N62S); and a CDR H3  comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 7 (04D01), SEQ ID NO: 17 (09D03), SEQ ID NO: 27 (11G01), SEQ ID NO: 36 (12A07, 22A02), SEQ ID NO: 43 (18H02), and SEQ ID NO: 59 (24C05). Throughout the specification a particular SEQ ID NO. is followed in parentheses by the antibody that was the origin of that sequence. For example, “SEQ ID NO: 5 (04D01)” means that SEQ ID NO: 5 comes from antibody 04D01. 
         [0042]    In some embodiments, the antibody comprises an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 5 (04D01), a CDR H2  comprising the amino acid sequence of SEQ ID NO: 6 (04D01), and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 7 (04D01). 
         [0043]    In some embodiments, the antibody comprises an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 15 (09D03), a CDR H2  comprising the amino acid sequence of SEQ ID NO: 16 (09D03), and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 17 (09D03). 
         [0044]    In some embodiments, the antibody comprises an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 25 (11G01), a CDR H2  comprising the amino acid sequence of SEQ ID NO: 26 (11G01), and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 27 (11G01). 
         [0045]    In some embodiments, the antibody comprises an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 34 (12A07), a CDR H2  comprising the amino acid sequence of SEQ ID NO: 35 (12A07), and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 36 (12A07, 22A02). 
         [0046]    In some embodiments, the antibody comprises an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 41 (18H02), a CDR H2  comprising the amino acid sequence of SEQ ID NO: 42 (18H02), and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 43 (18H02). 
         [0047]    In some embodiments, the antibody comprises an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 51 (22A02), a CDR H2  comprising the amino acid sequence of SEQ ID NO: 52 (22A02), and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 36 (12A07, 22A02). 
         [0048]    In some embodiments, the antibody comprises an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 57 (24C05) or SEQ ID NO: 75 (24C05), a CDR H2  comprising the amino acid sequence of SEQ ID NO: 58 (24C05), and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 59 (24C05). 
         [0049]    In certain embodiments, the antibody comprises an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 57 (24C05), a CDR H2  comprising the amino acid sequence of SEQ ID NO: 58 (24C05), and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 59 (24C05). 
         [0050]    In other embodiments, the antibody comprises an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 75 (24C05), a CDR H2  comprising the amino acid sequence of SEQ ID NO: 58 (24C05), and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 59 (24C05). 
         [0051]    In certain embodiments, the antibody comprises an immunoglobulin heavy chain variable region a CDR H1  comprising the amino acid sequence of SEQ ID NO: 57 (24C05) or SEQ ID NO: 75 (24C05), a CDR H2  comprising the amino acid sequence of SEQ ID NO: 148 (Sh24C05 Hv3-11 N62S), and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 59 (24C05). 
         [0052]    Preferably, the CDR H1 , CDR H2 , and CDR H3  sequences are interposed between human or humanized immunoglobulin FRs. The antibody can be an intact antibody or an antigen-binding antibody fragment. 
         [0053]    In some embodiments, the antibody comprises (a) an immunoglobulin light chain variable region comprising the structure CDR L1 -CDR L2 -CDR L3 , and (b) an immunoglobulin heavy chain variable region, wherein the IgG light chain variable region and the IgG heavy chain variable region together define a single binding site for binding human ErbB3. A CDR L1  comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 8 (04D01, 12A07, 22A02), SEQ ID NO: 18 (09D03), SEQ ID NO: 28 (11G01), SEQ ID NO: 44 (18H02), and SEQ ID NO: 60 (24C05); a CDR L2  comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 9 (04D01, 11G01, 12A07, 22A02), SEQ ID NO: 19 (09D03), SEQ ID NO: 45 (18H02), and SEQ ID NO: 61 (24C05); and a CDR L3  comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 10 (04D01, 12A07, 22A02), SEQ ID NO: 20 (09D03), SEQ ID NO: 29 (11G01), SEQ ID NO: 46 (18H02), and SEQ ID NO: 62 (24C05). 
         [0054]    In some embodiments, the antibody comprises an immunoglobulin light chain variable region comprising: a CDR L1  comprising the amino acid sequence of SEQ ID NO: 8 (04D01, 12A07, 22A02); a CDR L2  comprising the amino acid sequence of SEQ ID NO: 9 (04D01, 11G01, 12A07, 22A02); and a CDR L3  comprising the amino acid sequence of SEQ ID NO: 10 (04D01, 12A07, 22A02). 
         [0055]    In some embodiments, the antibody comprises an immunoglobulin light chain variable region comprising: a CDR IA  comprising the amino acid sequence of SEQ ID NO: 18 (09D03); a CDR L2  comprising the amino acid sequence of SEQ ID NO: 19 (09D03); and a CDR L3  comprising the amino acid sequence of SEQ ID NO: 20 (09D03). 
         [0056]    In some embodiments, the antibody comprises an immunoglobulin light chain variable region comprising: a CDR IA  comprising the amino acid sequence of SEQ ID NO: 28 (11G01); a CDR L2  comprising the amino acid sequence of SEQ ID NO: 9 (04D01, 11G01, 12A07, 22A02); and a CDR L3  comprising the amino acid sequence of SEQ ID NO: 29 (11G01). 
         [0057]    In some embodiments, the antibody comprises an immunoglobulin light chain variable region comprising: a CDR IA  comprising the amino acid sequence of SEQ ID NO: 44 (18H02); a CDR L2  comprising the amino acid sequence of SEQ ID NO: 45 (18H02); and a CDR L3  comprising the amino acid sequence of SEQ ID NO: 46 (18H02). 
         [0058]    In one embodiment, the antibody comprises an immunoglobulin light chain variable region comprising: a CDR IA  comprising the amino acid sequence of SEQ ID NO: 60 (24C05); a CDR L2  comprising the amino acid sequence of SEQ ID NO: 61 (24C05); and a CDR L3  comprising the amino acid sequence of SEQ ID NO: 62 (24C05). 
         [0059]    Preferably, the CDR L1 , CDR L2 , and CDR L3  sequences are interposed between human or humanized immunoglobulin FRs. The antibody can be an intact antibody or an antigen-binding antibody fragment. 
         [0060]    In some embodiments, the antibody comprises: (a) an IgG heavy chain variable region comprising the structure CDR H1 -CDR H2 -CDR H3  and (b) an IgG light chain variable region comprising the structure CDR L1 -CDR L2 -CDR L3 , wherein the heavy chain variable region and the light chain variable region together define a single binding site for binding human ErbB3. The CDR H1  is an amino acid sequence selected from the group consisting of SEQ ID NO: 5 (04D01), SEQ ID NO:15 (09D03), SEQ ID NO: 25 (11G01), SEQ ID NO: 34 (12A07), SEQ ID NO: 41 (18H02), SEQ ID NO: 51 (22A02), SEQ ID NO: 57 (24C05), and SEQ ID NO: 75 (24C05); the CDR H2  is an amino acid sequence selected from the group consisting of SEQ ID NO: 6 (04D01), SEQ ID NO:16 (09D03), SEQ ID NO: 26 (11G01), SEQ ID NO: 35 (12A07), SEQ ID NO: 42 (18H02), SEQ ID NO: 52 (22A02), SEQ ID NO: 58 (24C05), and SEQ ID NO: 148 (Sh24C05 Hv3-11 N62S); and the CDR H3  is an amino acid sequence selected from the group consisting of SEQ ID NO: 7 (04D01), SEQ ID NO: 17 (09D03), SEQ ID NO: 27 (11G01), SEQ ID NO: 36 (12A07, 22A02), SEQ ID NO: 43 (18H02), and SEQ ID NO: 59 (24C05). The CDR L1  is an amino acid sequence selected from the group consisting of SEQ ID NO: 8 (04D01, 12A07, 22A02), SEQ ID NO: 18 (09D03), SEQ ID NO: 28 (11G01), SEQ ID NO: 44 (18H02), and SEQ ID NO: 60 (24C05); the CDR L2  is an amino acid sequence selected from the group consisting of SEQ ID NO: 9 (04D01, 11G01, 12A07, 22A02), SEQ ID NO: 19 (09D03), SEQ ID NO: 45 (18H02), and SEQ ID NO: 61 (24C05); and the CDR L3  is an amino acid sequence selected from the group consisting of SEQ ID NO: 10 (04D01, 12A07, 22A02), SEQ ID NO: 20 (09D03), SEQ ID NO: 29 (11G01), SEQ ID NO: 46 (18H02), and SEQ ID NO: 62 (24C05). 
         [0061]    In another embodiment, the antibody comprises an immunoglobulin heavy chain variable region selected from the group consisting of SEQ ID NO: 2 (04D01), SEQ ID NO: 12 (09D03), SEQ ID NO: 22 (11G01), SEQ ID NO: 31 (12A07), SEQ ID NO: 38 (18H02), SEQ ID NO: 48 (22A02), SEQ ID NO: 54 (24C05), and SEQ ID NO: 154 (Sh24C05 Hv3-11 N62S), and an immunoglobulin light chain variable region selected from the group consisting of SEQ ID NO: 4 (04D01), SEQ ID NO: 14 (09D03), SEQ ID NO: 24 (11G01), SEQ ID NO: 33 (12A07), SEQ ID NO: 40 (18H02), SEQ ID NO: 50 (22A02), SEQ ID NO: 56 (24C05), SEQ ID NO: 166 (Sh24C05 Kv1-16), and SEQ ID NO: 168 (Sh24C05 Kv1-17). 
         [0062]    In another embodiment, the antibody comprises an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 (04D01), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 4 (04D01). 
         [0063]    In another embodiment, the antibody comprises an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12 (09D03), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 14 (09D03). 
         [0064]    In another embodiment, the antibody comprises an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 22 (11G01), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 24 (11G01). 
         [0065]    In another embodiment, the antibody comprises an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31 (12A07), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (12A07). 
         [0066]    In another embodiment, the antibody comprises an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 38 (18H02), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 40 (18H02). 
         [0067]    In another embodiment, the antibody comprises an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 48 (22A02), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 50 (22A02). 
         [0068]    In another embodiment, the antibody comprises an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54 (24C05), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 56 (24C05). 
         [0069]    In another embodiment, the antibody comprises an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 154 (Sh24C05 Hv3-11 N62S), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 166 (Sh24C05 Kv1-16). 
         [0070]    In another embodiment, the antibody comprises an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 154 (Sh24C05 Hv3-11 N62S), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 168 (Sh24C05 Kv1-17). 
         [0071]    In other embodiments, the antibody comprises (i) an immunoglobulin heavy chain selected from the group consisting of SEQ ID NO: 109 (04D01), SEQ ID NO: 113 (09D03), SEQ ID NO: 117 (11G01), SEQ ID NO: 121 (12A07), SEQ ID NO: 125 (18H02), SEQ ID NO: 129 (22A07), SEQ ID NO: 133 (24C05), SEQ ID NO: 190 (Sh24C05 Hv3-11 N62S IgG1), and SEQ ID NO: 192 (Sh24C05 Hv3-11 N62S IgG2), and (ii) an immunoglobulin light chain selected from the group consisting of SEQ ID NO: 111 (04D01), SEQ ID NO: 115 (09D03), SEQ ID NO: 119 (11G01), SEQ ID NO: 123 (12A07), SEQ ID NO: 127 (18H02), SEQ ID NO: 131 (22A07), SEQ ID NO: 135 (24C05), SEQ ID NO: 204 (Sh24C05 Kv1-16 kappa), and SEQ ID NO: 206 (Sh24C05 Kv1-17 kappa). 
         [0072]    In another embodiment, the antibody comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 109 (04D01), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 111 (04D01). 
         [0073]    In another embodiment, the antibody comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 113 (09D03), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 115 (09D03). 
         [0074]    In another embodiment, the antibody comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 117 (11G01), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 119 (11G01). 
         [0075]    In another embodiment, the antibody comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 121 (12A07), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 123 (12A07). 
         [0076]    In another embodiment, the antibody comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 125 (18H02), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 127 (18H02). 
         [0077]    In another embodiment, the antibody comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 129 (22A02), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 131 (22A02). 
         [0078]    In another embodiment, the antibody comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 133 (24C05), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 135 (24C05). 
         [0079]    In another embodiment, the antibody comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 190 (Sh24C05 Hv3-11 N62S IgG1), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 204 (Sh24C05 Kv1-16 kappa). 
         [0080]    In another embodiment, the antibody comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 192 (Sh24C05 Hv3-11 N62S IgG2), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 204 (Sh24C05 Kv1-16 kappa). 
         [0081]    In another embodiment, the antibody comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 190 (Sh24C05 Hv3-11 N62S IgG1), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 206 (Sh24C05 Kv1-17 kappa). 
         [0082]    In another embodiment, the antibody comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 192 (Sh24C05 Hv3-11 N62S IgG2), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 206 (Sh24C05 Kv1-17 kappa). 
         [0083]    As used herein, unless otherwise indicated, the term “antibody” means an intact antibody (e.g., an intact monoclonal antibody) or antigen-binding fragment of a antibody (e.g., an antigen-binding fragment of a monoclonal antibody), including an intact antibody or antigen-binding fragment that has been modified, engineered, or chemically conjugated. Examples of antibodies that have been modified or engineered include chimeric antibodies, humanized antibodies, and multispecific antibodies (e.g., bispecific antibodies). Examples of antigen-binding fragments include Fab, Fab′, (Fab′) 2 , Fv, single chain antibodies (e.g., scFv), minibodies, and diabodies. An example of a chemically conjugated antibody is an antibody conjugated to a toxin moiety. 
         [0084]      FIG. 1  shows a schematic representation of an intact monoclonal antibody that contains four polypeptide chains. Two of the polypeptide chains are called immunoglobulin heavy chains (H chains), and two of the polypeptide chains are called immunoglobulin light chains (L chains). The immunoglobulin heavy and light chains are connected by an interchain disulfide bond. The immunoglobulin heavy chains are connected by interchain disulfide bonds. A light chain consists of one variable region (V L  in  FIG. 1 ) and one constant region (C L  in  FIG. 1 ). The heavy chain consists of one variable region (V H  in  FIG. 1 ) and at least three constant regions (CH 1 , CH 2  and CH 3  in  FIG. 1 ). The variable regions determine the specificity of the antibody. 
         [0085]    Each variable region contains three hypervariable regions known as complementarity determining regions (CDRs) flanked by four relatively conserved regions known as framework regions (FRs). The three CDRs, referred to as CDR 1 , CDR 2 , and CDR 3 , contribute to the antibody binding specificity. 
         [0086]    In certain embodiments, an isolated antibody that binds human ErbB3 comprises an immunoglobulin heavy chain variable region comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the entire variable region or the framework region sequence of SEQ ID NO: 2 (04D01), SEQ ID NO: 12 (09D03), SEQ ID NO: 22 (11G01), SEQ ID NO: 31 (12A07), SEQ ID NO: 38 (18H02), SEQ ID NO: 48 (22A02), SEQ ID NO: 54 (24C05), and SEQ ID NO: 154 (Sh24C05 Hv3-11 N62S). 
         [0087]    In certain embodiments, an isolated antibody that binds human ErbB3 comprises an immunoglobulin light chain variable region comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the entire variable region or the framework region sequence of SEQ ID NO: 4 (04D01), SEQ ID NO: 14 (09D03), SEQ ID NO: 24 (11G01), SEQ ID NO: 33 (12A07), SEQ ID NO: 40 (18H02), SEQ ID NO: 50 (22A02), SEQ ID NO: 56 (24C05), SEQ ID NO: 166 (Sh24C05 Kv1-16), and SEQ ID NO: 168 (Sh24C05 Kv1-17). 
         [0088]    In each of the foregoing embodiments, it is contemplated herein that immunoglobulin heavy chain variable region sequences and/or light chain variable region sequences that together bind human ErbB3 may contain amino acid alterations (e.g., at least 1, 2, 3, 4, 5, or 10 amino acid substitutions, deletions, or additions) in the framework regions of the heavy and/or light chain variable regions. 
         [0089]    In some embodiments, an isolated antibody binds hErbB3 with a K D  of 350 pM, 300 pM, 250 pM, 200 pM, 150 pM, 100 pM, 75 pM, 50 pM, 20 pM, 10 pM or lower. Unless otherwise specified, K D  values are determined by surface plasmon resonance methods. The surface plasmon resonance methods can be performed using the conditions described, for example, in Examples 3 and 12, where the measurements were performed at 25° C. and 37° C., respectively. 
         [0090]    In some embodiments, the antibodies inhibit hErbB3 binding to NRG1-β1. For example, the antibodies can have an IC 50  (concentration at 50% of maximum inhibition) of about 5 nM, 2 nM or lower, when assayed using the protocols described in Examples 4 and 13. 
       II. Production of Antibodies 
       [0091]    Methods for producing antibodies disclosed herein are known in the art. For example, DNA molecules encoding light chain variable regions and heavy chain variable regions can be chemically synthesized using the sequence information provided herein. Synthetic DNA molecules can be ligated to other appropriate nucleotide sequences, including, e.g., constant region coding sequences, and expression control sequences, to produce conventional gene expression constructs encoding the desired antibodies. Production of defined gene constructs is within routine skill in the art. Alternatively, the sequences provided herein can be cloned out of hybridomas by conventional hybridization techniques or polymerase chain reaction (PCR) techniques, using synthetic nucleic acid probes whose sequences are based on sequence information provided herein, or prior art sequence information regarding genes encoding the heavy and light chains of murine antibodies in hybridoma cells. 
         [0092]    Nucleic acids encoding the antibodies disclosed herein can be incorporated (ligated) into expression vectors, which can be introduced into host cells through conventional transfection or transformation techniques. Exemplary host cells are  E. coli  cells, Chinese hamster ovary (CHO) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and myeloma cells that do not otherwise produce IgG protein. Transformed host cells can be grown under conditions that permit the host cells to express the genes that encode the immunoglobulin light and/or heavy chain variable regions. 
         [0093]    Specific expression and purification conditions will vary depending upon the expression system employed. For example, if a gene is to be expressed in  E. coli , it is first cloned into an expression vector by positioning the engineered gene downstream from a suitable bacterial promoter, e.g., Tip or Tac, and a prokaryotic signal sequence. The expressed secreted protein accumulates in refractile or inclusion bodies, and can be harvested after disruption of the cells by French press or sonication. The refractile bodies then are solubilized, and the proteins refolded and cleaved by methods known in the art. 
         [0094]    If a DNA construct encoding an antibody disclosed herein is to be expressed in eukayotic host cells, e.g., CHO cells, it is first inserted into an expression vector containing a suitable eukaryotic promoter, a secretion signal, IgG enhancers, and various introns. This expression vector optionally contains sequences encoding all or part of a constant region, enabling an entire, or a part of, a heavy and/or light chain to be expressed. In some embodiments, a single expression vector contains both heavy and light chain variable regions to be expressed. 
         [0095]    The gene construct can be introduced into eukaryotic host cells using conventional techniques. The host cells express V L  or V H  fragments, V L -V H  heterodimers, V H -V L  or V L -V H  single chain polypeptides, complete heavy or light immunoglobulin chains, or portions thereof, each of which may be attached to a moiety having another function (e.g., cytotoxicity). In some embodiments, a host cell is transfected with a single vector expressing a polypeptide expressing an entire, or part of, a heavy chain (e.g., a heavy chain variable region) or a light chain (e.g., a light chain variable region). In other embodiments, a host cell is transfected with a single vector encoding (a) a polypeptide comprising a heavy chain variable region and a polypeptide comprising a light chain variable region, or (b) an entire immunoglobulin heavy chain and an entire immunoglobulin light chain. In still other embodiments, a host cell is co-transfected with more than one expression vector (e.g., one expression vector expressing a polypeptide comprising an entire, or part of, a heavy chain or heavy chain variable region, and another expression vector expressing a polypeptide comprising an entire, or part of, a light chain or light chain variable region). 
         [0096]    A method of producing a polypeptide comprising an immunoglobulin heavy chain variable region or a polypeptide comprising an immunoglobulin light chain variable region may comprise growing a host cell transfected with an expression vector under conditions that permits expression of the polypeptide comprising the immunoglobulin heavy chain variable region or the polypeptide comprising the immunoglobulin light chain variable region. The polypeptide comprising a heavy chain variable region or the polypeptide comprising the light chain variable region then may be purified using techniques well known in the art, e.g., affinity tags such as glutathione-S-transferase (GST) and histidine tags. 
         [0097]    A method of producing a monoclonal antibody that binds human ErbB3, or an antigen-binding fragment of the antibody, may comprise growing a host cell transfected with: (a) an expression vector that encodes a complete or partial immunoglobulin heavy chain, and a separate expression vector that encodes a complete or partial immunoglobulin light chain; or (b) a single expression vector that encodes both chains (e.g., complete or partial chains), under conditions that permit expression of both chains. The intact antibody (or antigen-binding fragment) can be harvested and purified using techniques well known in the art, e.g., Protein A, Protein G, affinity tags such as glutathione-S-transferase (GST) and histidine tags. It is within ordinary skill in the art to express the heavy chain and the light chain from a single expression vector or from two separate expression vectors. 
       III. Modifications to the Antibodies 
       [0098]    Methods for reducing or eliminating the antigenicity of antibodies and antibody fragments are known in the art. When the antibodies are to be administered to a human, the antibodies preferably are “humanized” to reduce or eliminate antigenicity in humans. Preferably, a humanized antibody has the same or substantially the same affinity for the antigen as the non-humanized mouse antibody from which it was derived. 
         [0099]    In one humanization approach, chimeric proteins are created in which mouse immunoglobulin constant regions are replaced with human immunoglobulin constant regions. See, e.g., Morrison et al., 1984, P ROC . N AT . A CAD . S CI.  81:6851-6855, Neuberger et al., 1984, N ATURE  312:604-608; U.S. Pat. Nos. 6,893,625 (Robinson); 5,500,362 (Robinson); and 4,816,567 (Cabilly). 
         [0100]    In an approach known as CDR grafting, the CDRs of the light and heavy chain variable regions are grafted into frameworks from another species. For example, murine CDRs can be grafted into human FRs. In some embodiments, the CDRs of the light and heavy chain variable regions of an anti-ErbB3 antibody are grafted onto human FRs or consensus human FRs. To create consensus human FRs, FRs from several human heavy chain or light chain amino acid sequences are aligned to identify a consensus amino acid sequence. CDR grafting is described in U.S. Pat. Nos. 7,022,500 (Queen); 6,982,321 (Winter); 6,180,370 (Queen); 6,054,297 (Carter); 5,693,762 (Queen); 5,859,205 (Adair); 5,693,761 (Queen); 5,565,332 (Hoogenboom); 5,585,089 (Queen); 5,530,101 (Queen); Jones et al. (1986) N ATURE  321: 522-525; Riechmann et al. (1988) N ATURE  332: 323-327; Verhoeyen et al. (1988) S CIENCE  239: 1534-1536; and Winter (1998) FEBS L ETT  430: 92-94. 
         [0101]    In an approach called “SUPERHUMANIZATION™,” human CDR sequences are chosen from human germline genes, based on the structural similarity of the human CDRs to those of the mouse antibody to be humanized. See, e.g., U.S. Pat. No. 6,881,557 (Foote); and Tan et al., 2002, J. I MMUNOL  169:1119-1125. 
         [0102]    Other methods to reduce immunogenicity include “reshaping,” “hyperchimerization,” and “veneering/resurfacing.” See, e.g., Vaswami et al., 1998, A NNALS OF A   LLERGY, A   STHMA , &amp; I MMUNOL.  81:105; Roguska et al., 1996, P ROT . E NGINEER  9:895-904; and U.S. Pat. No. 6,072,035 (Hardman). In the veneering/resurfacing approach, the surface accessible amino acid residues in the murine antibody are replaced by amino acid residues more frequently found at the same positions in a human antibody. This type of antibody resurfacing is described, e.g., in U.S. Pat. No. 5,639,641 (Pedersen). 
         [0103]    Another approach for converting a mouse antibody into a form suitable for medical use in humans is known as ACTIVMAB™ technology (Vaccinex, Inc., Rochester, N.Y.), which involves a vaccinia virus-based vector to express antibodies in mammalian cells. High levels of combinatorial diversity of IgG heavy and light chains are said to be produced. See, e.g., U.S. Pat. Nos. 6,706,477 (Zauderer); 6,800,442 (Zauderer); and 6,872,518 (Zauderer). 
         [0104]    Another approach for converting a mouse antibody into a form suitable for use in humans is technology practiced commercially by KaloBios Pharmaceuticals, Inc. (Palo Alto, Calif.). This technology involves the use of a proprietary human “acceptor” library to produce an “epitope focused” library for antibody selection. 
         [0105]    Another approach for modifying a mouse antibody into a form suitable for medical use in humans is HUMAN ENGINEERING™ technology, which is practiced commercially by XOMA (US) LLC. See, e.g., PCT Publication No. WO 93/11794 and U.S. Pat. Nos. 5,766,886; 5,770,196; 5,821,123; and 5,869,619. 
         [0106]    Any suitable approach, including any of the above approaches, can be used to reduce or eliminate human immunogenicity of an antibody disclosed herein. 
         [0107]    Methods of making multispecific antibodies are known in the art. Multi-specific antibodies include bispecific antibodies. Bispecific antibodies are antibodies that have binding specificities for at least two different epitopes. Exemplary bispecific antibodies bind to two different epitopes of the antigen of interest. Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g., F(ab′) 2  bispecific antibodies and diabodies) as described, for example, in Milstein et al., N ATURE  305:537-539 (1983), WO 93/08829, Traunecker et al., EMBO J., 10:3655-3659 (1991), WO 94/04690, Suresh et al., M ETHODS IN  E NZYMOLOGY,  121:210 (1986), WO96/27011, Brennan et al., S CIENCE,  229: 81 (1985), Shalaby et al., J. E XP . M ED.,  175: 217-225 (1992), Kostelny et al., J. I MMUNOL.,  148(5):1547-1553 (1992), Hollinger et al., PNAS, 90:6444-6448, Gruber et al., J. I MMUNOL.,  152:5368 (1994), Wu et al., NAT. B IOTECHNOL.,  25(11): 1290-1297, U.S. Patent Publication No. 2007/0071675, and Bostrom et al., S CIENCE  323:1640-1644 (2009). 
         [0108]    In some embodiments, the antibody is conjugated to an effector agent such as a small molecule toxin or a radionuclide using standard in vitro conjugation chemistries. If the effector agent is a polypeptide, the antibody can be chemically conjugated to the effector or joined to the effector as a fusion protein. Construction of fusion proteins is within ordinary skill in the art. 
       IV. Use of the Antibodies 
       [0109]    The antibodies disclosed herein can be used to treat various forms of cancer, e.g., breast, ovarian, prostate, cervical, colorectal, lung (e.g., non-small cell lung cancer), pancreatic, gastric, skin, kidney, head and neck, and schwannoma cancers. The cancer cells are exposed to a therapeutically effective amount of the antibody so as to inhibit or reduce proliferation of the cancer cell. In some embodiments, the antibodies inhibit cancer cell proliferation by at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 100%. 
         [0110]    In some embodiments, the antibody inhibits or reduces proliferation of a tumor cell by inhibiting binding of human ErbB3 to an ErbB3 ligand, e.g., Neuregulin/Heregulin especially NRGβ1/NRG1-β1/NRGβ1/HRGβ1 and NRGα1/NRG1-α1/NRGα1/HRGα1. The antibody can be used in a method to inhibit tumor growth in a human patient. The method comprises administering to the patient a therapeutically effective amount of the antibody. 
         [0111]    Cancers associated with ErbB3 overexpression and/or activation include breast cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer (e.g., non-small cell lung cancer), some forms of brain cancer (e.g., schwannoma), melanomas, skin, kidney, and gastrointestinal cancers (e.g., colorectal, pancreatic, gastric, head and neck). 
         [0112]    As used herein, “treat, “treating” and “treatment” mean the treatment of a disease in a mammal, e.g., in a human. This includes: (a) inhibiting the disease, i.e., arresting its development; and (b) relieving the disease, i.e., causing regression of the disease state; and (c) curing the disease. 
         [0113]    Generally, a therapeutically effective amount of active component is in the range of 0.1 mg/kg to 100 mg/kg, e.g., 1 mg/kg to 100 mg/kg, 1 mg/kg to 10 mg/kg. The amount administered will depend on variables such as the type and extent of disease or indication to be treated, the overall health of the patient, the in vivo potency of the antibody, the pharmaceutical formulation, and the route of administration. The initial dosage can be increased beyond the upper level in order to rapidly achieve the desired blood-level or tissue level. Alternatively, the initial dosage can be smaller than the optimum, and the daily dosage may be progressively increased during the course of treatment. Human dosage can be optimized, e.g., in a conventional Phase I dose escalation study designed to run from 0.5 mg/kg to 20 mg/kg. Dosing frequency can vary, depending on factors such as route of administration, dosage amount and the disease being treated. Exemplary dosing frequencies are once per day, once per week and once every two weeks. A preferred route of administration is parenteral, e.g., intravenous infusion. Formulation of monoclonal antibody-based drugs is within ordinary skill in the art. In some embodiments, the monoclonal antibody is lyophilized and reconstituted in buffered saline at the time of administration. 
         [0114]    For therapeutic use, an antibody preferably is combined with a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” means buffers, carriers, and excipients suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The carrier(s) should be “acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient. Pharmaceutically acceptable carriers include buffers, solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known in the art. 
         [0115]    Pharmaceutical compositions containing antibodies disclosed herein can be presented in a dosage unit form and can be prepared by any suitable method. A pharmaceutical composition should be formulated to be compatible with its intended route of administration. Examples of routes of administration are intravenous (IV), intradermal, inhalation, transdermal, topical, transmucosal, and rectal administration. A preferred route of administration for monoclonal antibodies is IV infusion. Useful formulations can be prepared by methods well known in the pharmaceutical art. For example, see  Remington&#39;s Pharmaceutical Sciences,  18th ed. (Mack Publishing Company, 1990). Formulation components suitable for parenteral administration include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. 
         [0116]    For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The carrier should be stable under the conditions of manufacture and storage, and should be preserved against microorganisms. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol), and suitable mixtures thereof. 
         [0117]    Pharmaceutical formulations preferably are sterile. Sterilization can be accomplished, for example, by filtration through sterile filtration membranes. Where the composition is lyophilized, filter sterilization can be conducted prior to or following lyophilization and reconstitution. 
       EXAMPLES 
       [0118]    The following Examples are merely illustrative and are not intended to limit the scope or content of the invention in any way. 
       Example 1 
     Production of Anti-hErbB3 Monoclonal Antibodies 
       [0119]    Immunizations, fusions, and primary screens were conducted at Maine Biotechnology Services Inc. following the Repetitive Immunization Multiple Sites (RIMMS) protocol. Three AJ mice and three Balb/c mice were immunized with recombinant human ErbB3/Fc (R&amp;D Systems, Cat. No. 348-RB). Two sets of immunization were performed with either cleaved rhErbB3 (Immunization A) or with cleaved rhErbB3 cross-linked to its ligand, recombinant human NRG1-β1/HRG1-β1-EGF domain (R&amp;D Systems, Cat. No. 396-HB) (Immunization B). Two AJ mice per immunization with sera displaying high anti-ErbB3 activity by Enzyme Linked Immunosorbent Assay (ELISA) were chosen for subsequent fusion. Spleens and lymph nodes from the appropriate mice were harvested. B-cells then were harvested and fused with a myeloma line. Fusion products were serially diluted onto forty 96-well plates to near clonality. A total of 5280 supernatants from the resulting fusions were screened for binding to recombinant rhErbB3/Fc, using ELISA. The same supernatants were also screened for their binding to human ErbB3 overexpressed in CHO cells (by Mesoscale electrochemiluminescence assay). Three hundred supernatants identified as containing antibodies against ErbB3 were further characterized by in vitro biochemical and cell-based assays as discussed below. A panel of hybridomas was selected, and the hybridomas were subcloned and expanded. Hybridoma cell lines were transferred to BioXCell (formerly Bio-Express) for antibody expression and purification by affinity chromatography on Protein G resin under standard conditions. 
         [0120]    Anti-hErbB3 monoclonal antibody 04D01 was generated from Immunization A described above. Anti-hErbB3 monoclonal antibodies 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05 were generated from Immunization B described above. 
       Example 2 
     Sequence Analysis of Anti-hErbB3 Monoclonal Antibodies 
       [0121]    The light-chain isotype and heavy chain isotype of each monoclonal antibody in Example 1 was determined using the IsoStrip™ Mouse Monoclonal Antibody Isotyping Kit according the manufacturer&#39;s instructions (Roche Applied Science). All antibodies were determined to be Kappa light chain and IgG1 or IgG2b IgG heavy chain. 
         [0122]    The heavy and light chain variable regions of the mouse monoclonal antibodies were sequenced using 5′ RACE (Rapid Amplification of cDNA Ends). Total RNA was extracted from each monoclonal hybridoma cell line using the RNeasy® Miniprep kit according to the vendor&#39;s instructions (Qiagen). Full-length first strand cDNA containing 5′ ends was generated using either the GeneRacer™ Kit (Invitrogen) or SMARTer™ RACE cDNA Amplification Kit (Clontech) according to the manufacturer&#39;s instructions using random primers for 5′ RACE. 
         [0123]    The variable regions of the Kappa and Heavy (IgG1 or IgG2b) IgG chains were amplified by PCR, using KOD Hot Start Polymerase (Novagen) or Advantage 2 Polymerase Mix (Clontech) according to the manufacturer&#39;s instructions. For amplification of 5′ cDNA ends in conjunction with the GeneRacer™ Kit, the GeneRacer™ 5′ Primer, 5′ cgactggagcacgaggacactga 3′ (SEQ ID NO: 136) (Invitrogen) was used as a 5′ primer. For amplification of 5′ cDNA ends in conjunction with the SMARTer™ RACE cDNA Amplification Kit, the Universal Primer Mix A primer (Clontech), a mix of 5′CTAATACGACTCACTATAGGGCAAGCAGTGGTATCAACGCAGAGT 3′ (SEQ ID NO: 137) and 5′ CTAATACGACTCACTATAGGGC 3′ (SEQ ID NO: 138), was used as a 5′ primer. Heavy chain variable regions were amplified using the above 5′ primers and a 3′ IgG 1 Constant Region specific primer, either 5′ TATGCAAGGCTTACAACCACA 3′ (SEQ ID NO: 139) or 5′ GCCAGTGGATAGACAGATGGGGGTGTCG 3′ (SEQ ID NO: 140). IgG2b sequences were amplified with either 5′ AGGACAGGGGTTGATTGTTGA 3′ (SEQ ID NO: 141), 5′ GGCCAGTGGATAGACTGATGGGGGTGTTGT 3′ (SEQ ID NO: 142), or 5′ GGAGGAACCAGTTGTATCTCCACACCCA 3′ (SEQ ID NO: 143). Kappa chain variable regions were amplified with the above 5′ primers and a 3′ Kappa Constant Region specific primer, either 5′ CTCATTCCTGTTGAAGCTCTTGACAAT 3′ (SEQ ID NO: 144) or 5′ CGACTGAGGCACCTCCAGATGTT 3′ (SEQ ID NO: 145). 
         [0124]    Individual PCR products were isolated by agarose gel electrophoresis and purified using the Qiaquick® Gel Purification kit according to the manufacturer&#39;s instructions (Qiagen). The PCR products were subsequently cloned into the pCR®4Blunt plasmid using the Zero Blunt® TOPO® PCR Cloning Kit according to the manufacturer&#39;s instructions (Invitrogen) and transformed into DH5-α bacteria (Invitrogen) through standard molecular biology techniques. Plasmid DNA isolated from transformed bacterial clones was sequenced using M13 Forward (5′ GTAAAACGACGGCCAGT 3′) (SEQ ID NO: 146) and M13 Reverse primers (5′ CAGGAAACAGCTATGACC 3′) (SEQ ID NO: 147) by Beckman Genomics, using standard dideoxy DNA sequencing methods to identify the sequence of the variable region sequences. The sequences were analyzed using Vector NTI software (Invitrogen) and the IMGT/V-Quest software to identify and confirm variable region sequences. 
         [0125]    The nucleic acid sequences encoding and the protein sequences defining variable regions of the murine monoclonal antibodies are summarized below (amino terminal signal peptide sequences are not shown). CDR sequences (Kabat definition) are shown in bold/underlined in the amino acid sequences. 
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
           
               
                 Nucleic Acid Sequence Encoding the Heavy Chain Variable Region of the 04D01 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 1) 
                   
               
             
          
           
               
                 1 
                 caggtccaac tgcagcagcc tggggctgaa ctggtgaggc ctgggacttc agtgaagttg 
                   
               
               
                   
               
               
                 61 
                 tcctgcaagg cttctggcta caccttcacc agccactggt tgcactgggt gaagcagagg 
               
               
                   
               
               
                 121 
                 cctggacaag gccttgagtg gatcggagtg cttgatcctt ctgattttta tagtaactac 
               
               
                   
               
               
                 181 
                 aatcaaaact tcaagggcaa ggccacattg actgtagaca catcctccag cacagcctac 
               
               
                   
               
               
                 241 
                 atgcagctca gcagcctgac atctgaggac tctgcggtct attactgtgc acgaggccta 
               
               
                   
               
               
                 301 
                 ctatccgggg actatgctat ggactactgg ggtcaaggaa cctcagtcac cgtctcctca 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Heavy Chain Variable Region of the 04D01 Antibody 
                   
               
               
                 (SEQ ID NO: 2) 
                   
               
             
          
           
               
                 1 
                 qvqlqqpgae lvrpgtsvkl sckasgytft    shwlh   wvkqr pgqglewig   v       ldpsdfysny     
                   
               
               
                   
               
               
                 61 
                     nqnfkg   katl tvdtssstay mqlssltsed savyycar   gl       lsgdyamdy   w gqgtsvtvss 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Kappa Chain Variable Region of the 04D01 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 3) 
                   
               
             
          
           
               
                 1 
                 gatgttttga tgacccaaat tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 
                   
               
               
                   
               
               
                 61 
                 atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 
               
               
                   
               
               
                 121 
                 tacctgcaga aaccaggcca gtctccaaag tccctgatct acaaagtttc taaccgattt 
               
               
                   
               
               
                 181 
                 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 
               
               
                   
               
               
                 241 
                 agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc atatgttccg 
               
               
                   
               
               
                 301 
                 tggacgttcg gtggaggcac caagctggaa atcaaa 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Kappa Chain Variable Region of the 04D01 Antibody 
                   
               
               
                 (SEQ ID NO: 4) 
                   
               
             
          
           
               
                 1 
                 dvlmtqipls lpvslgdqas isc   rssqsiv       hsngntyle   w ylqkpgqspk sliy   kvsnrf     
                   
               
               
                   
               
               
                 61 
                     s   gvpdrfsgs gsgtdftlki srveaedlgv yyc   fqgsyvp       wt   fgggtkle ik 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Heavy Chain Variable Region of the 09D03 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 11) 
                   
               
             
          
           
               
                 1 
                 caggttactc taaaagagtc tggccctggg atattgcggc cctcccagac cctcagtctg 
                   
               
               
                   
               
               
                 61 
                 acttgttctt tctctgggtt ttcactgagc acttttggtt tgagtgtagg ctggattcgt 
               
               
                   
               
               
                 121 
                 cagccttcag ggaagggtct ggagtggctg gcacacattt ggtgggatga tgataagtac 
               
               
                   
               
               
                 181 
                 tataacccag cccttaagag tcggctcaca atctccaagg atacctccaa aaaccaggta 
               
               
                   
               
               
                 241 
                 ttcctcaaga tcgccaatgt ggacactgca gatactgcca catactactg tgctcgaata 
               
               
                   
               
               
                 301 
                 ggggcggacg cccttccttt tgactactgg ggccaaggca ccactctcac agtctcctca 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Heavy Chain Variable Region of the 09D03 Antibody 
                   
               
               
                 (SEQ ID NO: 12) 
                   
               
             
          
           
               
                 1 
                 qvtlkesgpg ilrpsqtlsl tcsfsgfsls    tfglsvg   wir qpsgkglewl a   hiwwdddky     
                   
               
               
                   
               
               
                 61 
                     ynpalks   rlt iskdtsknqv flkianvdta dtatyycar   i       gadalpfdy   w gqgttltvss 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Kappa Chain Variable Region of the 09D03 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 13) 
                   
               
             
          
           
               
                 1 
                 gatattgtgt tgactcagac tgcaccctct gtacctgtca ctcctggaga gtcagtatcc 
                   
               
               
                   
               
               
                 61 
                 atctcctgca ggtctagtaa gagtctcctg catagtaatg gcaacactta cttgtattgg 
               
               
                   
               
               
                 121 
                 ttcctgcaga ggccaggcca gtctcctcag ctcctgatat atcggatgtc caaccttgcc 
               
               
                   
               
               
                 181 
                 tcaggagtcc cagacaggtt cagtggcagt gggtcaggaa ctgctttcac actgagaatc 
               
               
                   
               
               
                 241 
                 agtagagtgg aggctgagga tgtgggtgtt tattactgta tgcaacatct agaatatcct 
               
               
                   
               
               
                 301 
                 ttcacgttcg gctcggggac aaagttggaa ataaaa 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Kappa Chain Variable Region of the 09D03 Antibody 
                   
               
               
                 (SEQ ID NO: 14) 
                   
               
             
          
           
               
                 1 
                 divltqtaps vpvtpgesys isc   rssksll       hsngntyly   w flqrpgqspq lliy   rmsnla     
                   
               
               
                   
               
               
                 61 
                     s   gvpdrfsgs gsgtaftlri srveaedvgv yyc   mqhleyp       ft   fgsgtkle ik 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Heavy Chain Variable Region of the 11G01 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 21) 
                   
               
             
          
           
               
                 1 
                 caggttcagc tgcaacagtc tgacgctgag ttggtgaaac ctggagcttc agtgaagata 
                   
               
               
                   
               
               
                 61 
                 tcctgcaagg tttctggcta caccttcact gaccatatta ttcactggat gaagcagagg 
               
               
                   
               
               
                 121 
                 cctgaacagg gcctggaatg gattggatat atttatccta gagatggtta tattaagtac 
               
               
                   
               
               
                 181 
                 aatgagaagt tcaagggcaa ggccacattg actgcagaca aatcctccag cacagcctac 
               
               
                   
               
               
                 241 
                 atgcaggtca acagcctgac atctgaggac tctgcagtct atttctgtgc aaggggttac 
               
               
                   
               
               
                 301 
                 tattatgcta tggactactg gggtcaagga acctcagtca ccgtctcctc a 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Heavy Chain Variable Region of the 11G01 Antibody 
                   
               
               
                 (SEQ ID NO: 22) 
                   
               
             
          
           
               
                 1 
                 qvqlqqsdae lvkpgasvki sckvsgytft    dhiih   wmkqr peqglewig   y       iyprdgyiky     
                   
               
               
                   
               
               
                 61 
                     nekfkg   katl tadkssstay mqvnsltsed savyfcar   gy       yyamdy   wgqg tsvtvss 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Kappa Chain Variable Region of the 11G01 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 23) 
                   
               
             
          
           
               
                 1 
                 gatgttttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 
                   
               
               
                   
               
               
                 61 
                 atctcttgca gatctagtca gagcattgta catagtattg gaaacaccta tttagaatgg 
               
               
                   
               
               
                 121 
                 tacctgcaga aaccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 
               
               
                   
               
               
                 181 
                 tctggggtcc cagagaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 
               
               
                   
               
               
                 241 
                 agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 
               
               
                   
               
               
                 301 
                 ttcacgttcg gctcggggac aaagttggaa ataaaa 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Kappa Chain Variable Region of the 11G01 Antibody 
                   
               
               
                 (SEQ ID NO: 24) 
                   
               
             
          
           
               
                 1 
                 dvlmtqtpls lpvslgdqas isc   rssqsiv       hsigntyle   w ylqkpgqspk lliy   kvsnrf     
                   
               
               
                   
               
               
                 61 
                     s   gvperfsgs gsgtdftlki srveaedlgv yyc   fqgshvp       ft   fgsgtkle ik 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Heavy Chain Variable Region of the 12A07 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 30) 
                   
               
             
          
           
               
                 1 
                 caggtccaac tgctgcagcc tggggctgag ctggtgaggc ctgggacttc agtgaagttg 
                   
               
               
                   
               
               
                 61 
                 tcctgcaaga cttctggcta caccttctcc agctactgga tgcactgggt aaagcagagg 
               
               
                   
               
               
                 121 
                 cctggacaag gccttgagtg gatcggaatg attgatcctt ctgatgttta tactaactac 
               
               
                   
               
               
                 181 
                 aatccaaagt tcaagggcaa ggccacattg actgttgaca catcctccag cacagcctac 
               
               
                   
               
               
                 241 
                 atgcagctca gcagcctgac atctgaggac tctgcggtct attactgtgc aagaaactac 
               
               
                   
               
               
                 301 
                 tctggggact actggggcca aggcaccact ctcacagtct cctca 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Heavy Chain Variable Region of the 12A07 Antibody 
                   
               
               
                 (SEQ ID NO: 31) 
                   
               
             
          
           
               
                 1 
                 qvqllqpgae lvrpgtsvkl scktsgytfs    sywmh   wvkqr pgqglewig   m       idpsdvytny     
                   
               
               
                   
               
               
                 61 
                     npkfkg   katl tvdtssstay mqlssltsed savyycar   ny       sgdy   wgqgtt ltvss 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Kappa Chain Variable Region of the 12A07 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 32) 
                   
               
             
          
           
               
                 1 
                 gatgttttga tgacccaaat tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 
                   
               
               
                   
               
               
                 61 
                 atctcttgta gatctagtca gagcattgtc catagtaatg gaaacaccta tttagaatgg 
               
               
                   
               
               
                 121 
                 tacctgcaga aaccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 
               
               
                   
               
               
                 181 
                 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 
               
               
                   
               
               
                 241 
                 agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc atatgttccg 
               
               
                   
               
               
                 301 
                 tggacgttcg gtggaggcac caagctggaa atcaaa 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Kappa Chain Variable Region of the 12A07 Antibody 
                   
               
               
                 (SEQ ID NO: 33) 
                   
               
             
          
           
               
                 1 
                 dvlmtqipls lpvslgdqas isc   rssqsiv       hsngntyle   w ylqkpgqspk lliy   kvsnrf     
                   
               
               
                   
               
               
                 61 
                     s   gvpdrfsgs gsgtdftlki srveaedlgv yyc f     qgsyvp       wt   fgggtkle ik 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Heavy Chain Variable Region of the 18H02 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 37) 
                   
               
             
          
           
               
                 1 
                 cagatccagt tggtacagtc tggacctgaa ctgaagaagc ctggagaggc agtcaagatc 
                   
               
               
                   
               
               
                 61 
                 tcctgcaagt cttctgggta taccttcaca acctatggaa tgagctgggt gaaacaggct 
               
               
                   
               
               
                 121 
                 ccaggaaggg ctttaaagtg gatgggctgg ataaacacct actctggagt gccaacatat 
               
               
                   
               
               
                 181 
                 gctgatgact tcaagggacg gtttgccttc tctttggaat cctctgccag cactgcctat 
               
               
                   
               
               
                 241 
                 ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc aagagggagg 
               
               
                   
               
               
                 301 
                 gatggttacc aagtggcctg gtttgcttac tggggccaag ggacgctggt cactgtctct 
               
               
                   
               
               
                 361 
                 gca 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Heavy Chain Variable Region of the 18H02 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 38) 
                   
               
             
          
           
               
                 1 
                 qiqlvqsgpe lkkpgeavki sckssgytft    tygms   wvkqa pgralkwmg   w       intysgvpty     
                   
               
               
                   
               
               
                 61 
                     addfkg   rfaf slessastay lqinnlkned tatyfcar   gr       dgyqvawfay    wgqgtlvtvs 
               
               
                   
               
               
                 121 
                 a 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Kappa Chain Variable Region of the 18H02 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 39) 
                   
               
             
          
           
               
                 1 
                 gaaacaactg tgacccagtc tccagcatcc ctgtccatgg ctataggaga taaagtcacc 
                   
               
               
                   
               
               
                 61 
                 atcagatgca taaccagcac tgatattgat gatgatatga actggttcca gcagaagcca 
               
               
                   
               
               
                 121 
                 ggggaacctc ctaagctcct tatttcagaa ggcaatactc ttcgtcctgg agtcccatcc 
               
               
                   
               
               
                 181 
                 cgattctccg gcagtggcta tggtacagat tttattttta caattgaaaa catgctctct 
               
               
                   
               
               
                 241 
                 gaagatgttg cagattacta ctgtttgcaa agtgataact tgccgtacac gttcggaggg 
               
               
                   
               
               
                 301 
                 gggaccaagc tggaaataaa a 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Kappa Chain Variable Region of the 18H02 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 40) 
                   
               
             
          
           
               
                 1 
                 ettvtqspas lsmaigdkvt irc   itstdid ddmn   wfqqkp geppkllis   e gntlrp   gvps 
                   
               
               
                   
               
               
                 61 
                 rfsgsgygtd fiftienmls edvadyyc   lq sdnlpyt   fgg gtkleik 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Heavy Chain Variable Region of the 22A02 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 47) 
                   
               
             
          
           
               
                 1 
                 caggtccaac tgcagcagcc tggggctgag ctggtgaggc ctgggacttc agtgaagttg 
                   
               
               
                   
               
               
                 61 
                 tcctgcaagg cttctggcta caccttcacc aactactgga tgcactgggt aaagcagagg 
               
               
                   
               
               
                 121 
                 cctggacaag gccttgagtg gatcggaatg attgatcctt ctgatagtta tactaactac 
               
               
                   
               
               
                 181 
                 aatccaaagt tcaagggtaa ggccacattg actgtagaca catcctccag cacagcctac 
               
               
                   
               
               
                 241 
                 atgcagctca gcagcctgac atctgaggac tctgcggtct attactgtgc aagaaactac 
               
               
                   
               
               
                 301 
                 tctggggact actggggcca aggcaccact ctcacagtct cctca 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Heavy Chain Variable Region of the 22A02 Antibody 
                   
               
               
                 (SEQ ID NO: 48) 
                   
               
             
          
           
               
                 1 
                 qvqlqqpgae lvrpgtsvkl sckasgytft    nywmh   wvkqr pgqglewig   m       idpsdsytny     
                   
               
               
                   
               
               
                 61 
                     npkfkg   katl tvdtssstay mqlssltsed savyycar   ny       sqdy   wgqgtt ltvss 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Kappa Chain Variable Region of the 22A02 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 49) 
                   
               
             
          
           
               
                 1 
                 gatgttttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 
                   
               
               
                   
               
               
                 61 
                 atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 
               
               
                   
               
               
                 121 
                 tacctgcaga aaccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 
               
               
                   
               
               
                 181 
                 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 
               
               
                   
               
               
                 241 
                 agcagagtgg aggctgagga tctgggagtt tattattgct ttcaaggttc atatgttccg 
               
               
                   
               
               
                 301 
                 tggacgttcg gtggaggcac caagctggaa atcaaa 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Kappa Chain Variable Region of the 22A02 Antibody 
                   
               
               
                 (SEQ ID NO: 50) 
                   
               
             
          
           
               
                 1 
                 dvlmtqtpls lpvslgdqas isc   rssqsiv       hsngntyle   w ylqkpgqspk lliy   kvsnrf     
                   
               
               
                   
               
               
                 61 
                     s   gvpdrfsgs gsgtdftlki srveaedlgv yyc   fqgsyvp       wt   fgggtkle ik 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Heavy Chain Variable Region of the 24C05 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 53) 
                   
               
             
          
           
               
                 1 
                 gaggtgcagc tggtggaatc tgggggaggc ttagtgaagc ctggagggtc cctgaaactc 
                   
               
               
                   
               
               
                 61 
                 tcctgtgcag cctctggatt cactttcagt gactatgcca tgtcttgggt tcgccagact 
               
               
                   
               
               
                 121 
                 ccggaaaaga ggctggagtg ggtcgcaacc attagtgatg gtggtactta cacctactat 
               
               
                   
               
               
                 181 
                 ccagacaatg taaagggccg attcaccatc tccagagaca atgccaagaa caacctgtac 
               
               
                   
               
               
                 241 
                 ctgcaaatga gccatctgaa gtctgaggac acagccatgt attactgtgc aagagaatgg 
               
               
                   
               
               
                 301 
                 ggtgattacg acggatttga ctactggggc caaggcacca ctctcacagt ctcctcg 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Heavy Chain Variable Region of the 24C05 Antibody 
                   
               
               
                 (SEQ ID NO: 54) 
                   
               
             
          
           
               
                 1 
                 evqlvesggg lvkpggslkl scaasgftfs    dyams   wvrqt pekrlewva   t       isdggtytyy     
                   
               
               
                   
               
               
                 61 
                     pdnvkg   rfti srdnaknnly lqmshlksed tamyycar   ew       gdydgfdy   wg qgttltvss 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Kappa Chain Variable Region of the 24C05 
                   
               
               
                 Antibody 
               
               
                 (SEQ ID NO: 55) 
                   
               
             
          
           
               
                 1 
                 gacatccaga tgacccagtc tccatcctcc ttatctgcct ctctgggaga aagagtcagt 
                   
               
               
                   
               
               
                 61 
                 ctcacttgtc gggcaagtca ggaaattagt ggttacttaa gctggcttca gcagaaacca 
               
               
                   
               
               
                 121 
                 gatggaacta ttaaacgcct gatctacgcc gcatccactt tagattctgg tgtcccaaaa 
               
               
                   
               
               
                 181 
                 aggttcagtg gcagtaggtc tgggtcagat tattctctca ccatcggcag ccttgagtct 
               
               
                   
               
               
                 241 
                 gaagatcttg cagactatta ctgtctacaa tatgatagtt atccgtacac gttcggaggg 
               
               
                   
               
               
                 301 
                 gggaccaagc tggaaataaa a 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Kappa Chain Variable Region of the 24C05 Antibody 
                   
               
               
                 (SEQ ID NO: 56) 
                   
               
             
          
           
               
                 1 
                 diqmtqspss lsaslgervs ltc   rasqeis       gyls   wlqqkp dgtikrliy   a       astlds   gvpk 
                   
               
               
                   
               
               
                 61 
                 rfsgsrsgsd ysltigsles edladyyc   lq       ydsypyt   fgg gtkleik 
               
             
          
         
       
     
         [0126]    The amino acid sequences defining the immunoglobulin heavy chain variable regions for the antibodies produced in Example 1 are aligned in  FIG. 2 . Amino terminal signal peptide sequences (for proper expression/secretion) are not shown. CDR 1 , CDR 2 , and CDR 3  (Kabat definition) are identified by boxes.  FIG. 3  shows an alignment of the separate CDR 1 , CDR 2 , and CDR 3  sequences for each antibody. 
         [0127]    The amino acid sequences defining the immunoglobulin light chain variable regions for the antibodies in Example 1 are aligned in  FIG. 4 . Amino terminal signal peptide sequences (for proper expression/secretion) are not shown. CDR 1 , CDR 2  and CDR 3  are identified by boxes.  FIG. 5  shows an alignment of the separate CDR 1 , CDR 2 , and CDR 3  sequences for each antibody. 
         [0128]    Table 1 is a concordance chart showing the SEQ ID NO. of each sequence discussed in this Example. 
         [0000]    
       
         
               
               
             
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 SEQ. ID 
                   
               
               
                 NO. 
                 Nucleic Acid or Protein 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 04D01 Heavy Chain Variable Region-nucleic acid 
               
               
                 2 
                 04D01 Heavy Chain Variable Region-protein 
               
               
                 3 
                 04D01 Light (kappa) Chain Variable 
               
               
                   
                 Region-nucleic acid 
               
               
                 4 
                 04D01 Light (kappa) Chain Variable 
               
               
                   
                 Region-protein 
               
               
                 5 
                 04D01 Heavy Chain CDR 1   
               
               
                 6 
                 04D01 Heavy Chain CDR 2   
               
               
                 7 
                 04D01 Heavy Chain CDR 3   
               
               
                 8 
                 04D01 Light (kappa) Chain CDR 1   
               
               
                 9 
                 04D01 Light (kappa) Chain CDR 2   
               
               
                 10 
                 04D01 Light (kappa) Chain CDR 3   
               
               
                 11 
                 09D03 Heavy Chain Variable Region-nucleic acid 
               
               
                 12 
                 09D03 Heavy Chain Variable Region-protein 
               
               
                 13 
                 09D03 Light (kappa) Chain Variable 
               
               
                   
                 Region-nucleic acid 
               
               
                 14 
                 09D03 Light (kappa) Chain Variable 
               
               
                   
                 Region-protein 
               
               
                 15 
                 09D03 Heavy Chain CDR 1   
               
               
                 16 
                 09D03 Heavy Chain CDR 2   
               
               
                 17 
                 09D03 Heavy Chain CDR 3   
               
               
                 18 
                 09D03 Light (kappa) Chain CDR 1   
               
               
                 19 
                 09D03 Light (kappa) Chain CDR 2   
               
               
                 20 
                 09D03 Light (kappa) Chain CDR 3   
               
               
                 21 
                 11G01 Heavy Chain Variable Region-nucleic acid 
               
               
                 22 
                 11G01 Heavy Chain Variable Region-protein 
               
               
                 23 
                 11G01 Light (kappa) Chain Variable 
               
               
                   
                 Region-nucleic acid 
               
               
                 24 
                 11G01 Light (kappa) Chain Variable 
               
               
                   
                 Region-protein 
               
               
                 25 
                 11G01 Heavy Chain CDR 1   
               
               
                 26 
                 11G01 Heavy Chain CDR 2   
               
               
                 27 
                 11G01 Heavy Chain CDR 3   
               
               
                 28 
                 11G01 Light (kappa) Chain CDR 1   
               
               
                 9 
                 11G01 Light (kappa) Chain CDR 2   
               
               
                 29 
                 11G01 Light (kappa) Chain CDR 3   
               
               
                 30 
                 12A07 Heavy Chain Variable Region-nucleic acid 
               
               
                 31 
                 12A07 Heavy Chain Variable Region-protein 
               
               
                 32 
                 12A07 Light (kappa) Chain Variable 
               
               
                   
                 Region-nucleic acid 
               
               
                 33 
                 12A07 Light (kappa) Chain Variable 
               
               
                   
                 Region-protein 
               
               
                 34 
                 12A07 Heavy Chain CDR 1   
               
               
                 35 
                 12A07 Heavy Chain CDR 2   
               
               
                 36 
                 12A07 Heavy Chain CDR 3   
               
               
                 8 
                 12A07 Light (kappa) Chain CDR 1   
               
               
                 9 
                 12A07 Light (kappa) Chain CDR 2   
               
               
                 10 
                 12A07 Light (kappa) Chain CDR 3   
               
               
                 37 
                 18H02 Heavy Chain Variable Region-nucleic acid 
               
               
                 38 
                 18H02 Heavy Chain Variable Region-protein 
               
               
                 39 
                 18H02 Light (kappa) Chain Variable 
               
               
                   
                 Region-nucleic acid 
               
               
                 40 
                 18H02 Light (kappa) Chain Variable 
               
               
                   
                 Region-protein 
               
               
                 41 
                 18H02 Heavy Chain CDR 1   
               
               
                 42 
                 18H02 Heavy Chain CDR 2   
               
               
                 43 
                 18H02 Heavy Chain CDR 3   
               
               
                 44 
                 18H02 Light (kappa) Chain CDR 1   
               
               
                 45 
                 18H02 Light (kappa) Chain CDR 2   
               
               
                 46 
                 18H02 Light (kappa) Chain CDR 3   
               
               
                 47 
                 22A02 Heavy Chain Variable Region-nucleic acid 
               
               
                 48 
                 22A02 Heavy Chain Variable Region-protein 
               
               
                 49 
                 22A02 Light (kappa) Chain Variable 
               
               
                   
                 Region-nucleic acid 
               
               
                 50 
                 22A02 Light (kappa) Chain Variable 
               
               
                   
                 Region-protein 
               
               
                 51 
                 22A02 Heavy Chain CDR 1   
               
               
                 52 
                 22A02 Heavy Chain CDR 2   
               
               
                 36 
                 22A02 Heavy Chain CDR 3   
               
               
                 8 
                 22A02 Light (kappa) Chain CDR 1   
               
               
                 9 
                 22A02 Light (kappa) Chain CDR 2   
               
               
                 10 
                 22A02 Light (kappa) Chain CDR 3   
               
               
                 53 
                 24C05 Heavy Chain Variable Region-nucleic acid 
               
               
                 54 
                 24C05 Heavy Chain Variable Region-protein 
               
               
                 55 
                 24C05 Light (kappa) Chain Variable 
               
               
                   
                 Region-nucleic acid 
               
               
                 56 
                 24C05 Light (kappa) Chain Variable 
               
               
                   
                 Region-protein 
               
               
                 57 
                 24C05 Heavy Chain CDR 1   
               
               
                 58 
                 24C05 Heavy Chain CDR 2   
               
               
                 59 
                 24C05 Heavy Chain CDR 3   
               
               
                 60 
                 24C05 Light (kappa) Chain CDR 1   
               
               
                 61 
                 24C05 Light (kappa) Chain CDR 2   
               
               
                 62 
                 24C05 Light (kappa) Chain CDR 3   
               
               
                   
               
             
          
         
       
     
         [0129]    Mouse monoclonal antibody heavy chain CDR sequences (Kabat, Chothia, and IMGT definitions) are shown in Table 2. 
         [0000]    
       
         
               
               
               
               
             
               
             
               
               
               
               
             
               
             
               
               
               
               
             
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                   
                 CDR1 
                 CDR2 
                 CDR3 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Kabat 
               
             
          
           
               
                 04D01 
                 SHWLH 
                 
                   VLDPSDFYSNYNQNFKG 
                 
                 GLLSGDYAMDY 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 6) 
                 (SEQ ID NO: 7) 
               
               
                   
                 NO: 5) 
                   
                   
               
               
                 09D03 
                 TFGLSVG 
                 
                   HIWWDDDKYYNPALKS 
                 
                 IGADALPFDY 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 16) 
                 (SEQ ID NO: 17) 
               
               
                   
                 NO: 15) 
                   
                   
               
               
                 11G01 
                 DHIIH 
                 
                   YIYPRDGYIKYNEKFKG 
                 
                 GYYYAMDY 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 26) 
                 (SEQ ID NO: 27) 
               
               
                   
                 NO: 25) 
                   
                   
               
               
                 12A07 
                 SYWMH 
                 
                   MIDPSDVYTNYNPKFKG 
                 
                 NYSGDY 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 35) 
                 (SEQ ID NO: 36) 
               
               
                   
                 NO: 34) 
                   
                   
               
               
                 18H02 
                 TYGMS 
                 
                   WINTYSGVPTYADDFKG 
                 
                 GRDGYQVAWFAY 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 42) 
                 (SEQ ID NO: 43) 
               
               
                   
                 NO: 41) 
                   
                   
               
               
                 22A02 
                 NYWMH 
                 
                   MIDPSDSYTNYNPKFKG 
                 
                 NYSGDY 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 52) 
                 (SEQ ID NO: 36) 
               
               
                   
                 NO: 51) 
                   
                   
               
               
                 24C05 
                 DYAMS 
                 
                   TISDGGTYTYYPDNVKG 
                 
                 EWGDYDGFDY 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 58) 
                 (SEQ ID NO: 59) 
               
               
                   
                 NO: 57) 
                   
                   
               
               
                   
               
             
          
           
               
                 Chothia 
               
             
          
           
               
                 04D01 
                 
                   GYTFTSH 
                 
                 DPSDFY 
                 GLLSGDYAMDY 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 64) 
                 (SEQ ID NO: 7) 
               
               
                   
                 NO: 63) 
                   
                   
               
               
                 09D03 
                 
                   GFSLSTFGL 
                 
                 WWDDD 
                 IGADALPFDY 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 66) 
                 (SEQ ID NO: 17) 
               
               
                   
                 NO: 65) 
                   
                   
               
               
                 11G01 
                 
                   GYTFTDH 
                 
                 YPRDGY 
                 GYYYAMDY 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 68) 
                 (SEQ ID NO: 27) 
               
               
                   
                 NO: 67) 
                   
                   
               
               
                 12A07 
                 
                   GYTFSSY 
                 
                 DPSDVY 
                 NYSGDY 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 70) 
                 (SEQ ID NO: 36) 
               
               
                   
                 NO: 69) 
                   
                   
               
               
                 18H02 
                 
                   GYTFTTY 
                 
                 NTYSGV 
                 GRDGYQVAWFAY 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 72) 
                 (SEQ ID NO: 43) 
               
               
                   
                 NO: 71) 
                   
                   
               
               
                 22A02 
                 
                   GYTFTNY 
                 
                 DPSDSY 
                 NYSGDY 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 74) 
                 (SEQ ID NO: 36) 
               
               
                   
                 NO: 73) 
                   
                   
               
               
                 24C05 
                 
                   GFTFSDY 
                 
                 SDGGTY 
                 EWGDYDGFDY 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 76) 
                 (SEQ ID NO: 59) 
               
               
                   
                 NO: 75) 
                   
                   
               
               
                   
               
             
          
           
               
                 IMGT 
               
             
          
           
               
                 04D01 
                 GYTFTSHW 
                 LDPSDFYS 
                 
                   ARGLLSGDYAMDY 
                 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 78) 
                 (SEQ ID NO: 79) 
               
               
                   
                 NO: 77) 
                   
                   
               
               
                 09D03 
                 GFSLSTFGLS 
                 IWWDDDK 
                 
                   ARIGADALPFDY 
                 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 81) 
                 (SEQ ID NO: 82) 
               
               
                   
                 NO: 80) 
                   
                   
               
               
                 11G01 
                 GYTFTDHI 
                 IYPRDGYI 
                 
                   ARGYYYAMDY 
                 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 84) 
                 (SEQ ID NO: 85) 
               
               
                   
                 NO: 83) 
                   
                   
               
               
                 12A07 
                 GYTFSSYW 
                 IDPSDVYT 
                 
                   ARNYSGDY 
                 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 87) 
                 (SEQ ID NO: 88) 
               
               
                   
                 NO: 86) 
                   
                   
               
               
                 18H02 
                 GYTFTTYG 
                 INTYSGVP 
                 
                   ARGRDGYQVAWFAY 
                 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 90) 
                 (SEQ ID NO: 91) 
               
               
                   
                 NO: 89) 
                   
                   
               
               
                 22A02 
                 GYTFTNYW 
                 IDPSDSYT 
                 
                   ARNYSGDY 
                 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 93) 
                 (SEQ ID NO: 88) 
               
               
                   
                 NO: 92) 
                   
                   
               
               
                 24C05 
                 GFTFSDYA 
                 ISDGGTYT 
                 
                   AREWGDYDGFDY 
                 
               
               
                   
                 (SEQ ID 
                 (SEQ ID NO: 95) 
                 (SEQ ID NO: 96) 
               
               
                   
                 NO: 94) 
               
               
                   
               
             
          
         
       
     
         [0130]    Mouse monoclonal antibody Kappa light chain CDR sequences (Kabat, Chothia, and IMGT definitions) are shown in Table 3. 
         [0000]    
       
         
               
               
               
               
             
               
             
               
               
               
               
             
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                   
                 CDR1 
                 CDR2 
                 CDR3 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Kabat/Chothia 
               
             
          
           
               
                 04D01 
                 
                   RSSQSIVHSNGNTYLE 
                 
                 
                   KVSNRFS 
                 
                 
                   FQGSYVPWT 
                 
               
               
                   
                 (SEQ ID NO: 8) 
                 (SEQ ID 
                 (SEQ ID NO: 10) 
               
               
                   
                   
                 NO: 9) 
                   
               
               
                 09D03 
                 
                   RSSKSLLHSNGNTYLY 
                 
                 
                   RMSNLAS 
                 
                 
                   MQHLEYPFT 
                 
               
               
                   
                 (SEQ ID NO: 18) 
                 (SEQ ID 
                 (SEQ ID NO: 20) 
               
               
                   
                   
                 NO: 19) 
                   
               
               
                 11G01 
                 
                   RSSQSIVHSIGNTYLE 
                 
                 
                   KVSNRFS 
                 
                 
                   FQGSHVPFT 
                 
               
               
                   
                 (SEQ ID NO: 28) 
                 (SEQ ID 
                 (SEQ ID NO: 29) 
               
               
                   
                   
                 NO: 9) 
                   
               
               
                 12A07 
                 
                   RSSQSIVHSNGNTYLE 
                 
                 
                   KVSNRFS 
                 
                 
                   FQGSYVPWT 
                 
               
               
                   
                 (SEQ ID NO: 8) 
                 (SEQ ID 
                 (SEQ ID NO: 10) 
               
               
                   
                   
                 NO: 9) 
                   
               
               
                 18H02 
                 
                   ITSTDIDDDMN 
                 
                 
                   EGNTLRP 
                 
                 
                   LQSDNLPYT 
                 
               
               
                   
                 (SEQ ID NO: 44) 
                 (SEQ ID 
                 (SEQ ID NO: 46) 
               
               
                   
                   
                 NO: 45) 
                   
               
               
                 22A02 
                 
                   RSSQSIVHSNGNTYLE 
                 
                 
                   KVSNRFS 
                 
                 
                   FQGSYVPWT 
                 
               
               
                   
                 (SEQ ID NO: 8) 
                 (SEQ ID 
                 (SEQ ID NO: 10) 
               
               
                   
                   
                 NO: 9) 
                   
               
               
                 24C05 
                 
                   RASQEISGYLS 
                 
                 
                   AASTLDS 
                 
                 
                   LQYDSYPYT 
                 
               
               
                   
                 (SEQ ID NO: 60) 
                 (SEQ ID 
                 (SEQ ID NO: 62) 
               
               
                   
                   
                 NO: 61) 
                   
               
               
                   
               
             
          
           
               
                 IMGT 
               
             
          
           
               
                 04D01 
                 QSIVHSNGNTY 
                 KVS 
                 FQGSYVPWT 
               
               
                   
                 (SEQ ID NO: 97) 
                   
                 (SEQ ID NO: 10) 
               
               
                 09D03 
                 KSLLHSNGNTY 
                 RMS 
                 MQHLEYPFT 
               
               
                   
                 (SEQ ID NO: 98) 
                   
                 (SEQ ID NO: 20) 
               
               
                 11G01 
                 QSIVHSIGNTY 
                 KVS 
                 FQGSHVPFT 
               
               
                   
                 (SEQ ID NO: 99) 
                   
                 (SEQ ID NO: 29) 
               
               
                 12A07 
                 QSIVHSNGNTY 
                 KVS 
                 FQGSYVPWT 
               
               
                   
                 (SEQ ID NO: 97) 
                   
                 (SEQ ID NO: 10) 
               
               
                 18H02 
                 TDIDDD 
                 EGN 
                 LQSDNLPYT 
               
               
                   
                 (SEQ ID NO: 100) 
                   
                 (SEQ ID NO: 46) 
               
               
                 22A02 
                 QSIVHSNGNTY 
                 KVS 
                 FQGSYVPWT 
               
               
                   
                 (SEQ ID NO: 97) 
                   
                 (SEQ ID NO: 10) 
               
               
                 24C05 
                 QEISGY 
                 AAS 
                 LQYDSYPYT 
               
               
                   
                 (SEQ ID NO: 101) 
                   
                 (SEQ ID NO: 62) 
               
               
                   
               
             
          
         
       
     
         [0131]    In Tables 2 and 3, the longest CDR sequences for the immunoglobulin heavy chain and light chain are shown in bold. 
         [0132]    To create the complete heavy or kappa chain antibody sequences, each variable sequence above is combined with its respective constant region. For example, a complete heavy chain comprises a heavy variable sequence followed by the murine IgG1 or IgG2b heavy chain constant sequence and a complete kappa chain comprises a kappa variable sequence followed by the murine kappa light chain constant sequence. 
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
           
               
                 Nucleic Acid Sequence Encoding the Murine IgG1 Heavy Chain Constant Region 
                   
               
               
                 (SEQ ID NO: 102) 
                   
               
             
          
           
               
                 1 
                 gccaaaacga cacccccatc tgtctatcca ctggcccctg gatctgctgc ccaaactaac 
                   
               
               
                 61 
                 tccatggtga ccctgggatg cctggtcaag ggctatttcc ctgagccagt gacagtgacc 
               
               
                 121 
                 tggaactctg gatccctgtc cagcggtgtg cacaccttcc cagctgtcct gcagtctgac 
               
               
                 181 
                 ctctacactc tgagcagctc agtgactgtc ccctccagca cctggcccag ccagaccgtc 
               
               
                 241 
                 acctgcaacg ttgcccaccc ggccagcagc accaaggtgg acaagaaaat tgtgcccagg 
               
               
                 301 
                 gattgtggtt gtaagccttg catatgtaca gtcccagaag tatcatctgt cttcatcttc 
               
               
                 361 
                 cccccaaagc ccaaggatgt gctcaccatt actctgactc ctaaggtcac gtgtgttgtg 
               
               
                 421 
                 gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag 
               
               
                 481 
                 gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc 
               
               
                 541 
                 agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc 
               
               
                 601 
                 aacagtgcag ctttccctgc ccccatcgag aaaaccatct ccaaaaccaa aggcagaccg 
               
               
                 661 
                 aaggctccac aggtgtacac cattccacct cccaaggagc agatggccaa ggataaagtc 
               
               
                 721 
                 agtctgacct gcatgataac agacttcttc cctgaagaca ttactgtgga gtggcagtgg 
               
               
                 781 
                 aatgggcagc cagcggagaa ctacaagaac actcagccca tcatggacac agatggctct 
               
               
                 841 
                 tacttcgtct acagcaagct caatgtgcag aagagcaact gggaggcagg aaatactttc 
               
               
                 901 
                 acctgctctg tgttacatga gggcctgcac aaccaccata ctgagaagag cctctcccac 
               
               
                 961 
                 tctcctggta aa 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Murine IgG1 Heavy Chain Constant Region 
                   
               
               
                 (SEQ ID NO: 103) 
                   
               
             
          
           
               
                 1 
                 akttppsvyp lapgsaaqtn smvtlgclvk gyfpepvtvt wnsgslssgv htfpavlqsd 
                   
               
               
                 61 
                 lytlsssvtv psstwpsqtv tcnvahpass tkvdkkivpr dcgckpcict vpevssvfif 
               
               
                 121 
                 ppkpkdvlti tltpkvtcvv vdiskddpev qfswfvddve vhtaqtqpre eqfnstfrsv 
               
               
                 181 
                 selpimhqdw lngkefkory nsaafpapie ktisktkgrp kapqvytipp pkeqmakdkv 
               
               
                 241 
                 sltcmitdff peditvewqw ngqpaenykn tqpimdtdgs yfvysklnvq ksnweagntf 
               
               
                 301 
                 tcsvlheglh nhhtekslsh spgk 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Murine IgG2b Heavy Chain Constant Region 
                   
               
               
                 (SEQ ID NO: 104) 
                   
               
             
          
           
               
                 1 
                 gccaaaacaa cacccccatc agtctatcca ctggcccctg ggtgtggaga tacaactggt 
                   
               
               
                 61 
                 tcctctgtga ctctgggatg cctggtcaag ggctacttcc ctgagtcagt gactgtgact 
               
               
                 121 
                 tggaactctg gatccctgtc cagcagtgtg cacaccttcc cagctctcct gcagtctgga 
               
               
                 181 
                 ctctacacta tgagcagctc agtgactgtc ccctccagca cctggccaag tcagaccgtc 
               
               
                 241 
                 acctgcagcg ttgctcaccc agccagcagc accacggtgg acaaaaaact tgagcccagc 
               
               
                 301 
                 gggcccattt caacaatcaa cccctgtcct ccatgcaagg agtgtcacaa atgcccagct 
               
               
                 361 
                 cctaacctcg agggtggacc atccgtcttc atcttccctc caaatatcaa ggatgtactc 
               
               
                 421 
                 atgatctccc tgacacccaa ggtcacgtgt gtggtggtgg atgtgagcga ggatgaccca 
               
               
                 481 
                 gacgtccaga tcagctggtt tgtgaacaac gtggaagtac acacagctca gacacaaacc 
               
               
                 541 
                 catagagagg attacaacag tactatccgg gtggtcagca ccctccccat ccagcaccag 
               
               
                 601 
                 gactggatga gtggcaagga gttcaaatgc aaggtcaaca acaaagacct cccatcaccc 
               
               
                 661 
                 atcgagagaa ccatctcaaa aattaaaggg ctagtcagag ctccacaagt atacatcttg 
               
               
                 721 
                 ccgccaccag cagagcagtt gtccaggaaa gatgtcagtc tcacttgcct ggtcgtgggc 
               
               
                 781 
                 ttcaaccctg gagacatcag tgtggagtgg accagcaatg ggcatacaga ggagaactac 
               
               
                 841 
                 aaggacaccg caccagtcct agactctgac ggttcttact tcatatatag caagctcaat 
               
               
                 901 
                 atgaaaacaa gcaagtggga gaaaacagat tccttctcat gcaacgtgag acacgagggt 
               
               
                 961 
                 ctgaaaaatt actacctgaa gaagaccatc tcccggtctc cgggtaaa 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Murine IgG2b Heavy Chain Constant Region 
                   
               
               
                 (SEQ ID NO: 105) 
                   
               
             
          
           
               
                 1 
                 akttppsvyp lapgcgdttg ssvtlgclvk gyfpesvtvt wnsgslsssv htfpallqsg 
                   
               
               
                 61 
                 lytmsssvtv psstwpsqtv tcsvahpass ttvdkkleps gpistinpcp pckechkcpa 
               
               
                 121 
                 pnleggpsvf ifppnikdvl misltpkvtc vvvdvseddp dvqiswfvnn vevhtaqtqt 
               
               
                 181 
                 hredynstir vvstlpiqhq dwmsgkefkc kvnnkdlpsp iertiskikg lvrapqvyil 
               
               
                 241 
                 pppaeqlsrk dvsltclvvg fnpgdisvew tsnghteeny kdtapvldsd gsyfiyskln 
               
               
                 301 
                 mktskwektd sfscnvrheg lknyylkkti srspgk 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Murine Kappa Light Chain Constant Region 
                   
               
               
                 (SEQ ID NO: 106) 
                   
               
             
          
           
               
                 1 
                 cgggctgatg ctgcaccaac tgtatccatc ttcccaccat ccagtgagca gttaacatct 
                   
               
               
                 61 
                 ggaggtgcct cagtcgtgtg cttcttgaac aacttctacc ccagagacat caatgtcaag 
               
               
                 121 
                 tggaagattg atggcagtga acgacaaaat ggtgtcctga acagttggac tgatcaggac 
               
               
                 181 
                 agcaaagaca gcacctacag catgagcagc accctcacat tgaccaagga cgagtatgaa 
               
               
                 241 
                 cgacataaca gctatacctg tgaggccact cacaagacat caacttcacc cattgtcaag 
               
               
                 301 
                 agcttcaaca ggaatgagtg t 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Murine Kappa Light Chain Constant Region 
                   
               
               
                 (SEQ ID NO: 107) 
                   
               
             
          
           
               
                 1 
                 radaaptvsi fppsseqlts ggasvvcfln nfyprdinvk wkidgserqn gvlnswtdqd 
                   
               
               
                 61 
                 skdstysmss tltltkdeye rhnsytceat hktstspivk sfnrnec 
               
             
          
         
       
     
         [0133]    The following sequences represent the actual or contemplated full length heavy and light chain sequences (i.e., containing both the variable and constant regions sequences) for each antibody described in this Example. Signal sequences for proper secretion of the antibodies are also included at the 5′ end of the DNA sequences or the amino terminal end of the protein sequences. The variable region sequences can be ligated to other constant region sequences, to produce active full length IgG heavy and light chains. 
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
           
               
                 Nucleic Acid Sequence Encoding the Full Length Heavy Chain Sequence 
                   
               
               
                 (Heavy Chain Variable Region and IgG1 Constant Region) of 04D01 
               
               
                 (SEQ ID NO: 108) 
                   
               
             
          
           
               
                 1 
                 atgggatgga gctgtatcat tgtcctcttg gtatcaacag ctacaggtgt ccactcccag 
                   
               
               
                 61 
                 gtccaactgc agcagcctgg ggctgaactg gtgaggcctg ggacttcagt gaagttgtcc 
               
               
                 121 
                 tgcaaggctt ctggctacac cttcaccagc cactggttgc actgggtgaa gcagaggcct 
               
               
                 181 
                 ggacaaggcc ttgagtggat cggagtgctt gatccttctg atttttatag taactacaat 
               
               
                 241 
                 caaaacttca agggcaaggc cacattgact gtagacacat cctccagcac agcctacatg 
               
               
                 301 
                 cagctcagca gcctgacatc tgaggactct gcggtctatt actgtgcacg aggcctacta 
               
               
                 361 
                 tccggggact atgctatgga ctactggggt caaggaacct cagtcaccgt ctcctcagcc 
               
               
                 421 
                 aaaacgacac ccccatctgt ctatccactg gcccctggat ctgctgccca aactaactcc 
               
               
                 481 
                 atggtgaccc tgggatgcct ggtcaagggc tatttccctg agccagtgac agtgacctgg 
               
               
                 541 
                 aactctggat ccctgtccag cggtgtgcac accttcccag ctgtcctgca gtctgacctc 
               
               
                 601 
                 tacactctga gcagctcagt gactgtcccc tccagcacct ggcccagcca gaccgtcacc 
               
               
                 661 
                 tgcaacgttg cccacccggc cagcagcacc aaggtggaca agaaaattgt gcccagggat 
               
               
                 721 
                 tgtggttgta agccttgcat atgtacagtc ccagaagtat catctgtctt catcttcccc 
               
               
                 781 
                 ccaaagccca aggatgtgct caccattact ctgactccta aggtcacgtg tgttgtggta 
               
               
                 841 
                 gacatcagca aggatgatcc cgaggtccag ttcagctggt ttgtagatga tgtggaggtg 
               
               
                 901 
                 cacacagctc agacgcaacc ccgggaggag cagttcaaca gcactttccg ctcagtcagt 
               
               
                 961 
                 gaacttccca tcatgcacca ggactggctc aatggcaagg agttcaaatg cagggtcaac 
               
               
                 1021 
                 agtgcagctt tccctgcccc catcgagaaa accatctcca aaaccaaagg cagaccgaag 
               
               
                 1081 
                 gctccacagg tgtacaccat tccacctccc aaggagcaga tggccaagga taaagtcagt 
               
               
                 1141 
                 ctgacctgca tgataacaga cttcttccct gaagacatta ctgtggagtg gcagtggaat 
               
               
                 1201 
                 gggcagccag cggagaacta caagaacact cagcccatca tggacacaga tggctcttac 
               
               
                 1261 
                 ttcgtctaca gcaagctcaa tgtgcagaag agcaactggg aggcaggaaa tactttcacc 
               
               
                 1321 
                 tgctctgtgt tacatgaggg cctgcacaac caccatactg agaagagcct ctcccactct 
               
               
                 1381 
                 cctggtaaa 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Heavy Chain Sequence 
                   
               
               
                 (Heavy Chain Variable Region and IgG1 Constant Region) of 04D01 
               
               
                 (SEQ ID NO: 109) 
                   
               
             
          
           
               
                 1 
                 mgwsciivll vstatgvhsq vqlqqpgael vrpgtsvkls ckasgytfts hwlhwvkqrp 
                   
               
               
                 61 
                 gqglewigvl dpsdfysnyn qnfkgkatlt vdtssstaym qlssltseds avyycargll 
               
               
                 121 
                 sgdyamdywg qgtsvtvssa kttppsvypl apgsaaqtns mvtlgclvkg yfpepvtvtw 
               
               
                 181 
                 nsgslssgvh tfpavlqsdl ytlsssvtvp sstwpsqtvt cnvahpasst kvdkkivprd 
               
               
                 241 
                 cgckpcictv pevssvfifp pkpkdvltit ltpkvtcvvv diskddpevq fswfvddvev 
               
               
                 301 
                 htaqtqpree qfnstfrsys elpimhqdwl ngkefkcrvn saafpapiek tisktkgrpk 
               
               
                 361 
                 apqvytippp keqmakdkvs ltcmitdffp editvewqwn gqpaenyknt qpimdtdgsy 
               
               
                 421 
                 fvysklnvqk snweagntft csvlheglhn hhtekslshs pgk 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Light Chain Sequence 
                   
               
               
                 (Kappa Chain Variable Region and Constant Region) of 04D01 
               
               
                 (SEQ ID NO: 110) 
                   
               
             
          
           
               
                 1 
                 atgaagttgc ctgttaggct gttggtgctg atgttctgga ttcctgcttc cagcagtgat 
                   
               
               
                 61 
                 gttttgatga cccaaattcc actctccctg cctgtcagtc ttggagatca agcctccatc 
               
               
                 121 
                 tcttgcagat ctagtcagag cattgtacat agtaatggaa acacctattt agaatggtac 
               
               
                 181 
                 ctgcagaaac caggccagtc tccaaagtcc ctgatctaca aagtttctaa ccgattttct 
               
               
                 241 
                 ggggtcccag acaggttcag tggcagtgga tcagggacag atttcacact caagatcagc 
               
               
                 301 
                 agagtggagg ctgaggatct gggagtttat tactgctttc aaggttcata tgttccgtgg 
               
               
                 361 
                 acgttcggtg gaggcaccaa gctggaaatc aaacgggctg atgctgcacc aactgtatcc 
               
               
                 421 
                 atcttcccac catccagtga gcagttaaca tctggaggtg cctcagtcgt gtgcttcttg 
               
               
                 481 
                 aacaacttct accccagaga catcaatgtc aagtggaaga ttgatggcag tgaacgacaa 
               
               
                 541 
                 aatggtgtcc tgaacagttg gactgatcag gacagcaaag acagcaccta cagcatgagc 
               
               
                 601 
                 agcaccctca cattgaccaa ggacgagtat gaacgacata acagctatac ctgtgaggcc 
               
               
                 661 
                 actcacaaga catcaacttc acccattgtc aagagcttca acaggaatga gtgt 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Light Chain Sequence 
                   
               
               
                 (Kappa Chain Variable Region and Constant Region) of 04D01 
               
               
                 (SEQ ID NO: 111) 
                   
               
             
          
           
               
                 1 
                 mklpvrllvl mfwipasssd vlmtqiplsl pvslgdqasi scrssqsivh sngntylewy 
                   
               
               
                 61 
                 lqkpgqspks liykvsnrfs gvpdrfsgsg sgtdftlkis rveaedlgvy ycfqgsyvpw 
               
               
                 121 
                 tfgggtklei kradaaptvs ifppsseqlt sggasvvcfl nnfyprdinv kwkidgserq 
               
               
                 181 
                 ngvinswtdq dskdstysms stltltkdey erhnsytcea thktstspiv ksfnrnec 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Heavy Chain Sequence 
                   
               
               
                 (Heavy Chain Variable Region and IgG2b Constant Region) of 09D03 
               
               
                 (SEQ ID NO: 112) 
                   
               
             
          
           
               
                 1 
                 atgggcaggc ttacttcttc attcctgtta ctgattgtcc ctgcatatgt cctgtcccag 
                   
               
               
                 61 
                 gttactctaa aagagtctgg ccctgggata ttgcggccct cccagaccct cagtctgact 
               
               
                 121 
                 tgttctttct ctgggttttc actgagcact tttggtttga gtgtaggctg gattcgtcag 
               
               
                 181 
                 ccttcaggga agggtctgga gtggctggca cacatttggt gggatgatga taagtactat 
               
               
                 241 
                 aacccagccc ttaagagtcg gctcacaatc tccaaggata cctccaaaaa ccaggtattc 
               
               
                 301 
                 ctcaagatcg ccaatgtgga cactgcagat actgccacat actactgtgc tcgaataggg 
               
               
                 361 
                 gcggacgccc ttccttttga ctactggggc caaggcacca ctctcacagt ctcctcagcc 
               
               
                 421 
                 aaaacaacac ccccatcagt ctatccactg gcccctgggt gtggagatac aactggttcc 
               
               
                 481 
                 tccgtgacct ctgggtgcct ggtcaagggg tacttccctg agccagtgac tgtgacttgg 
               
               
                 541 
                 aactctggat ccctgtccag cagtgtgcac accttcccag ctctcctgca gtctggactc 
               
               
                 601 
                 tacactatga gcagctcagt gactgtcccc tccagcacct ggccaagtca gaccgtcacc 
               
               
                 661 
                 tgcagcgttg ctcacccagc cagcagcacc acggtggaca aaaaacttga gcccagcggg 
               
               
                 721 
                 cccatttcaa caatcaaccc ctgtcctcca tgcaaggagt gtcacaaatg cccagctcct 
               
               
                 781 
                 aacctcgagg gtggaccatc cgtcttcatc ttccctccaa atatcaagga tgtactcatg 
               
               
                 841 
                 atctccctga cacccaaggt cacgtgtgtg gtggtggatg tgagcgagga tgacccagac 
               
               
                 901 
                 gtccagatca gctggtttgt gaacaacgtg gaagtacaca cagctcagac acaaacccat 
               
               
                 961 
                 agagaggatt acaacagtac tatccgggtg gtcagcaccc tccccatcca gcaccaggac 
               
               
                 1021 
                 tggatgagtg gcaaggagtt caaatgcaag gtgaacaaca aagacctccc atcacccatc 
               
               
                 1081 
                 gagagaacca tctcaaaaat taaagggcta gtcagagctc cacaagtata cactttgccg 
               
               
                 1141 
                 ccaccagcag agcagttgtc caggaaagat gtcagtctca cttgcctggt cgtgggcttc 
               
               
                 1201 
                 aaccctggag acatcagtgt ggagtggacc agcaatgggc atacagagga gaactacaag 
               
               
                 1261 
                 gacaccgcac cagttcttga ctctgacggt tcttacttca tatatagcaa gctcaatatg 
               
               
                 1321 
                 aaaacaagca agtgggagaa aacagattcc ttctcatgca acgtgagaca cgagggtctg 
               
               
                 1381 
                 aaaaattact acctgaagaa gaccatctcc cggtctccgg gtaaa 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Heavy Chain Sequence 
                   
               
               
                 (Heavy Chain Variable Region and IgG2b Constant Region) of 09D03 
               
               
                 (SEQ ID NO: 113) 
                   
               
             
          
           
               
                 1 
                 mgrltssfll livpayvlsq vtlkesgpgi lrpsqt1slt csfsgfslst fglsvgwirq 
                   
               
               
                 61 
                 psgkglewla hiwwdddkyy npalksrlti skdtsknqvf lkianvdtad tatyycarig 
               
               
                 121 
                 adalpfdywg qgttltvssa kttppsvypl apgcgdttgs svtsgclvkg yfpepvtvtw 
               
               
                 181 
                 nsgslsssvh tfpallqsgl ytmsssvtvp sstwpsqtvt csvahpasst tvdkklepsg 
               
               
                 241 
                 pistinpcpp ckechkcpap nleggpsvfi fppnikdvlm isltpkvtcv vvdvseddpd 
               
               
                 301 
                 vqiswfvnnv evhtaqtqth redynstiry vstlpiqhqd wmsgkefkck vnnkdlpspi 
               
               
                 361 
                 ertiskikgl vrapqvytlp ppaeqlsrkd vsltclvvgf npgdisvewt snghteenyk 
               
               
                 421 
                 dtapvldsdg syfiysklnm ktskwektds fscnvrhegl knyylkktis rspgk 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Light Chain Sequence 
                   
               
               
                 (Kappa Chain Variable Region and Constant Region) of 09D03 
               
               
                 (SEQ ID NO: 114) 
                   
               
             
          
           
               
                 1 
                 atgaggtgcc tagctgagtt cctggggctg cttgtgctct ggatccctgg agccattggg 
                   
               
               
                 61 
                 gatattgtgt tgactcagac tgcaccctct gtacctgtca ctcctggaga gtcagtatcc 
               
               
                 121 
                 atctcctgca ggtctagtaa gagtctcctg catagtaatg gcaacactta cttgtattgg 
               
               
                 181 
                 ttcctgcaga ggccaggcca gtctcctcag ctcctgatat atcggatgtc caaccttgcc 
               
               
                 241 
                 tcaggagtcc cagacaggtt cagtggcagt gggtcaggaa ctgctttcac actgagaatc 
               
               
                 301 
                 agtagagtgg aggctgagga tgtgggtgtt tattactgta tgcaacatct agaatatcct 
               
               
                 361 
                 ttcacgttcg gctcggggac aaagttggaa ataaaacggg ctgatgctgc accaactgta 
               
               
                 421 
                 tccatcttcc caccatccag tgagcagtta acatctggag gtgcctcagt cgtgtgcttc 
               
               
                 481 
                 ttgaacaact tctaccccag agacatcaat gtcaagtgga agattgatgg cagtgaacga 
               
               
                 541 
                 caaaatggtg tcctgaacag ttggactgat caggacagca aagacagcac ctacagcatg 
               
               
                 601 
                 agcagcaccc tcacattgac caaggacgag tatgaacgac ataacagcta tacctgtgag 
               
               
                 661 
                 gccactcaca agacatcaac ttcacccatt gtcaagagct tcaacaggaa tgagtgt 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Light Chain Sequence 
                   
               
               
                 (Kappa Chain Variable Region and Constant Region) of 09D03 
               
               
                 (SEQ ID NO: 115) 
                   
               
             
          
           
               
                 1 
                 mrclaeflgl lvlwipgaig divltqtaps vpvtpgesys iscrssksll hsngntylyw 
                   
               
               
                 61 
                 flqrpgqspq lliyrmsnla sgvpdrfsgs gsgtaftlri srveaedvgv yycmqhleyp 
               
               
                 121 
                 ftfgsgtkle ikradaaptv sifppsseql tsggasvvcf lnnfyprdin vkwkidgser 
               
               
                 181 
                 qngvinswtd qdskdstysm sstltltkde yerhnsytce athktstspi vksfnrnec 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Heavy Chain Sequence 
                   
               
               
                 (Heavy Chain Variable Region and IgG1 Constant Region) of 11G01 
               
               
                 (SEQ ID NO: 116) 
                   
               
             
          
           
               
                 1 
                 atggaatgga gctgggtctc tctcttcttc ctgtcagtaa ctacaggtgt ccactcccag 
                   
               
               
                 61 
                 gttcagctgc aacagtctga cgctgagttg gtgaaacctg gagcttcagt gaagatatcc 
               
               
                 121 
                 tgcaaggttt ctggctacac cttcactgac catattattc actggatgaa gcagaggcct 
               
               
                 181 
                 gaacagggcc tggaatggat tggatatatt tatcctagag atggttatat taagtacaat 
               
               
                 241 
                 gagaagttca agggcaaggc cacattgact gcagacaaat cctccagcac agcctacatg 
               
               
                 301 
                 caggtcaaca gcctgacatc tgaggactct gcagtctatt tctgtgcaag gggttactat 
               
               
                 361 
                 tatgctatgg actactgggg tcaaggaacc tcagtcaccg tctcctcagc caaaacgaca 
               
               
                 421 
                 cccccatctg tctatccact ggcccctgga tctgctgccc aaactaactc catggtgacc 
               
               
                 481 
                 ctgggatgcc tggtcaaggg ctatttccct gagccagtga cagtgacctg gaactctgga 
               
               
                 541 
                 tccctgtcca gcggtgtgca caccttccca gctgtcctgc agtctgacct ctacactctg 
               
               
                 601 
                 agcagctcag tgactgtccc ctccagcacc tggcccagcc agaccgtcac ctgcaacgtt 
               
               
                 661 
                 gcccacccgg ccagcagcac caaggtggac aagaaaattg tgcccaggga ttgtggttgt 
               
               
                 721 
                 aagccttgca tatgtacagt cccagaagta tcatctgtct tcatcttccc cccaaagccc 
               
               
                 781 
                 aaggatgtgc tcaccattac tctgactcct aaggtcacgt gtgttgtggt agacatcagc 
               
               
                 841 
                 aaggatgatc ccgaggtcca gttcagctgg tttgtagatg atgtggaggt gcacacagct 
               
               
                 901 
                 cagacgcaac cccgggagga gcagttcaac agcactttcc gctcagtcag tgaacttccc 
               
               
                 961 
                 atcatgcacc aggactggct caatggcaag gagttcaaat gcagggtcaa cagtgcagct 
               
               
                 1021 
                 ttccctgccc ccatcgagaa aaccatctcc aaaaccaaag gcagaccgaa ggctccacag 
               
               
                 1081 
                 gtgtacacca ttccacctcc caaggagcag atggccaagg ataaagtcag tctgacctgc 
               
               
                 1141 
                 atgataacag acttcttccc tgaagacatt actgtggagt ggcagtggaa tgggcagcca 
               
               
                 1201 
                 gcggagaact acaagaacac tcagcccatc atggacacag atggctctta cttcgtctac 
               
               
                 1261 
                 agcaagctca atgtgcagaa gagcaactgg gaggcaggaa atactttcac ctgctctgtg 
               
               
                 1321 
                 ttacatgagg gcctgcacaa ccaccatact gagaagagcc tctcccactc tcctggtaaa 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Heavy Chain Sequence 
                   
               
               
                 (Heavy Chain Variable Region and IgG1 Constant Region) of 11G01 
               
               
                 (SEQ ID NO: 117) 
                   
               
             
          
           
               
                 1 
                 mewswvslff lsvttgvhsq vqlqqsdael vkpgasvkis ckvsgytftd hiihwmkqrp 
                   
               
               
                 61 
                 eqglewigyi yprdgyikyn ekfkgkatlt adkssstaym qvnsltseds avyfcargyy 
               
               
                 121 
                 yamdywgqgt svtvssaktt ppsvyplapg saaqtnsmvt lgclvkgyfp epvtvtwnsg 
               
               
                 181 
                 slssgvhtfp avlqsdlytl sssvtvpsst wpsqtvtcnv ahpasstkvd kkivprdcgc 
               
               
                 241 
                 kpcictvpev ssvfifppkp kdvltitltp kvtcvvvdis kddpevqfsw fvddvevhta 
               
               
                 301 
                 qtqpreeqfn stfrsyselp imhqdwlngk efkcrvnsaa fpapiektis ktkgrpkapq 
               
               
                 361 
                 vytipppkeq makdkvsltc mitdffpedi tvewqwngqp aenykntqpi mdtdgsyfvy 
               
               
                 421 
                 sklnvqksnw eagntftcsv lheglhnhht ekslshspgk 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Light Chain Sequence 
                   
               
               
                 (Kappa Chain Variable Region and Constant Region) of 11G01 
               
               
                 (SEQ ID NO: 118) 
                   
               
             
          
           
               
                 1 
                 atgaagttgc ctgttaggct gttggtgctg atgttctgga ttcctgcttc cagaagtgat 
                   
               
               
                 61 
                 gttttgatga cccaaactcc actctccctg cctgtcagtc ttggagatca agcctccatc 
               
               
                 121 
                 tcttgcagat ctagtcagag cattgtacat agtattggaa acacctattt agaatggtac 
               
               
                 181 
                 ctgcagaaac caggccagtc tccaaagctc ctgatctaca aagtttccaa ccgattttct 
               
               
                 241 
                 ggggtcccag agaggttcag tggcagtgga tcagggacag atttcacact caagatcagc 
               
               
                 301 
                 agagtggagg ctgaggatct gggagtttat tactgctttc aaggttcaca tgttccattc 
               
               
                 361 
                 acgttcggct cggggacaaa gttggaaata aaacgggctg atgctgcacc aactgtatcc 
               
               
                 421 
                 atcttcccac catccagtga gcagttaaca tctggaggtg cctcagtcgt gtgcttcttg 
               
               
                 481 
                 aacaacttct accccaaaga catcaatgtc aagtggaaga ttgatggcag tgaacgacaa 
               
               
                 541 
                 aatggcgtcc tgaacagttg gactgatcag gacagcaaag acagcaccta cagcatgagc 
               
               
                 601 
                 agcaccctca cgttgaccaa ggacgagtat gaacgacata acagctatac ctgtgaggcc 
               
               
                 661 
                 actcacaaga catcaacttc acccattgtc aagagcttca acaggaatga gtgt 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Light Chain Sequence 
                   
               
               
                 (Kappa Chain Variable Region and Constant Region) of 11G01 
               
               
                 (SEQ ID NO: 119) 
                   
               
             
          
           
               
                 1 
                 mklpvrllvl mfwipasrsd vlmtqtplsl pvslgdqasi scrssqsivh signtylewy 
                   
               
               
                 61 
                 lqkpgqspkl liykvsnrfs gvperfsgsg sgtdftlkis rveaedlgvy ycfqgshvpf 
               
               
                 121 
                 tfgsgtklei kradaaptvs ifppsseqlt sggasvvcfl nnfypkdinv kwkidgserq 
               
               
                 181 
                 ngvinswtdq dskdstysms stltltkdey erhnsytcea thktstspiv ksfnrnec 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Heavy Chain Sequence 
                   
               
               
                 (Heavy Chain Variable Region and IgG1 Constant Region) of 12A07 
               
               
                 (SEQ ID NO: 120) 
                   
               
             
          
           
               
                 1 
                 atgggatgga gctgtatcat tgtcctcttg gtatcaacag ctacatgtgt ccactcccag 
                   
               
               
                 61 
                 gtccaactgc tgcagcctgg ggctgagctg gtgaggcctg ggacttcagt gaagttgtcc 
               
               
                 121 
                 tgcaagactt ctggctacac cttctccagc tactggatgc actgggtaaa gcagaggcct 
               
               
                 181 
                 ggacaaggcc ttgagtggat cggaatgatt gatccttctg atgtttatac taactacaat 
               
               
                 241 
                 ccaaagttca agggcaaggc cacattgact gttgacacat cctccagcac agcctacatg 
               
               
                 301 
                 cagctcagca gcctgacatc tgaggactct gcggtctatt actgtgcaag aaactactct 
               
               
                 361 
                 ggggactact ggggccaagg caccactctc acagtctcct cagccaaaac gacaccccca 
               
               
                 421 
                 tctgtctatc cactggcccc tggatctgct gcccaaacta actccatggt gaccctggga 
               
               
                 481 
                 tgcctggtca agggctattt ccctgagcca gtgacagtga cctggaactc tggatccctg 
               
               
                 541 
                 tccagcggtg tgcacacctt cccagctgtc ctgcagtctg acctctacac tctgagcagc 
               
               
                 601 
                 tcagtgactg tcccctccag cacctggccc agccagaccg tcacctgcaa cgttgcccac 
               
               
                 661 
                 ccggccagca gcaccaaggt ggacaagaaa attgtgccca gggattgtgg ttgtaagcct 
               
               
                 721 
                 tgcatatgta cagtcccaga agtatcatct gtcttcatct tccccccaaa gcccaaggat 
               
               
                 781 
                 gtgctcacca ttactctgac tcctaaggtc acgtgtgttg tggtagacat cagcaaggat 
               
               
                 841 
                 gatcccgagg tccagttcag ctggtttgta gatgatgtgg aggtgcacac agctcagacg 
               
               
                 901 
                 caaccccggg aggagcagtt caacagcact ttccgctcag tcagtgaact tcccatcatg 
               
               
                 961 
                 caccaggact ggctcaatgg caaggagttc aaatgcaggg tcaacagtgc agctttccct 
               
               
                 1021 
                 gcccccatcg agaaaaccat ctccaaaacc aaaggcagac cgaaggctcc acaggtgtac 
               
               
                 1081 
                 accattccac ctcccaagga gcagatggcc aaggataaag tcagtctgac ctgcatgata 
               
               
                 1141 
                 acagacttct tccctgaaga cattactgtg gagtggcagt ggaatgggca gccagcggag 
               
               
                 1201 
                 aactacaaga acactcagcc catcatggac acagatggct cttacttcgt ctacagcaag 
               
               
                 1261 
                 ctcaatgtgc agaagagcaa ctgggaggca ggaaatactt tcacctgctc tgtgttacat 
               
               
                 1321 
                 gagggcctgc acaaccacca tactgagaag agcctctccc actctcctgg taaa 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Heavy Chain Sequence 
                   
               
               
                 (Heavy Chain Variable Region and IgG1 Constant Region) of 12A07 
               
               
                 (SEQ ID NO: 121) 
                   
               
             
          
           
               
                 1 
                 mgwsciivll vstatcvhsq vqllqpgael vrpgtsvkls cktsgytfss ywmhwvkqrp 
                   
               
               
                 61 
                 gqglewigmi dpsdvytnyn pkfkgkatlt vdtssstaym qlssltseds avyycarnys 
               
               
                 121 
                 gdywgqgttl tvssakttpp svyplapgsa aqtnsmvtlg clvkgyfpep vtvtwnsgsl 
               
               
                 181 
                 ssgvhtfpav lqsdlytlss svtvpsstwp sqtvtcnvah passtkvdkk ivprdcgckp 
               
               
                 241 
                 cictvpevss vfifppkpkd vltitltpkv tcvvvdiskd dpevqfswfv ddvevhtaqt 
               
               
                 301 
                 qpreeqfnst frsyselpim hqdwlngkef kcrvnsaafp apiektiskt kgrpkapqvy 
               
               
                 361 
                 tipppkeqma kdkvsltcmi tdffpeditv ewqwngqpae nykntqpimd tdgsyfvysk 
               
               
                 421 
                 lnvqksnwea gntftcsvlh eglhnhhtek slshspgk 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Light Chain Sequence 
                   
               
               
                 (Kappa Chain Variable Region and Constant Region) of 12A07 
               
               
                 (SEQ ID NO: 122) 
                   
               
             
          
           
               
                 1 
                 atgaagttgc ctgttaggct gttggtgctg atgttctgga ttcctgcttc cagcagtgat 
                   
               
               
                 61 
                 gttttgatga cccaaattcc actctccctg cctgtcagtc ttggagatca agcctccatc 
               
               
                 121 
                 tcttgtagat ctagtcagag cattgtccat agtaatggaa acacctattt agaatggtac 
               
               
                 181 
                 ctgcagaaac caggccagtc tccaaagctc ctgatctaca aagtttccaa ccgattttct 
               
               
                 241 
                 ggggtcccag acaggttcag tggcagtgga tcagggacag atttcacact caagatcagc 
               
               
                 301 
                 agagtggagg ctgaggatct gggagtttat tactgctttc aaggttcata tgttccgtgg 
               
               
                 361 
                 acgttcggtg gaggcaccaa gctggaaatc aaacgggctg atgctgcacc aactgtatcc 
               
               
                 421 
                 atcttcccac catccagtga gcagttaaca tctggaggtg cctcagtcgt gtgcttcttg 
               
               
                 481 
                 aacaacttct accccagaga catcaatgtc aagtggaaga ttgatggcag tgaacgacaa 
               
               
                 541 
                 aatggtgtcc tgaacagttg gactgatcag gacagcaaag acagcaccta cagcatgagc 
               
               
                 601 
                 agcaccctca cattgaccaa ggacgagtat gaacgacata acagctatac ctgtgaggcc 
               
               
                 661 
                 actcacaaga catcaacttc acccattgtc aagagcttca acaggaatga gtgt 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Light Chain Sequence 
                   
               
               
                 (Kappa Chain Variable Region and Constant Region) of 12A07 
               
               
                 (SEQ ID NO: 123) 
                   
               
             
          
           
               
                 1 
                 mklpvrllvl mfwipasssd vlmtqiplsl pvslgdqasi scrssqsivh sngntylewy 
                   
               
               
                 61 
                 lqkpgqspk1 liykvsnrfs gvpdrfsgsg sgtdftlkis rveaedlgvy ycfqgsyvpw 
               
               
                 121 
                 tfgggtklei kradaaptvs ifppsseqlt sggasvvcfl nnfyprdinv kwkidgserq 
               
               
                 181 
                 ngvinswtdq dskdstysms stltltkdey erhnsytcea thktstspiv ksfnrnec 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Heavy Chain Sequence 
                   
               
               
                 (Heavy Chain Variable Region and IgG1 Constant Region) of 18H02 
               
               
                 (SEQ ID NO: 124) 
                   
               
             
          
           
               
                 1 
                 atgggttggc tgtggaactt gctattcctg atggcagctg cccaaagtgc ccaagcacag 
                   
               
               
                 61 
                 atccagttgg tacagtctgg acctgaactg aagaagcctg gagaggcagt caagatctcc 
               
               
                 121 
                 tgcaagtctt ctgggtatac cttcacaacc tatggaatga gctgggtgaa acaggctcca 
               
               
                 181 
                 ggaagggctt taaagtggat gggctggata aacacctact ctggagtgcc aacatatgct 
               
               
                 241 
                 gatgacttca agggacggtt tgccttctct ttggaatcct ctgccagcac tgcctatttg 
               
               
                 301 
                 cagatcaaca acctcaaaaa tgaggacacg gctacatatt tctgtgcaag agggagggat 
               
               
                 361 
                 ggttaccaag tggcctggtt tgcttactgg ggccaaggga cgctggtcac tgtctctgca 
               
               
                 421 
                 gccaaaacga cacccccatc tgtctatcca ctggcccctg gatctgctgc ccaaactaac 
               
               
                 481 
                 tccatggtga ccctgggatg cctggtcaag ggctatttcc ctgagccagt gacagtgacc 
               
               
                 541 
                 tggaactctg gatccctgtc cagcggtgtg cacaccttcc cagctgtcct gcagtctgac 
               
               
                 601 
                 ctctacactc tgagcagctc agtgactgtc ccctccagca cctggcccag ccagaccgtc 
               
               
                 661 
                 acctgcaacg ttgcccaccc ggccagcagc accaaggtgg acaagaaaat tgtgcccagg 
               
               
                 721 
                 gattgtggtt gtaagccttg catatgtaca gtcccagaag tatcatctgt cttcatcttc 
               
               
                 781 
                 cccccaaagc ccaaggatgt gctcaccatt actctgactc ctaaggtcac gtgtgttgtg 
               
               
                 841 
                 gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag 
               
               
                 901 
                 gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc 
               
               
                 961 
                 agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc 
               
               
                 1021 
                 aacagtgcag ctttccctgc ccccatcgag aaaaccatct ccaaaaccaa aggcagaccg 
               
               
                 1081 
                 aaggctccac aggtgtacac cattccacct cccaaggagc agatggccaa ggataaagtc 
               
               
                 1141 
                 agtctgacct gcatgataac agacttcttc cctgaagaca ttactgtgga gtggcagtgg 
               
               
                 1201 
                 aatgggcagc cagcggagaa ctacaagaac actcagccca tcatggacac agatggctct 
               
               
                 1261 
                 tacttcgtct acagcaagct caatgtgcag aagagcaact gggaggcagg aaatactttc 
               
               
                 1321 
                 acctgctctg tgttacatga gggcctgcac aaccaccata ctgagaagag cctctcccac 
               
               
                 1381 
                 tctcctggta aatga 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Heavy Chain Sequence 
                   
               
               
                 (Heavy Chain Variable Region and IgG1 Constant Region) of 18H02 
               
               
                 (SEQ ID NO: 125) 
                   
               
             
          
           
               
                 1 
                 mgwlwnllfl maaaqsaqaq iqlvqsgpel kkpgeavkis ckssgytftt ygmswvkqap 
                   
               
               
                 61 
                 gralkwmgwi ntysgvptya ddfkgrfafs lessastayl qinnlknedt atyfcargrd 
               
               
                 121 
                 gyqvawfayw gqgtivtvsa akttppsvyp lapgsaaqtn smvtlgclvk gyfpepvtvt 
               
               
                 181 
                 wnsgslssgv htfpavlqsd lytlsssvtv psstwpsqtv tcnvahpass tkvdkkivpr 
               
               
                 241 
                 dcgckpcict vpevssvfif ppkpkdvlti tltpkvtcvv vdiskddpev qfswfvddve 
               
               
                 301 
                 vhtaqtqpre eqfnstfrsv selpimhqdw lngkefkory nsaafpapie ktisktkgrp 
               
               
                 361 
                 kapqvytipp pkeqmakdkv sltcmitdff peditvewqw ngqpaenykn tqpimdtdgs 
               
               
                 421 
                 yfvysklnvq ksnweagntf tcsvlheglh nhhtekslsh spgk 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Light Chain Sequence 
                   
               
               
                 (Kappa Chain Variable Region and Constant Region) of 18H02 
               
               
                 (SEQ ID NO: 126) 
                   
               
             
          
           
               
                 1 
                 atgttctcac tagctcttct cctcagtctt cttctcctct gtgtctctga ttctagggca 
                   
               
               
                 61 
                 gaaacaactg tgacccagtc tccagcatcc ctgtccatgg ctataggaga taaagtcacc 
               
               
                 121 
                 atcagatgca taaccagcac tgatattgat gatgatatga actggttcca gcagaagcca 
               
               
                 181 
                 ggggaacctc ctaagctcct tatttcagaa ggcaatactc ttcgtcctgg agtcccatcc 
               
               
                 241 
                 cgattctccg gcagtggcta tggtacagat tttattttta caattgaaaa catgctctct 
               
               
                 301 
                 gaagatgttg cagattacta ctgtttgcaa agtgataact tgccgtacac gttcggaggg 
               
               
                 361 
                 gggaccaagc tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 
               
               
                 421 
                 tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 
               
               
                 481 
                 cccagagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggtgtcctg 
               
               
                 541 
                 aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcaca 
               
               
                 601 
                 ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 
               
               
                 661 
                 tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Light Chain Sequence 
                   
               
               
                 (Kappa Chain Variable Region and Constant Region) of 18H02 
               
               
                 (SEQ ID NO: 127) 
                   
               
             
          
           
               
                 1 
                 mfslalllsl lllcvsdsra ettvtqspas lsmaigdkvt ircitstdid ddmnwfqqkp 
                   
               
               
                 61 
                 geppkllise gntlrpgvps rfsgsgygtd fiftienmis edvadyyclq sdnlpytfgg 
               
               
                 121 
                 gtkleikrad aaptvsifpp sseqltsgga svvcflnnfy prdinvkwki dgserqngvl 
               
               
                 181 
                 nswtdqdskd stysmsstlt ltkdeyerhn sytceathkt stspivksfn rnec 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Heavy Chain Sequence 
                   
               
               
                 (Heavy Chain Variable Region and IgG1 Constant Region) of 22A02 
               
               
                 (SEQ ID NO: 128) 
                   
               
             
          
           
               
                 1 
                 atgggatgga gctgtatcat tgtcctcttg gtatcaacag ctacaggtgt ccactcccag 
                   
               
               
                 61 
                 gtccaactgc agcagcctgg ggctgagctg gtgaggcctg ggacttcagt gaagttgtcc 
               
               
                 121 
                 tgcaaggctt ctggctacac cttcaccaac tactggatgc actgggtaaa gcagaggcct 
               
               
                 181 
                 ggacaaggcc ttgagtggat cggaatgatt gatccttctg atagttatac taactacaat 
               
               
                 241 
                 ccaaagttca agggtaaggc cacattgact gtagacacat cctccagcac agcctacatg 
               
               
                 301 
                 cagctcagca gcctgacatc tgaggactct gcggtctatt actgtgcaag aaactactct 
               
               
                 361 
                 ggggactact ggggccaagg caccactctc acagtctcct cagccaaaac gacaccccca 
               
               
                 421 
                 tctgtctatc cactggcccc tggatctgct gcccaaacta actccatggt gaccctggga 
               
               
                 481 
                 tgcctggtca agggctattt ccctgagcca gtgacagtga cctggaactc tggatccctg 
               
               
                 541 
                 tccagcggtg tgcacacctt cccagctgtc ctgcagtctg acctctacac tctgagcagc 
               
               
                 601 
                 tcagtgactg tcccctccag cacctggccc agccagaccg tcacctgcaa cgttgcccac 
               
               
                 661 
                 ccggccagca gcaccaaggt ggacaagaaa attgtgccca gggattgtgg ttgtaagcct 
               
               
                 721 
                 tgcatatgta cagtcccaga agtatcatct gtcttcatct tccccccaaa gcccaaggat 
               
               
                 781 
                 gtgctcacca ttactctgac tcctaaggtc acgtgtgttg tggtagacat cagcaaggat 
               
               
                 841 
                 gatcccgagg tccagttcag ctggtttgta gatgatgtgg aggtgcacac agctcagacg 
               
               
                 901 
                 caaccccggg aggagcagtt caacagcact ttccgctcag tcagtgaact tcccatcatg 
               
               
                 961 
                 caccaggact ggctcaatgg caaggagttc aaatgcaggg tcaacagtgc agctttccct 
               
               
                 1021 
                 gcccccatcg agaaaaccat ctccaaaacc aaaggcagac cgaaggctcc acaggtgtac 
               
               
                 1081 
                 accattccac ctcccaagga gcagatggcc aaggataaag tcagtctgac ctgcatgata 
               
               
                 1141 
                 acagacttct tccctgaaga cattactgtg gagtggcagt ggaatgggca gccagcggag 
               
               
                 1201 
                 aactacaaga acactcagcc catcatggac acagatggct cttacttcgt ctacagcaag 
               
               
                 1261 
                 ctcaatgtgc agaagagcaa ctgggaggca ggaaatactt tcacctgctc tgtgttacat 
               
               
                 1321 
                 gagggcctgc acaaccacca tactgagaag agcctctccc actctcctgg taaa 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Heavy Chain Sequence 
                   
               
               
                 (Heavy Chain Variable Region and IgG1 Constant Region) of 22A02 
               
               
                 (SEQ ID NO: 129) 
                   
               
             
          
           
               
                 1 
                 mgwsciivll vstatgvhsq vqlqqpgael vrpgtsvkls ckasgytftn ywmhwvkqrp 
                   
               
               
                 61 
                 gqglewigmi dpsdsytnyn pkfkgkatlt vdtssstaym qlssltseds avyycarnys 
               
               
                 121 
                 gdywgqgttl tvssakttpp svyplapgsa aqtnsmvtlg clvkgyfpep vtvtwnsgsl 
               
               
                 181 
                 ssgvhtfpav lqsdlytlss svtvpsstwp sqtvtcnvah passtkvdkk ivprdcgckp 
               
               
                 241 
                 cictvpevss vfifppkpkd vltitltpkv tcvvvdiskd dpevqfswfv ddvevhtaqt 
               
               
                 301 
                 qpreeqfnst frsyselpim hqdwlngkef kcrvnsaafp apiektiskt kgrpkapqvy 
               
               
                 361 
                 tipppkeqma kdkvsltcmi tdffpeditv ewqwngqpae nykntqpimd tdgsyfvysk 
               
               
                 421 
                 lnvqksnwea gntftcsvlh eglhnhhtek slshspgk 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Light Chain Sequence 
                   
               
               
                 (Kappa Chain Variable Region and Constant Region) of 22A02 
               
               
                 (SEQ ID NO: 130) 
                   
               
             
          
           
               
                 1 
                 atgaagttgc ctgttaggct gttggtgctg atgttctgga ttcctgcttc cagcagtgat 
                   
               
               
                 61 
                 gttttgatga cccaaactcc actctccctg cctgtcagtc ttggagatca agcctccatc 
               
               
                 121 
                 tcttgcagat ctagtcagag cattgtacat agtaatggaa acacctattt agaatggtac 
               
               
                 181 
                 ctgcagaaac caggccagtc tccaaagctc ctgatctaca aagtttccaa ccgattttct 
               
               
                 241 
                 ggggtcccag acaggttcag tggcagtgga tcagggacag atttcacact caagatcagc 
               
               
                 301 
                 agagtggagg ctgaggatct gggagtttat tattgctttc aaggttcata tgttccgtgg 
               
               
                 361 
                 acgttcggtg gaggcaccaa gctggaaatc aaacgggctg atgctgcacc aactgtatcc 
               
               
                 421 
                 atcttcccac catccagtga gcagttaaca tctggaggtg cctcagtcgt gtgcttcttg 
               
               
                 481 
                 aacaacttct accccagaga catcaatgtc aagtggaaga ttgatggcag tgaacgacaa 
               
               
                 541 
                 aatggtgtcc tgaacagttg gactgatcag gacagcaaag acagcaccta cagcatgagc 
               
               
                 601 
                 agcaccctca cattgaccaa ggacgagtat gaacgacata acagctatac ctgtgaggcc 
               
               
                 661 
                 actcacaaga catcaacttc acccattgtc aagagcttca acaggaatga gtgt 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Light Chain Sequence 
                   
               
               
                 (Kappa Chain Variable Region and Constant Region) of 22A02 
               
               
                 (SEQ ID NO: 131) 
                   
               
             
          
           
               
                 1 
                 mklpvrllvl mfwipasssd vlmtqtp1sl pvslgdqasi scrssqsivh sngntylewy 
                   
               
               
                 61 
                 lqkpgqspk1 liykvsnrfs gvpdrfsgsg sgtdftlkis rveaedlgvy ycfqgsyvpw 
               
               
                 121 
                 tfgggtklei kradaaptvs ifppsseqlt sggasvvcfl nnfyprdinv kwkidgserq 
               
               
                 181 
                 ngvinswtdq dskdstysms stltltkdey erhnsytcea thktstspiv ksfnrnec 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Heavy Chain Sequence 
                   
               
               
                 (Heavy Chain Variable Region and IgG1 Constant Region) of 24C05 
               
               
                 (SEQ ID NO: 132) 
                   
               
             
          
           
               
                 1 
                 atgaacttcg ggctcagctt gatgttcctt gtccttgtct taaaaggtgt ccagtgtgag 
                   
               
               
                 61 
                 gtgcagctgg tggaatctgg gggaggctta gtgaagcctg gagggtccct gaaactctcc 
               
               
                 121 
                 tgtgcagcct ctggattcac tttcagtgac tatgccatgt cttgggttcg ccagactccg 
               
               
                 181 
                 gaaaagaggc tggagtgggt cgcaaccatt agtgatggtg gtacttacac ctactatcca 
               
               
                 241 
                 gacaatgtaa agggccgatt caccatctcc agagacaatg ccaagaacaa cctgtacctg 
               
               
                 301 
                 caaatgagcc atctgaagtc tgaggacaca gccatgtatt actgtgcaag agaatggggt 
               
               
                 361 
                 gattacgacg gatttgacta ctggggccaa ggcaccactc tcacagtctc ctcggccaaa 
               
               
                 421 
                 acgacacccc catctgtcta tccactggcc cctggatctg ctgcccaaac taactccatg 
               
               
                 481 
                 gtgaccctgg gatgcctggt caagggctat ttccctgagc cagtgacagt gacctggaac 
               
               
                 541 
                 tctggatccc tgtccagcgg tgtgcacacc ttcccagctg tcctgcagtc tgacctctac 
               
               
                 601 
                 actctgagca gctcagtgac tgtcccctcc agcacctggc ccagccagac cgtcacctgc 
               
               
                 661 
                 aacgttgccc acccggccag cagcaccaag gtggacaaga aaattgtgcc cagggattgt 
               
               
                 721 
                 ggttgtaagc cttgcatatg tacagtccca gaagtatcat ctgtcttcat cttcccccca 
               
               
                 781 
                 aagcccaagg atgtgctcac cattactctg actcctaagg tcacgtgtgt tgtggtagac 
               
               
                 841 
                 atcagcaagg atgatcccga ggtccagttc agctggtttg tagatgatgt ggaggtgcac 
               
               
                 901 
                 acagctcaga cgcaaccccg ggaggagcag ttcaacagca ctttccgctc agtcagtgaa 
               
               
                 961 
                 cttcccatca tgcaccagga ctggctcaat ggcaaggagt tcaaatgcag ggtcaacagt 
               
               
                 1021 
                 gcagctttcc ctgcccccat cgagaaaacc atctccaaaa ccaaaggcag accgaaggct 
               
               
                 1081 
                 ccacaggtgt acaccattcc acctcccaag gagcagatgg ccaaggataa agtcagtctg 
               
               
                 1141 
                 acctgcatga taacagactt cttccctgaa gacattactg tggagtggca gtggaatggg 
               
               
                 1201 
                 cagccagcgg agaactacaa gaacactcag cccatcatgg acacagatgg ctcttacttc 
               
               
                 1261 
                 gtctacagca agctcaatgt gcagaagagc aactgggagg caggaaatac tttcacctgc 
               
               
                 1321 
                 tctgtgttac atgagggcct gcacaaccac catactgaga agagcctctc ccactctcct 
               
               
                 1381 
                 ggtaaa 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Heavy Chain Sequence 
                   
               
               
                 (Heavy Chain Variable Region and IgG1 Constant Region) of 24C05 
               
               
                 (SEQ ID NO: 133) 
                   
               
             
          
           
               
                 1 
                 mnfglslmfl vlvlkgvqce vqlvesgggl vkpggslkls caasgftfsd yamswvrqtp 
                   
               
               
                 61 
                 ekrlewvati sdggtytyyp dnvkgrftis rdnaknnlyl qmshlksedt amyycarewg 
               
               
                 121 
                 dydgfdywgq gttltvssak ttppsvypla pgsaaqtnsm vtlgclvkgy fpepvtvtwn 
               
               
                 181 
                 sgslssgvht fpavlqsdly tlsssvtvps stwpsqtvtc nvahpasstk vdkkivprdc 
               
               
                 241 
                 gckpcictvp evssvfifpp kpkdvltitl tpkvtcvvvd iskddpevqf swfvddvevh 
               
               
                 301 
                 taqtqpreeq fnstfrsyse 1pimhqdwln gkefkcrvns aafpapiekt isktkgrpka 
               
               
                 361 
                 pqvytipppk eqmakdkvsl tcmitdffpe ditvewqwng qpaenykntq pimdtdgsyf 
               
               
                 421 
                 vysklnvqks nweagntftc svlheglhnh htekslshsp gk 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Light Chain Sequence 
                   
               
               
                 (Kappa Chain Variable Region and Constant Region) of 24C05 
               
               
                 (SEQ ID NO: 134) 
                   
               
             
          
           
               
                 1 
                 atggacatga gggttcctgc tcacgttttt ggcttcttgt tgctctggtt tccaggtacc 
                   
               
               
                 61 
                 agatgtgaca tccagatgac ccagtctcca tcctccttat ctgcctctct gggagaaaga 
               
               
                 121 
                 gtcagtctca cttgtcgggc aagtcaggaa attagtggtt acttaagctg gcttcagcag 
               
               
                 181 
                 aaaccagatg gaactattaa acgcctgatc tacgccgcat ccactttaga ttctggtgtc 
               
               
                 241 
                 ccaaaaaggt tcagtggcag taggtctggg tcagattatt ctctcaccat cggcagcctt 
               
               
                 301 
                 gagtctgaag atcttgcaga ctattactgt ctacaatatg atagttatcc gtacacgttc 
               
               
                 361 
                 ggagggggga ccaagctgga aataaaacgg gctgatgctg caccaactgt atccatcttc 
               
               
                 421 
                 ccaccatcca gtgagcagtt aacatctgga ggtgcctcag tcgtgtgctt cttgaacaac 
               
               
                 481 
                 ttctacccca gagacatcaa tgtcaagtgg aagattgatg gcagtgaacg acaaaatggt 
               
               
                 541 
                 gtcctgaaca gttggactga tcaggacagc aaagacagca cctacagcat gagcagcacc 
               
               
                 601 
                 ctcacattga ccaaggacga gtatgaacga cataacagct atacctgtga ggccactcac 
               
               
                 661 
                 aagacatcaa cttcacccat tgtcaagagc ttcaacagga atgagtgt 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Light Chain Sequence 
                   
               
               
                 (Kappa Chain Variable Region and Constant Region) of 24C05 
               
               
                 (SEQ ID NO: 135) 
                   
               
             
          
           
               
                 1 
                 mdmrvpahvf gflllwfpgt rcdiqmtqsp sslsaslger vsltcrasqe isgylswlqq 
                   
               
               
                 61 
                 kpdgtikrli yaastldsgv pkrfsgsrsg sdysltigsl esedladyyc lqydsypytf 
               
               
                 121 
                 gggtkleikr adaaptvsif ppsseqltsg gasvvcflnn fyprdinvkw kidgserqng 
               
               
                 181 
                 vlnswtdqds kdstysmsst ltltkdeyer hnsytceath ktstspivks fnrnec 
               
             
          
         
       
     
         [0134]    For convenience, Table 4 provides a concordance chart showing the correspondence between the full length sequences of the antibodies discussed in this Example with those presented in the Sequence Listing. 
         [0000]    
       
         
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                 SEQ ID 
                   
               
               
                 NO. 
                 Nucleic Acid or Protein 
               
               
                   
               
             
             
               
                 108 
                 04D01 Heavy Variable + IgG1 Constant-nucleic acid 
               
               
                 109 
                 04D01 Heavy Variable + IgG1 Constant-protein 
               
               
                 110 
                 04D01 Kappa Variable + Constant-nucleic acid 
               
               
                 111 
                 04D01 Kappa Variable + Constant-protein 
               
               
                 112 
                 09D03 Heavy Variable + IgG2b Constant-nucleic acid 
               
               
                 113 
                 09D03 Heavy Variable + IgG2b Constant-protein 
               
               
                 114 
                 09D03 Kappa Variable + Constant-nucleic acid 
               
               
                 115 
                 09D03 Kappa Variable + Constant-protein 
               
               
                 116 
                 11G01 Heavy Variable + IgG1 Constant-nucleic acid 
               
               
                 117 
                 11G01 Heavy Variable + IgG1 Constant-protein 
               
               
                 118 
                 11G01 Kappa Variable + Constant-nucleic acid 
               
               
                 119 
                 11G01 Kappa Variable + Constant-protein 
               
               
                 120 
                 12A07 Heavy Variable + IgG1 Constant-nucleic acid 
               
               
                 121 
                 12A07 Heavy Variable + IgG1 Constant-protein 
               
               
                 122 
                 12A07 Kappa Variable + Constant-nucleic acid 
               
               
                 123 
                 12A07 Kappa Variable + Constant-protein 
               
               
                 124 
                 18H02 Heavy Variable + IgG1 Constant-nucleic acid 
               
               
                 125 
                 18H02 Heavy Variable + IgG1 Constant-protein 
               
               
                 126 
                 18H02 Kappa Variable + Constant-nucleic acid 
               
               
                 127 
                 18H02 Kappa Variable + Constant-protein 
               
               
                 128 
                 22A02 Heavy Variable + IgG1 Constant-nucleic acid 
               
               
                 129 
                 22A02 Heavy Variable + IgG1 Constant-protein 
               
               
                 130 
                 22A02 Kappa Variable + Constant-nucleic acid 
               
               
                 131 
                 22A02 Kappa Variable + Constant-protein 
               
               
                 132 
                 24C05 Heavy Variable + IgG1 Constant-nucleic acid 
               
               
                 133 
                 24C05 Heavy Variable + IgG1 Constant--protein 
               
               
                 134 
                 24C05 Kappa Variable + Constant-nucleic acid 
               
               
                 135 
                 24C05 Kappa Variable + Constant-protein 
               
               
                   
               
             
          
         
       
     
       Example 3 
     Binding Affinities 
       [0135]    The binding affinities and kinetics of the binding of monoclonal antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05 to recombinant human ErbB3/Fc fusion protein (rhErbB3-Fc) were measured by surface plasmon resonance using a Biacore® T100 (Biacore) instrument. 
         [0136]    Rabbit anti-mouse IgGs (Biacore, Cat. No. BR-1008-38) were immobilized on carboxymethylated dextran CM4 sensor chips (Biacore, Cat. No. BR-1005-34) by amine coupling (BIAcore, Cat. No. BR-1000-50) using a standard coupling protocol according to vendor&#39;s instructions. The analyses were performed at 25° C., using PBS (Invitrogen, Cat. No. 14040-133) containing 0.05% surfactant P20 (Biacore, Cat. No. BR-1000-54) as running buffer. 
         [0137]    The antibodies were captured in individual flow cells at a flow rate of 10 μl/minute. Injection time was varied for each antibody to yield an R max  between 30 and 60 RU. Buffer or rhErbB3-Fc diluted in running buffer was injected sequentially over a reference surface (no antibody captured) and the active surface (antibody to be tested) for 300 seconds at 60 μl/minute. The dissociation phase was monitored for up to 3600 seconds. The surface was then regenerated with two 60-seconds injection of 10 mM Glycine-HCl, pH 1.7 (made from Glycine pH 1.5 (Biacore, Cat. No. BR-1003-54) and pH 2.0 (Biacore, Cat. No. BR-1003-55)) at a flow rate of 60 μl/minute. The rhErbB3-Fc concentration range tested was 0.125 nM to 20 nM. 
         [0138]    Kinetic parameters were determined using the kinetic function of the BIA evaluation software (Biacore) with double reference subtraction. Kinetic parameters for each antibody, k a  (association rate constant), k d  (dissociation rate constant) and K D  (equilibrium dissociation constant) were determined. Kinetic values of the monoclonal antibodies on rhErbB3-Fc at 25° C. are summarized in Table 5. 
         [0000]    
       
         
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                   
                   
                 Standard 
                   
                 Standard 
                   
                 Standard 
                   
               
               
                 Antibody 
                 k a  (1/Ms) 
                 Deviation 
                 k d  (1/s) 
                 Deviation 
                 K D  (M) 
                 Deviation 
                 n 
               
               
                   
               
             
             
               
                 04D01 
                 3.8E+05 
                 3.0E+04 
                 9.3E−05 
                 1.9E−05 
                 2.5E−10 
                 5.6E−11 
                 5 
               
               
                 09D03 
                 2.7E+05 
                 3.2E+04 
                 2.0E−05 
                 1.2E−05 
                 8.0E−11 
                 5.5E−11 
                 3 
               
               
                 11G01 
                 2.7E+05 
                 9.2E+04 
                 2.2E−05 
                 9.6E−06 
                 9.1E−11 
                 5.5E−11 
                 4 
               
               
                 12A07 
                 6.2E+05 
                 8.1E+04 
                 1.9E−04 
                 1.0E−04 
                 3.0E−10 
                 1.4E−10 
                 3 
               
               
                 18H02 
                 2.8E+05 
                 3.1E+04 
                 2.5E−05 
                 8.8E−06 
                 9.1E−11 
                 3.7E−11 
                 4 
               
               
                 22A02 
                 7.0E+05 
                 8.1E+04 
                 2.2E−04 
                 1.4E−04 
                 3.2E−10 
                 2.4E−10 
                 3 
               
               
                 24C05 
                 1.5E+06 
                 2.0E+05 
                 9.2E−06 
                 3.0E−06 
                 6.5E−12 
                 2.8E−12 
                 4 
               
               
                   
               
             
          
         
       
     
         [0139]    The data in Table 5 demonstrate that the antibodies bind rhErbB3 with a K D  of about 350 pM or less, 250 pM or less, 200 pM or less, 150 pM or less, 100 pM or less, 50 pM or less, or 10 pM or less. 
       Example 4 
     Neutralization Activity 
       [0140]    In this example, the antibodies produced in Example 1 were tested for ability to inhibit rhErbB3 binding to NRG1-β1 and NRG1-α1. The antibodies were tested by electrochemiluminescence (ECL) assay for inhibition of hErbB3 binding to NRG1-β1. MA2400 96-well standard binding plates (Meso Scale Discovery, Cat. No. L15XA-6) were coated with 50 μl of 0.5 μg/mL rhErbB3/Fc (R&amp;D systems, Cat. No. 348-RB) in PBS (Invitrogen, Cat. No. 14040-133) for overnight at 4° C. with no agitation. The plates then were washed 3 times with PBS+0.1% Tween20 (Sigma P5927) and blocked with 200 μl of PBS containing 5% BSA (Sera Care Life Sciences, Cat. No. AP-4510-80) for 1.5 hour at room temperature. After washing the plates 3 times with PBS, 25 μA of the antibody dilutions were added to the plates for another hour at room temperature with agitation. Ligand NRG1-β1 (R&amp;D Systems, Cat. No. 377-HB, 26 kDa) was added to the wells at the final concentration of 0.25 μg/ml. The plates were washed three times with PBS and incubated with 25 μl of 1 μg/mL biotinylated antibody against human NRG1-β1 (R&amp;D systems, Cat. No BAF377) preincubated for one hour with SULTO-TAG Streptavidin (Meso Scale Discovery, Cat. No R32AD-5) for one hour at room temperature with agitation. The plates then were washed 3 times with PBS, and 150 μl of 1× read buffer (Meso Scale Discovery, Cat. No. R92TC-1) was added to each well before the plates were analyzed on a Sector® Imager 2400 (Meso Scale Discovery) instrument. 
         [0141]    The interaction of NRG1-β1 with ErbB3 was inhibited by antibodies 04D01, 12A07, 18H02, 22A02 and 24C05 ( FIG. 6A ). The interaction of NRG1-β1 with rhErbB3 was enhanced by antibody 09D03, but not as well as by antibody 11G01 ( FIG. 6B ). 
         [0142]    The murine anti-human ErbB3 antibody IC 50  values for neutralization of NRG1-β1 binding to rhErbB3 for the antibodies (i.e., 04D01, 12A07, 18H02, 22A02 and 24C05) were calculated and are summarized in Table 6. 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 6 
               
             
             
               
                   
                   
               
               
                   
                 IC 50  (nM) 
                   
               
             
          
           
               
                   
                   
                   
                 Standard 
                   
               
               
                   
                 Antibody 
                 Average 
                 Deviation 
                 n 
               
               
                   
                   
               
               
                   
                 04D01 
                 0.2232 
                 0.0711 
                 4 
               
               
                   
                 12A07 
                 0.2351 
                 0.0530 
                 4 
               
               
                   
                 18H02 
                 0.3460 
                 0.0873 
                 4 
               
               
                   
                 22A02 
                 0.2418 
                 0.0755 
                 4 
               
               
                   
                 24C05 
                 0.3367 
                 0.0764 
                 4 
               
               
                   
                   
               
             
          
         
       
     
         [0143]    The results show that antibodies 04D01, 12A07, 18H02, 22A02, and 24C05 efficiently neutralized NRG1-β1 binding to rhErbB3. Antibodies 09D03 and 11G01 enhanced hNRG1-β1 binding to hErbB3. 
         [0144]    The antibodies were tested by ECL assay for inhibition of hErbB3 binding to the second ErbB3 ligand, NRG1-α1. To assay inhibition of binding of NRG1-α1 to rhErbB3, the same method used for NRG1-β1 was used, except for the following changes: concentrations of plated rhErbB3/Fc (R&amp;D 4518-RB) and of ligand NRG1-α1 (Thermo Scientific, RP-317-P1AX) were 1 μg/ml and 1.5 μg/ml, respectively. 
         [0145]    The interaction of NRG1-α1 with rhErbB3 was inhibited by 11G01, 12A07, 18H02, 22A02, and 24C05 IgG1, and was enhanced by antibody 09D03 ( FIG. 7 ). 
       Example 5 
     Binding to ErbB3 domain II 
       [0146]    In this example, the antibodies produced in Example 1 were tested for binding to the dimerization domain (domain 2) of hErbB3-ECD. Domain 2 of hErbB3 (118 amino acids, position 210-327) was cloned in place of domain 2 of Her2 (119 amino acids, position AA220-338) into the full-length Her2 receptor. The hybrid construct Her2/3d2 was cloned into pLenti6.3 and packaged by transient transfection of 293T cells into a Lentivirus using the ViraPower™ Lentiviral Support Kit (Invitrogen, Cat. No. K497000). CHO cells were infected with the lentivirus expressing the Her2/3d2 hybrid protein. The binding of the anti-ErbB3 hybridoma supernatants to Her2/3d2 were tested on these engineered CHO cells by ECL with sulfo-tagged anti-mouse antibodies. Data on the binding of the hybridoma supernatants to the chimeric protein Her2/3d2 expressed on the cell surface of CHO cells are summarized in  FIG. 8 . These results show that antibodies 09D03 and 11G01 bound to the ErbB3 domain 11, AA210-327. 
       Example 6 
     Anti-Proliferative Activity 
       [0147]    This example describes a characterization of the antibodies produced in Example 1 for their ability to inhibit NRG1-β1 dependent proliferation of cells. Antibodies were tested in the BaF/3 cell system engineered to express both human Her2 and ErbB3 and in the human MCF7 breast cancer cells which naturally express both Her2 and ErbB3 and grow in response to NRG1-β1 stimulation. 
         [0148]    BaF/3 cells were infected by two lentiviruses engineered to express human Her2 or human ErbB3. Infected cells were selected with blasticidin (15 μg/ml; Invitrogen, Cat. No. R21001) and individual colonies were isolated and tested for expression of both receptors. Her2/ErbB3 expressing clones were maintained in culture under blasticidin selection with [80% RPMI Medium 1640 (GIBCO, Cat. No. 11875-093), 10% fetal bovine serum (GIBCO, Cat. No. 10438-026) and 10% WEHI cell conditioned media {90% ISCOVE&#39;s Modified Dulbecco&#39;s Medium (GIBCO, Cat. No. 12440053), 10% fetal bovine serum (GIBCO, Cat. No. 10438-026)+2 mM L-glutamine (GIBCO, Cat. No. 25030-081)+0.0025 mM mercaptoethanol (Invitrogen, Cat. No. 21985-023)}]. To screen for antagonistic ErbB3 antibodies, cells were rinsed with PBS, and grown in the absence of blasticidin and WEHI conditioned media. Assays were conducted in a 96-well plate (5,000 cells/well) in the presence of NRG1-β1 (100 ng/ml) and various concentrations of antibodies (0.018-5000 ng/ml in 100 μl final volume). MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays were conducted 3-4 days post NRG1-β1 stimulation. 
         [0149]    An example of the dose-dependent inhibition of NRG1-β1 dependent cell proliferation of Her2/ErbB3-BaF/3 by murine anti-human ErbB3 antibodies is shown in  FIG. 9 . Inhibition data of NRG1-β1 dependent Her2/ErbB3-BaF/3 cell line proliferation with monoclonal antibodies (i.e., 04D01, 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05) are summarized in Table 7. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 Her2/ErbB3-BaF/3, NRG1-β1 dep. Proliferation 
               
             
          
           
               
                   
                   
                 IC 50  (nM)- 
                   
                   
               
               
                   
                 Antibody 
                 Average 
                 Standard deviation 
                 n 
               
               
                   
                   
               
               
                   
                 04D01 
                 0.373 
                 0.061 
                 3 
               
               
                   
                 09D03 
                 1.395 
                 0.268 
                 3 
               
               
                   
                 11G01 
                 1.934 
                 0.116 
                 3 
               
               
                   
                 12A07 
                 0.854 
                 0.059 
                 3 
               
               
                   
                 18H02 
                 1.930 
                 0.276 
                 3 
               
               
                   
                 22A02 
                 1.291 
                 0.151 
                 3 
               
               
                   
                 24C05 
                 0.145 
                 0.031 
                 3 
               
               
                   
                   
               
             
          
         
       
     
         [0150]    The results in Table 7 show that antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05 strongly inhibited NRG1-β1-induced proliferation of BaF/3 cells expressing Her2/ErbB3. 
         [0151]    MCF7 cells (ATCC, Cat. No. HTB-22) were maintained as recommended by ATCC. Cells were plated at 5,000 cells/well in a 96-well plate. Cells were starved overnight in the absence of serum. The following day, NRG1-β1 (40 ng/ml) and various concentrations of antibodies (12.8 pg/ml-20 μg/ml in 100 μl final volume) were added to the cells. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays were conducted three days post NRG1-β1 stimulation. 
         [0152]    An example of the dose-dependent inhibition of NRG1-β1 dependent proliferation of MCF7 cells by murine anti-human ErbB3 antibodies is shown in  FIG. 10 . Inhibition data of NRG1-β1 dependent MCF7 cell proliferation with antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05 are summarized in Table 8. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 MCF7 cells, NRG1-β1 dependent Proliferation 
               
             
          
           
               
                   
                   
                 IC 50  (nM)- 
                   
                   
               
               
                   
                 Antibody 
                 Average 
                 Standard deviation 
                 n 
               
               
                   
                   
               
               
                   
                 04D01 
                 0.47 
                 0.23 
                 3 
               
               
                   
                 09D03 
                 2.28 
                 0.60 
                 3 
               
               
                   
                 11G01 
                 1.98 
                 1.34 
                 3 
               
               
                   
                 12A07 
                 0.74 
                 0.48 
                 3 
               
               
                   
                 18H02 
                 1.00 
                 0.20 
                 3 
               
               
                   
                 22A02 
                 1.62 
                 0.60 
                 3 
               
               
                   
                 24C05 
                 0.39 
                 0.04 
                 3 
               
               
                   
                   
               
             
          
         
       
     
         [0153]    The results in Table 8 demonstrate that antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02, and 24C05 strongly inhibited NRG1-β1-induced proliferation of MCF7 cells. 
         [0154]    The antibodies produced in Example 1 were also tested for their ability to inhibit proliferation of ErbB3 expressing human cancer cells. Breast cancer cells SKBR-3 overexpress Her2 and are sensitive to Her2-specific inhibitory antibodies. 
         [0155]    SKBR-3 cells (ATCC, Cat. No. HTB-30) were maintained as recommended by ATCC. Cells were plated at 5,000 cells/well in a 96-well plate in the presence of 5 μg/ml of antibodies but without exogenous NRG1-β1. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays were conducted after three days in culture. 
         [0156]    An example of inhibition of cell proliferation of SKBR-3 cells by murine anti-human ErbB3 antibodies is shown in  FIG. 11 . The results in  FIG. 11  show that antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05 inhibited proliferation of SKBR-3 cells. 
       Example 7 
     Inhibition of Downstream Signaling 
       [0157]    This example describes a characterization of the antibodies produced in Example 1 for their ability to inhibit NRG1-β1 dependent phosphorylation of ErbB3 and the downstream kinase Akt, as the readout for PI3K activation. These antibodies were also tested for their ability to inhibit steady state phosphorylation of ErbB3 and Akt in exponentially growing cells. 
         [0158]    Breast cancer cells SKBR-3 and MCF7 and prostate cancer cells DU145 were maintained as recommended by ATCC. Cells were starved overnight in 0% FBS, treated for one hour with 5 μg/ml of antibody followed by NRG1-β1 stimulation. Lysates were either analyzed by ELISA with the Phospho-ErbB3 kit from R&amp;D Systems (Cat. No DYC1769) or with the Phospho-Akt ELISA kit from Cell Signaling (Cat. No 7143). 
         [0159]    An example of the inhibition of the NRG1-β1 induced phosphorylation of ErbB3 in SKBR-3 cells by murine anti-human ErbB3 antibodies is shown in  FIG. 12 . The results in  FIG. 12  demonstrated that antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05 inhibited at least 50% of the phosphorylation of ErbB3 induced by NRG1-β1 in SKBR-3 cells. 
         [0160]    An example of the inhibition of the NRG1-β1 induced phosphorylation of Akt in MCF7 and DU145 cells by murine anti-human ErbB3 antibodies is shown in  FIG. 13A  and  FIG. 13B , respectively. The results in  FIGS. 13A and 13B  demonstrated that antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05 inhibited at least 80% of the phosphorylation of Akt in response to the NRG1-β1 in both MCF7 and DU145 cells. 
         [0161]    The capacity of the anti-ErbB3 antibodies to inhibit the steady state phosphorylation status of ErbB3 and Akt in a breast cancer cell line SKBR-3 and a pancreatic cancer cell line B×PC3 were tested by treating these exponentially growing cells for one hour in presence of antibodies at 5 μg/ml. 
         [0162]    Western blot analysis of these experiments demonstrated that antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05 inhibited the steady state level of phosphorylation of Akt and ErbB3 in both SKBR-3 and B×PC3 cells. 
       Example 8 
     Inhibition of NRG1-β1-Induced EGFR Phosphorylation 
       [0163]    In this example, the antibodies produced in Example 1 were tested for their ability to inhibit NRG1-β1 dependent phosphorylation of EGFR in the ovarian cancer cell line NCI/ADR-RES. NCI/ADR-RES cells (DTP/DCTD NCI tumor repository) were starved overnight in 0% FBS, pre-treated with antibody (5 μg/ml) for one hour followed by NRG1-β1 (20 ng/ml) stimulation for 15 minutes. The phosphorylation of EGFR on tyrosine 1068 was analyzed by Western blot. The results of this experiment demonstrated that antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05 inhibited the phosphorylation of EGFR in response to the NRG1-β1 in NCI/ADR-RES cells. 
       Example 9 
     Inhibition of EGF-Induced ErbB3 Phosphorylation 
       [0164]    In this example, the antibodies produced in Example 1 were tested for their ability to inhibit EGF dependent phosphorylation of ErbB3 in the EGFR overexpressing, epidermoid cancer cell line A431. A431 cells (ATCC, Cat. No CRL-1555) were starved overnight in 0% FBS, pre-treated with antibody (5 μg/ml) for one hour followed by EGF (R&amp;D Systems, Cat. No. 236-EG) (50 ng/ml) stimulation for 15 minutes. The phosphorylation of ErbB3 was analyzed by Western blot. The results of this experiment demonstrated that antibodies 04D01, 09D03, 12A07, 18H02, 22A02 and 24C05 inhibited to various extents the phosphorylation of ErbB3 in response to the EGF in A431 cells. 
       Example 10 
     Inhibition of NRG1-β1-Induced her2/ErbB3 Heterodimer Formation 
       [0165]    This example describes a characterization of the antibodies produced in Example 1 for their ability to inhibit the formation of the Her2/ErbB3 dimer in response to NRG1-β1 in SKBR-3 cells. Breast cancer cells SKBR-3 were starved overnight in 0% FBS, treated for one hour with 5 μg/ml of antibody followed by NRG1-β1 stimulation (30 ng/ml, 30 min). Lysates were immunoprecipitated with anti-Her2 antibody (R&amp;D Systems, Cat. No. BAF1129) and analyzed by Western blot with polyclonal anti-ErbB3 antibody (Santa Cruz, Cat. No. SC285). 
         [0166]    The results of this experiment demonstrated that antibodies 04D01, 09D03, 11G01, 12A07, 18H02, 22A02 and 24C05 inhibited NRG1-β1-induced Her2/ErbB3 dimer formation in SKBR-3 cells. 
       Example 11 
     Inhibition of B×PC3 Tumor Xenograft Growth 
       [0167]    The ability of murine monoclonal antibodies produced in Example 1 to inhibit tumor growth was tested in a pancreatic B×PC3 xenograft model. Human pancreatic B×PC3 cells were grown in culture in 37° C. in an atmosphere containing 5% CO2, using RMPI medium containing 10% fetal bovine serum. B×PC3 cells were inoculated subcutaneously into the flank of 8-week old female CB.17 SCID mice (Taconic Labs) with 10×10 6  cells per mouse in 50% matrigel (BD Biosciences, Cat No. 356237). Tumor measurements were taken twice weekly using vernier calipers. Tumor volume was calculated using the formula: width×width×length/2. When tumors reached approximately 200 mm 3 , the mice were randomized into 9 groups of 10 mice each. One group received PBS and another received human IgG control (huIgG). Each of the other eight groups received one of the antibody, 04D01, 09D03, 18H02, 11G01, 24C05, 22A02, or 12A07. All antibodies were dosed at 20 mg/kg body weight, twice per week, by intra-peritoneal injection for 6 weeks. Tumor volumes and mouse body weights were recorded twice per week. Tumor growth inhibition was analyzed using ANOVA and is expressed as percent inhibition compared to the PBS control. 
         [0168]    The results in  FIG. 14  show that antibody 24C05 inhibited tumor growth by 76% in this model (p&lt;0.001). Antibodies 04D01, 18H02 and 11G01 also inhibited tumor growth in this model at 64%, 71%, and 72%, respectively (p&lt;0.001). Antibodies 12A07 and 22A02 demonstrated the least activity, i.e., near 40% tumor growth inhibition, while antibody 09D03 gave 60% tumor growth inhibition in this model. 
       Example 12 
     Humanization of Anti-ErbB3 Antibodies 
       [0169]    A. Construction of Humanized and Chimeric Anti-ErbB3 Antibodies 
         [0170]    This Example describes the humanization of the murine antibody designated 24C05, and the characterization of the resulting humanized antibodies. The humanized anti-ErbB3 antibodies were designed using the SUPERHUMANIZATION™ method (Arana Therapeutics Ltd. and Hwang, W. Y. et al. (2005) METHODS 36:35-42) or the CDR grafting method with back mutations (some human framework residues were changed to murine residues) (See e.g., U.S. Pat. Nos. 5,530,101; 5,693,761; 5,693,762; 5,585,089; 6,180,370; 7,022,500). With the exception of heavy chain CDR1, the Kabat CDR definitions were used for CDR grafting onto human frameworks. A combination of Kabat and Chothia definitions were used for grafting heavy CDR1. The designed amino acid sequences were converted to codon-optimized DNA sequences and synthesized by DNA2.0, Inc. to include (in the following order): 5′ HindIII restriction site, Kozak consensus sequence, amino terminal signal sequence, humanized variable region, human IgG1 or Kappa constant region, stop codon, and a 3′ EcoRI restriction site. Additionally, one humanized heavy chain, Sh24C05 Hv3-11 Heavy IgG1, was mutated using overlap extension PCR to enhance humanization, resulting in the Sh24C05 Hv3-11 N62S heavy chain IgG1. A human IgG2 version of the Sh24C05 Hv3-11 N62S heavy chain was also constructed. 
         [0171]    The anti-ErbB3 antibody chains humanized according to the SUPERHUMANIZATION™ method, as described herein, are designated with the prefix “Sh” before the antibody chain name. The anti-ErbB3 antibody chains humanized by the CDR grafting method with back mutations, as described herein, are designated with the prefix “Hu” before the antibody chain name. 
         [0172]    Chimeric (murine variable region and human constant region) 24C05 heavy (human IgG1) and light (human Kappa) chains were also constructed. The murine variable regions were fused to the human constant region using overlap extension PCR, including (in the following order): 5′ HindIII restriction site, Kozak consensus sequence, amino terminal signal sequence, mouse variable region, human IgG1 or Kappa constant region, stop codon, and 3′ EcoRI restriction site. 
         [0173]    The humanized and chimeric heavy chains were subcloned into pEE6.4 (Lonza Biologics) via HindIII and EcoRI sites using In-Fusion™ PCR cloning (Clontech). The humanized and chimeric Kappa light chains were subcloned into pEE14.4 (Lonza Biologics) via HindIII and EcoRI sites using In-Fusion™ PCR cloning. 
         [0174]    Humanized antibody chains or chimeric antibody chains were transiently transfected into 293T cells to produce antibody. Antibody was either purified or used in cell culture media supernatant for subsequent in vitro analysis. Binding of the chimeric and humanized antibodies to human ErbB3 was measured as described below. The results are summarized in Table 15. 
         [0175]    Additionally, some humanized antibody heavy and light chain combinations were stably expressed in CHOK1 SV cells using the GS System™ (Lonza Biologics) in order to produce large quantities of purified humanized antibody. A single expression vector was constructed by combining pEE6.4 and pEE14.4 based vectors. First, pEE6.4 containing full length humanized heavy chain cDNA was digested with NotI and SalI to isolate the hCMV-MIE promoter+full length humanized heavy chain cDNA+SV40 polyA fragment. This fragment was inserted into the pEE14.4 vector already containing full length humanized light chain cDNA via NotI/SalI sites, thus creating an expression vector that simultaneously expresses heavy and light chains. The combined heavy and light chain vector was linearized and transfected into CHOK1SV cells. Stable clones were selected in the presence of methionine sulfoximine. 
         [0176]    Each of the possible combinations of the humanized immunoglobulin heavy chain and immunoglobulin light chain variable regions are set forth below in Table 9. 
         [0000]    
       
         
               
               
             
           
               
                 TABLE 9 
               
               
                   
               
               
                 Light Chain Variable Region 
                 Heavy Chain Variable Region 
               
               
                   
               
             
             
               
                 Hu24C05 KvA (SEQ ID NO: 174) 
                 Hu24C05 HvA (SEQ ID NO: 162) 
               
               
                 Hu24C05 KvA (SEQ ID NO: 174) 
                 Sh24C05 Hv3-21 (SEQ ID NO: 156) 
               
               
                 Hu24C05 KvA (SEQ ID NO: 174) 
                 Sh24C05 Hv3-23 (SEQ ID NO: 158) 
               
               
                 Hu24C05 KvA (SEQ ID NO: 174) 
                 Sh24C05 Hv3-30 (SEQ ID NO: 160) 
               
               
                 Hu24C05 KvA (SEQ ID NO: 174) 
                 Sh24C05 Hv3-7 (SEQ ID NO: 150) 
               
               
                 Hu24C05 KvA (SEQ ID NO: 174) 
                 Sh24C05 Hv3-11 (SEQ ID NO: 152) 
               
               
                 Hu24C05 KvA (SEQ ID NO: 174) 
                 Sh24C05 Hv3-11 N62S (SEQ ID NO: 154) 
               
               
                 Sh24C05 Kv1-16 (SEQ ID NO: 166) 
                 Hu24C05 HvA (SEQ ID NO: 162) 
               
               
                 Sh24C05 Kv1-16 (SEQ ID NO: 166) 
                 Sh24C05 Hv3-21 (SEQ ID NO: 156) 
               
               
                 Sh24C05 Kv1-16 (SEQ ID NO: 166) 
                 Sh24C05 Hv3-23 (SEQ ID NO: 158) 
               
               
                 Sh24C05 Kv1-16 (SEQ ID NO: 166) 
                 Sh24C05 Hv3-30 (SEQ ID NO: 160) 
               
               
                 Sh24C05 Kv1-16 (SEQ ID NO: 166) 
                 Sh24C05 Hv3-7 (SEQ ID NO: 150) 
               
               
                 Sh24C05 Kv1-16 (SEQ ID NO: 166) 
                 Sh24C05 Hv3-11 (SEQ ID NO: 152) 
               
               
                 Sh24C05 Kv1-16 (SEQ ID NO: 166) 
                 Sh24C05 Hv3-11 N62S (SEQ ID NO: 154) 
               
               
                 Sh24C05 Kv1-17 (SEQ ID NO: 168) 
                 Hu24C05 HvA (SEQ ID NO: 162) 
               
               
                 Sh24C05 Kv1-17 (SEQ ID NO: 168) 
                 Sh24C05 Hv3-21 (SEQ ID NO: 156) 
               
               
                 Sh24C05 Kv1-17 (SEQ ID NO: 168) 
                 Sh24C05 Hv3-23 (SEQ ID NO: 158) 
               
               
                 Sh24C05 Kv1-17 (SEQ ID NO: 168) 
                 Sh24C05 Hv3-30 (SEQ ID NO: 160) 
               
               
                 Sh24C05 Kv1-17 (SEQ ID NO: 168) 
                 Sh24C05 Hv3-7 (SEQ ID NO: 150) 
               
               
                 Sh24C05 Kv1-17 (SEQ ID NO: 168) 
                 Sh24C05 Hv3-11 (SEQ ID NO: 152) 
               
               
                 Sh24C05 Kv1-17 (SEQ ID NO: 168) 
                 Sh24C05 Hv3-11 N62S (SEQ ID NO: 154) 
               
               
                 Sh24C05 Kv1-33 (SEQ ID NO: 170) 
                 Hu24C05 HvA (SEQ ID NO: 162) 
               
               
                 Sh24C05 Kv1-33 (SEQ ID NO: 170) 
                 Sh24C05 Hv3-21 (SEQ ID NO: 156) 
               
               
                 Sh24C05 Kv1-33 (SEQ ID NO: 170) 
                 Sh24C05 Hv3-23 (SEQ ID NO: 158) 
               
               
                 Sh24C05 Kv1-33 (SEQ ID NO: 170) 
                 Sh24C05 Hv3-30 (SEQ ID NO: 160) 
               
               
                 Sh24C05 Kv1-33 (SEQ ID NO: 170) 
                 Sh24C05 Hv3-7 (SEQ ID NO: 150) 
               
               
                 Sh24C05 Kv1-33 (SEQ ID NO: 170) 
                 Sh24C05 Hv3-11 (SEQ ID NO: 152) 
               
               
                 Sh24C05 Kv1-33 (SEQ ID NO: 170) 
                 Sh24C05 Hv3-11 N62S (SEQ ID NO: 154) 
               
               
                 Sh24C05 Kv1-9 (SEQ ID NO: 164) 
                 Hu24C05 HvA (SEQ ID NO: 162) 
               
               
                 Sh24C05 Kv1-9 (SEQ ID NO: 164) 
                 Sh24C05 Hv3-21 (SEQ ID NO: 156) 
               
               
                 Sh24C05 Kv1-9 (SEQ ID NO: 164) 
                 Sh24C05 Hv3-23 (SEQ ID NO: 158) 
               
               
                 Sh24C05 Kv1-9 (SEQ ID NO: 164) 
                 Sh24C05 Hv3-30 (SEQ ID NO: 160) 
               
               
                 Sh24C05 Kv1-9 (SEQ ID NO: 164) 
                 Sh24C05 Hv3-7 (SEQ ID NO: 150) 
               
               
                 Sh24C05 Kv1-9 (SEQ ID NO: 164) 
                 Sh24C05 Hv3-11 (SEQ ID NO: 152) 
               
               
                 Sh24C05 Kv1-9 (SEQ ID NO: 164) 
                 Sh24C05 Hv3-11 N62S (SEQ ID NO: 154) 
               
               
                 Sh24C05 Kv1-39 (SEQ ID NO: 172) 
                 Hu24C05 HvA (SEQ ID NO: 162) 
               
               
                 Sh24C05 Kv1-39 (SEQ ID NO: 172) 
                 Sh24C05 Hv3-21 (SEQ ID NO: 156) 
               
               
                 Sh24C05 Kv1-39 (SEQ ID NO: 172) 
                 Sh24C05 Hv3-23 (SEQ ID NO: 158) 
               
               
                 Sh24C05 Kv1-39 (SEQ ID NO: 172) 
                 Sh24C05 Hv3-30 (SEQ ID NO: 160) 
               
               
                 Sh24C05 Kv1-39 (SEQ ID NO: 172) 
                 Sh24C05 Hv3-7 (SEQ ID NO: 150) 
               
               
                 Sh24C05 Kv1-39 (SEQ ID NO: 172) 
                 Sh24C05 Hv3-11 (SEQ ID NO: 152) 
               
               
                 Sh24C05 Kv1-39 (SEQ ID NO: 172) 
                 Sh24C05 Hv3-11 N62S (SEQ ID NO: 154) 
               
               
                   
               
             
          
         
       
     
         [0177]    The nucleic acid sequences encoding and the protein sequences defining variable regions of the humanized 24C05 antibodies are summarized below (amino terminal signal peptide sequences are not shown). CDR sequences (Kabat definition) are shown in bold and are underlined in the amino acid sequences. 
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
           
               
                 Nucleic Acid Sequence Encoding the Sh24C05 Hv3-7 Heavy Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 149) 
                   
               
             
          
           
               
                 1 
                 gaggttcagc tggtggaatc tggcggtggg cttgtacaac caggaggctc cctcagactg 
                   
               
               
                 61 
                 agttgtgccg cttcagggtt cacattctcc gactatgcga tgtcatgggt gcgccaagca 
               
               
                 121 
                 cccgggaaag gactggagtg ggttgccact atcagcgatg gcggaacgta tacctattac 
               
               
                 181 
                 cctgacaatg tgaagggtcg gttcaccatt tccagggata acgcaaagaa cagtctctac 
               
               
                 241 
                 ctgcagatga acagcctgag ggctgaggac accgccgtct actactgcgc ccgagaatgg 
               
               
                 301 
                 ggagattatg atgggtttga ctattggggc cagggcactt tggtgacagt cagttct 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Sh24C05 Hv3-7 Heavy Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 150) 
                   
               
             
          
           
               
                 1 
                 evqlvesggg lvqpggslrl scaasgftfs    dyams   wvrga pgkglewva   t isdggtytyy     
                   
               
               
                 61 
                     pdnvkg   rfti srdnaknsly lqmnslraed tavyycar   ew gdydgfdy   wg qgtivtvss 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Sh24C05 Hv3-11 Heavy Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 151) 
                   
               
             
          
           
               
                 1 
                 caagttcagc tggtggaatc tggcggtggg cttgtaaagc caggaggctc cctcagactg 
                   
               
               
                 61 
                 agttgtgccg cttcagggtt cacattctcc gactatgcga tgtcatggat caggcaagca 
               
               
                 121 
                 cccgggaaag gactggagtg ggttagcact atcagcgatg gcggaacgta tacctattac 
               
               
                 181 
                 cctgacaatg tgaagggtcg gttcaccatt tccagggata acgcaaagaa cagtctctac 
               
               
                 241 
                 cttcagatga acagcctgag ggctgaggac accgccgtct actactgcgc ccgagaatgg 
               
               
                 301 
                 ggagattatg atgggtttga ctattggggc cagggcactt tggtgacagt cagttct 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Sh24C05 Hv3-11 Heavy Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 152) 
                   
               
             
          
           
               
                 1 
                 qvqlvesggg lvkpggslrl scaasgftfs    dyams   wirga pgkglewvs   t isdggtytyy     
                   
               
               
                 61 
                     pdnvkg   rfti srdnaknsly lqmnslraed tavyycar   ew gdydgfdy   wg qgtlvtvss 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Sh24C05 Hv3-11 N62S Heavy Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 153) 
                   
               
             
          
           
               
                 1 
                 caagttcagc tggtggaatc tggcggtggg cttgtaaagc caggaggctc cctcagactg 
                   
               
               
                 61 
                 agttgtgccg cttcagggtt cacattctcc gactatgcga tgtcatggat caggcaagca 
               
               
                 121 
                 cccgggaaag gactggagtg ggttagcact atcagcgatg gcggaacgta tacctattac 
               
               
                 181 
                 cctgactccg tgaagggtcg gttcaccatt tccagggata acgcaaagaa cagtctctac 
               
               
                 241 
                 cttcagatga acagcctgag ggctgaggac accgccgtct actactgcgc ccgagaatgg 
               
               
                 301 
                 ggagattatg atgggtttga ctattggggc cagggcactt tggtgacagt cagttct 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Sh24C05 Hv3-11 N62S Heavy Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 154) 
                   
               
             
          
           
               
                 1 
                 qvqlvesggg lvkpggslrl scaasgftfs    dyams   wirga pgkglewvs   t isdggtytyy     
                   
               
               
                 61 
                     pdsvkg   rfti srdnaknsly lqmnslraed tavyycar   ew gdydgfdy   wg qgtlvtvss 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Sh24C05 Hv3-21 Heavy Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 155) 
                   
               
             
          
           
               
                 1 
                 gaggttcagc tggtggaatc tggcggtggg cttgtaaagc caggaggctc cctcagactg 
                   
               
               
                 61 
                 agttgtgccg cttcagggtt cacattctcc gactatgcga tgtcatgggt gcgccaagca 
               
               
                 121 
                 cccgggaaag gactggagtg ggttagcact atcagcgatg gcggaacgta tacctattac 
               
               
                 181 
                 cctgacaatg tgaagggtcg gttcaccatt tccagggata acgcaaagaa cagtctctat 
               
               
                 241 
                 ttgcagatga acagcctgag ggctgaggac accgccgtct actactgcgc ccgagaatgg 
               
               
                 301 
                 ggagattatg atgggtttga ctattggggc cagggcactt tggtgacagt cagttct 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Sh24C05 Hv3-21 Heavy Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 156) 
                   
               
             
          
           
               
                 1 
                 evqlvesggg lvkpggslrl scaasgftfs    dyams   wvrqa pgkglewvs   t isdggtytyy     
                   
               
               
                 61 
                     pdnvkg   rfti srdnaknsly lqmnslraed tavyycar   ew gdydgfdy   wg qgtlvtvss 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Sh24C05 Hv3-23 Heavy Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 157) 
                   
               
             
          
           
               
                 1 
                 gaggttcagc ttctggaatc tggcggtggg cttgtacagc caggaggctc cctcagactg 
                   
               
               
                 61 
                 agttgtgccg cttcagggtt cacattctcc gactatgcga tgtcatgggt gcgccaagca 
               
               
                 121 
                 cccgggaaag gactggagtg ggtttcaact atcagcgatg gcggaacgta tacctattac 
               
               
                 181 
                 cctgacaatg tgaagggtcg gttcaccatt tccagggata acagcaagaa cacactctat 
               
               
                 241 
                 ctccagatga acagcctgag ggctgaggac accgccgtct actactgcgc ccgagaatgg 
               
               
                 301 
                 ggagattatg atgggtttga ctattggggc cagggcactt tggtgacagt cagttct 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Sh24C05 Hv3-23 Heavy Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 158) 
                   
               
             
          
           
               
                 1 
                 evqllesggg lvqpggslrl scaasgftfs    dyams   wvrqa pgkglewvs   t isdggtytyy     
                   
               
               
                 61 
                     pdnvkg   rfti srdnskntly lqmnslraed tavyycar   ew gdydgfdy   wg qgtlvtvss 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Sh24C05 Hv3-30 Heavy Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 159) 
                   
               
             
          
           
               
                 1 
                 caggttcagc tggtggaatc tggcggtggg gtagtacaac caggacggtc cctcagactg 
                   
               
               
                 61 
                 agttgtgccg cttcagggtt cacattctcc gactatgcga tgtcatgggt gcgccaagca 
               
               
                 121 
                 cccgggaaag gactggagtg ggttgccact atcagcgatg gcggaacgta tacctattac 
               
               
                 181 
                 cctgacaatg tgaagggtcg gttcaccatt tccagggata actcaaagaa caccctctat 
               
               
                 241 
                 ctccaaatga gtagcctgag ggctgaggac accgccgtct actactgcgc ccgagaatgg 
               
               
                 301 
                 ggagattatg atgggtttga ctattggggc cagggcactt tggtgacagt cagttct 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Sh24C05 Hv3-30 Heavy Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 160) 
                   
               
             
          
           
               
                 1 
                 qvqlvesggg vvqpgrslrl scaasgftfs    dyams   wvrqa pgkglewva   t isdggtytyy     
                   
               
               
                 61 
                     pdnvkg   rfti srdnskntly lqmsslraed tavyycar   ew gdydgfdy   wg qgtlvtvss 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Hu24C05 HvA Heavy Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 161) 
                   
               
             
          
           
               
                 1 
                 gaggttcagc tggtggaatc tggcggtggg cttgtaaagc caggaggctc cctcagactg 
                   
               
               
                 61 
                 agttgtgccg cttcagggtt cacattctcc gactatgcga tgtcatgggt gcgccaagca 
               
               
                 121 
                 cccgggaaag gactggagtg ggttgccact atcagcgatg gcggaacgta tacctattac 
               
               
                 181 
                 cctgacaatg tgaagggtcg gttcaccatt tccagggata acgcaaagaa cagtctctac 
               
               
                 241 
                 cttcagatga acagcctgag ggctgaggac accgccgtct actactgcgc ccgagaatgg 
               
               
                 301 
                 ggagattatg atgggtttga ctattggggc cagggcactt tggtgacagt cagttct 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Hu24C05 HvA Heavy Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 162) 
                   
               
             
          
           
               
                 1 
                 evqlvesggg lvkpggslrl scaasgftfs    dyams   wvrqa pgkglewva   t isdggtytyy     
                   
               
               
                 61 
                     pdnvkg   rfti srdnaknsly lqmnslraed tavyycar   ew gdydgfdy   wg qgtlvtvss 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Sh24C05 Kv1-9 Kappa Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 163) 
                   
               
             
          
           
               
                 1 
                 gatattcagt tgacccaatc acctagcttc ctctcagctt ccgtgggcga cagagttacc 
                   
               
               
                 61 
                 ataacctgtc gggcaagcca ggagatttct gggtacctgt cctggtacca acagaagccc 
               
               
                 121 
                 ggaaaagccc ctaagctgtt gatctatgct gcgtcaacct tggatagcgg tgtcccgagt 
               
               
                 181 
                 cgattctccg gttctggctc cggaacagag ttcactctga caatttctag ccttcagcca 
               
               
                 241 
                 gaagatttcg ccacgtacta ttgcctccag tacgacagct atccctatac atttgggcag 
               
               
                 301 
                 ggcactaaac tggagatcaa a 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Sh24C05 Kv1-9 Kappa Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 164) 
                   
               
             
          
           
               
                 1 
                 diqltqspsf lsasvgdrvt itc   rasqeis gyls   wyqqkp gkapklliy   a astlds   gvps 
                   
               
               
                 61 
                 rfsgsgsgte ftltisslqp edfatyyc   lq ydsypyt   fgq gtkleik 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Sh24C05 Kv1-16 Kappa Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 165) 
                   
               
             
          
           
               
                 1 
                 gatattcaga tgacccaatc acctagcagt ctctcagctt ccgtgggcga cagagttacc 
                   
               
               
                 61 
                 ataacctgtc gggcaagcca ggagatttct gggtacctgt cctggtttca acagaagccc 
               
               
                 121 
                 ggaaaggccc cgaagagctt gatctatgct gcgtcaacct tggatagcgg tgtcccgagt 
               
               
                 181 
                 cgattctccg gttctggctc cggaaccgac tttactctga caatttctag ccttcagcca 
               
               
                 241 
                 gaagatttcg ccacgtacta ttgcctccag tacgacagct atccctatac atttgggcag 
               
               
                 301 
                 ggcactaaac tggagatcaa a 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Sh24C05 Kv1-16 Kappa Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 166) 
                   
               
             
          
           
               
                 1 
                 diqmtqspss lsasvgdrvt itc   rasqeis gyls   wfqqkp gkapksliy   a astlds   gvps 
                   
               
               
                 61 
                 rfsgsgsgtd ftltisslqp edfatyyc   lq ydsypyt   fgq gtkleik 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Sh24C05 Kv1-17 Kappa Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 167) 
                   
               
             
          
           
               
                 1 
                 gatattcaga tgacccaatc acctagcagt ctctcagctt ccgtgggcga cagagttacc 
                   
               
               
                 61 
                 ataacctgtc gggcaagcca ggagatttct gggtacctgt cctggtatca acagaagccc 
               
               
                 121 
                 ggaaaagccc caaagaggtt gatctatgct gcgtcaacct tggatagcgg tgtcccgagt 
               
               
                 181 
                 cgattctccg gttctggctc cggaaccgag ttcactctga caatttctag ccttcagcca 
               
               
                 241 
                 gaagatttcg ccacgtacta ttgcctccag tacgacagct atccctatac atttgggcag 
               
               
                 301 
                 ggcactaaac tggagatcaa a 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Sh24C05 Kv1-17 Kappa Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 168) 
                   
               
             
          
           
               
                 1 
                 diqmtqspss lsasvgdrvt itc   rasqeis gyls   wyqqkp gkapkrliy   a astlds   gvps 
                   
               
               
                 61 
                 rfsgsgsgte ftltisslqp edfatyyc   lq ydsypyt   fgq gtkleik 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Sh24C05 Kv1-33 Kappa Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 169) 
                   
               
             
          
           
               
                 1 
                 gatattcaga tgacccaatc acctagcagt ctctcagctt ccgtgggcga cagagttacc 
                   
               
               
                 61 
                 ataacctgtc gggcaagcca ggagatttct gggtacctgt cctggtacca acagaagccc 
               
               
                 121 
                 ggaaaggccc ccaagctgtt gatctatgct gcgtcaacct tggatagcgg tgtcccgagt 
               
               
                 181 
                 cgattctccg gttctggctc cggaacagac tttactttta caatttctag ccttcagcca 
               
               
                 241 
                 gaggacatcg ccacgtacta ttgcctccag tacgacagct atccctatac atttgggcag 
               
               
                 301 
                 ggcactaaac tggagatcaa a 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Sh24C05 Kv1-33 Kappa Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 170) 
                   
               
             
          
           
               
                 1 
                 diqmtqspss lsasvgdrvt itc   rasqeis gyls   wyqqkp gkapklliy   a astlds   gvps 
                   
               
               
                 61 
                 rfsgsgsgtd ftftisslqp ediatyyc   lq ydsypyt   fgq gtkleik 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Sh24C05 Kv1-39 Kappa Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 171) 
                   
               
             
          
           
               
                 1 
                 gatattcaga tgacccaatc acctagcagt ctctcagctt ccgtgggcga cagagttacc 
                   
               
               
                 61 
                 ataacctgtc gggcaagcca ggagatttct gggtacctgt cctggtatca acagaagccc 
               
               
                 121 
                 ggaaaagccc ctaagctgtt gatctatgct gcgtcaacct tggatagcgg tgtcccgagt 
               
               
                 181 
                 cgattctccg gttctggctc cggaactgac ttcactctga caatttctag ccttcagcca 
               
               
                 241 
                 gaagatttcg ccacgtacta ttgcctccag tacgacagct atccctatac atttgggcag 
               
               
                 301 
                 ggcactaaac tggagatcaa a 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Sh24C05 Kv1-39 Kappa Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 172) 
                   
               
             
          
           
               
                 1 
                 diqmtqspss lsasvgdrvt itc   rasqeis gyls   wyqqkp gkapklliy   a astlds   gvps 
                   
               
               
                 61 
                 rfsgsgsgtd ftltisslqp edfatyyc   lq ydsypyt   fgq gtkleik 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Hu24C05 KvA Kappa Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 173) 
                   
               
             
          
           
               
                 1 
                 gatattcaga tgacccaatc acctagcagt ctctcagctt ccgtgggcga cagagttacc 
                   
               
               
                 61 
                 ataacctgtc gggcaagcca ggagatttct gggtacctgt cctggctgca acagaagccc 
               
               
                 121 
                 ggaggcgcca tcaagaggtt gatctatgct gcgtcaacct tggatagcgg tgtcccgagt 
               
               
                 181 
                 cgattctccg gttctggctc cggaagtgac tacactctga caatttctag ccttcagcca 
               
               
                 241 
                 gaagatttcg ccacgtacta ttgcctccag tacgacagct atccctatac atttgggcag 
               
               
                 301 
                 ggcactaaac tggagatcaa a 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Hu24C05 KvA Kappa Chain Variable Region 
                   
               
               
                 (SEQ ID NO: 174) 
                   
               
             
          
           
               
                 1 
                 diqmtqspss lsasvgdrvt itc   rasqeis gyls   wlqqkp ggaikrliy   a astlds   gvps 
                   
               
               
                 61 
                 rfsgsgsgsd ytltisslqp edfatyyc   lq ydsypyt   fgq gtkleik 
               
             
          
         
       
     
         [0178]    The amino acid sequences defining the immunoglobulin heavy chain variable regions for the antibodies produced in Example 12 are aligned in  FIG. 15 . Amino terminal signal peptide sequences (for proper expression/secretion) are not shown. CDR 1 , CDR 2 , and CDR 3  (Kabat definition) are identified by boxes. 
         [0179]    The amino acid sequences defining the immunoglobulin light chain variable regions for the antibodies in Example 12 are aligned in  FIG. 16 . Amino terminal signal peptide sequences (for proper expression/secretion) are not shown. CDR 1 , CDR 2  and CDR 3  are identified by boxes. 
         [0180]    Table 10 is a concordance chart showing the SEQ ID NO. of each sequence discussed in this Example. 
         [0000]    
       
         
               
               
             
               
               
             
           
               
                 TABLE 10 
               
               
                   
               
               
                 SEQ. ID 
                   
               
               
                 NO. 
                 Nucleic Acid or Protein 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 149 
                 Sh24C05 Hv3-7 Heavy Chain Variable Region-nucleic acid 
               
               
                 150 
                 Sh24C05 Hv3-7 Heavy Chain Variable Region-protein 
               
               
                 57 
                 Sh24C05 Hv3-7 Heavy Chain CDR 1   
               
               
                 58 
                 Sh24C05 Hv3-7 Heavy Chain CDR 2   
               
               
                 59 
                 Sh24C05 Hv3-7 Heavy Chain CDR 3   
               
               
                 151 
                 Sh24C05 Hv3-11 Heavy Chain Variable Region-nucleic acid 
               
               
                 152 
                 Sh24C05 Hv3-11 Heavy Chain Variable Region-protein 
               
               
                 57 
                 Sh24C05 Hv3-11 Heavy Chain CDR 1   
               
               
                 58 
                 Sh24C05 Hv3-11 Heavy Chain CDR 2   
               
               
                 59 
                 Sh24C05 Hv3-11 Heavy Chain CDR 3   
               
               
                 153 
                 Sh24C05 Hv3-11 N62S Heavy Chain Variable Region-nucleic 
               
               
                   
                 acid 
               
               
                 154 
                 Sh24C05 Hv3-11 N62S Heavy Chain Variable Region-protein 
               
               
                 57 
                 Sh24C05 Hv3-11 N62S Heavy Chain CDR 1   
               
               
                 148 
                 Sh24C05 Hv3-11 N62S Heavy Chain CDR 2   
               
               
                 59 
                 Sh24C05 Hv3-11 N62S Heavy Chain CDR 3   
               
               
                 155 
                 Sh24C05 Hv3-21 Heavy Chain Variable Region-nucleic acid 
               
               
                 156 
                 Sh24C05 Hv3-21 Heavy Chain Variable Region-protein 
               
               
                 57 
                 Sh24C05 Hv3-21 Heavy Chain CDR 1   
               
               
                 58 
                 Sh24C05 Hv3-21 Heavy Chain CDR 2   
               
               
                 59 
                 Sh24C05 Hv3-21 Heavy Chain CDR 3   
               
               
                 157 
                 Sh24C05 Hv3-23 Heavy Chain Variable Region-nucleic acid 
               
               
                 158 
                 Sh24C05 Hv3-23 Heavy Chain Variable Region-protein 
               
               
                 57 
                 Sh24C05 Hv3-23 Heavy Chain CDR 1   
               
               
                 58 
                 Sh24C05 Hv3-23 Heavy Chain CDR 2   
               
               
                 59 
                 Sh24C05 Hv3-23 Heavy Chain CDR 3   
               
               
                 159 
                 Sh24C05 Hv3-30 Heavy Chain Variable Region-nucleic acid 
               
               
                 160 
                 Sh24C05 Hv3-30 Heavy Chain Variable Region-protein 
               
               
                 57 
                 Sh24C05 Hv3-30 Heavy Chain CDR 1   
               
               
                 58 
                 Sh24C05 Hv3-30 Heavy Chain CDR 2   
               
               
                 59 
                 Sh24C05 Hv3-30 Heavy Chain CDR 3   
               
               
                 161 
                 Hu24C05 HvA Heavy Chain Variable Region-nucleic acid 
               
               
                 162 
                 Hu24C05 HvA Heavy Chain Variable Region-protein 
               
               
                 57 
                 Hu24C05 HvA Heavy Chain CDR 1   
               
               
                 58 
                 Hu24C05 HvA Heavy Chain CDR 2   
               
               
                 59 
                 Hu24C05 HvA Heavy Chain CDR 3   
               
               
                 163 
                 Sh24C05 Kv1-9 Light (kappa) Chain Variable 
               
               
                   
                 Region-nucleic acid 
               
               
                 164 
                 Sh24C05 Kv1-9 Light (kappa) Chain Variable 
               
               
                   
                 Region-protein 
               
               
                 60 
                 Sh24C05 Kv1-9 Light (kappa) Chain CDR 1   
               
               
                 61 
                 Sh24C05 Kv1-9 Light (kappa) Chain CDR 2   
               
               
                 62 
                 Sh24C05 Kv1-9 Light (kappa) Chain CDR 3   
               
               
                 165 
                 Sh24C05 Kv1-16 Light (kappa) Chain Variable 
               
               
                   
                 Region-nucleic acid 
               
               
                 166 
                 Sh24C05 Kv1-16 Light (kappa) Chain Variable 
               
               
                   
                 Region-protein 
               
               
                 60 
                 Sh24C05 Kv1-16 Light (kappa) Chain CDR 1   
               
               
                 61 
                 Sh24C05 Kv1-16 Light (kappa) Chain CDR 2   
               
               
                 62 
                 Sh24C05 Kv1-16 Light (kappa) Chain CDR 3   
               
               
                 167 
                 Sh24C05 Kv1-17 Light (kappa) Chain Variable 
               
               
                   
                 Region-nucleic acid 
               
               
                 168 
                 Sh24C05 Kv1-17 Light (kappa) Chain Variable 
               
               
                   
                 Region-protein 
               
               
                 60 
                 Sh24C05 Kv1-17 Light (kappa) Chain CDR 1   
               
               
                 61 
                 Sh24C05 Kv1-17 Light (kappa) Chain CDR 2   
               
               
                 62 
                 Sh24C05 Kv1-17 Light (kappa) Chain CDR 3   
               
               
                 169 
                 Sh24C05 Kv1-33 Light (kappa) Chain Variable 
               
               
                   
                 Region-nucleic acid 
               
               
                 170 
                 Sh24C05 Kv1-33 Light (kappa) Chain Variable 
               
               
                   
                 Region-protein 
               
               
                 60 
                 Sh24C05 Kv1-33 Light (kappa) Chain CDR 1   
               
               
                 61 
                 Sh24C05 Kv1-33 Light (kappa) Chain CDR 2   
               
               
                 62 
                 Sh24C05 Kv1-33 Light (kappa) Chain CDR 3   
               
               
                 171 
                 Sh24C05 Kv1-39 Light (kappa) Chain Variable 
               
               
                   
                 Region-nucleic acid 
               
               
                 172 
                 Sh24C05 Kv1-39 Light (kappa) Chain Variable 
               
               
                   
                 Region-protein 
               
               
                 60 
                 Sh24C05 Kv1-39 Light (kappa) Chain CDR 1   
               
               
                 61 
                 Sh24C05 Kv1-39 Light (kappa) Chain CDR 2   
               
               
                 62 
                 Sh24C05 Kv1-39 Light (kappa) Chain CDR 3   
               
               
                 173 
                 Hu24C05 KvA Light (kappa) Chain Variable 
               
               
                   
                 Region-nucleic acid 
               
               
                 174 
                 Hu24C05 KvA Light (kappa) Chain Variable 
               
               
                   
                 Region-protein 
               
               
                 60 
                 Hu24C05 KvA Light (kappa) Chain CDR 1   
               
               
                 61 
                 Hu24C05 KvA Light (kappa) Chain CDR 2   
               
               
                 62 
                 Hu24C05 KvA Light (kappa) Chain CDR 3   
               
               
                   
               
             
          
         
       
     
         [0181]    Humanized monoclonal antibody heavy chain CDR sequences (Kabat, Chothia, and IMGT definitions) are shown in Table 11. 
         [0000]    
       
         
               
               
               
               
             
               
             
               
               
               
               
             
               
             
               
               
               
               
             
               
             
               
               
               
               
             
           
               
                 TABLE 11 
               
               
                   
               
               
                   
                 CDR1 
                 CDR2 
                 CDR3 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Kabat 
               
             
          
           
               
                 24C05 
                 DYAMS 
                 
                   TISDGGTYTYYPDNVKG 
                 
                 EWGDYDGFDY 
               
               
                   
                 (SEQ ID NO: 57) 
                 (SEQ ID NO: 58) 
                 (SEQ ID NO: 59) 
               
               
                 Hv3-7 
                 DYAMS 
                 
                   TISDGGTYTYYPDNVKG 
                 
                 EWGDYDGFDY 
               
               
                   
                 (SEQ ID NO: 57) 
                 (SEQ ID NO: 58) 
                 (SEQ ID NO: 59) 
               
               
                 Sh24C05 
                 DYAMS 
                 
                   TISDGGTYTYYPDNVKG 
                 
                 EWGDYDGFDY 
               
               
                 Hv3-11 
                 (SEQ ID NO: 57) 
                 (SEQ ID NO: 58) 
                 (SEQ ID NO: 59) 
               
               
                 Sh24C05 
                 DYAMS 
                 
                   TISDGGTYTYYPDSVKG 
                 
                 EWGDYDGFDY 
               
               
                 Hv3-11 N62S 
                 (SEQ ID NO: 57) 
                 (SEQ ID NO: 148) 
                 (SEQ ID NO: 59) 
               
               
                 Sh24C05 
                 DYAMS 
                 
                   TISDGGTYTYYPDNVKG 
                 
                 EWGDYDGFDY 
               
               
                 Hv3-21 
                 (SEQ ID NO: 57) 
                 (SEQ ID NO: 58) 
                 (SEQ ID NO: 59) 
               
               
                 Sh24C05 
                 DYAMS 
                 
                   TISDGGTYTYYPDNVKG 
                 
                 EWGDYDGFDY 
               
               
                 Hv3-23 
                 (SEQ ID NO: 57) 
                 (SEQ ID NO: 58) 
                 (SEQ ID NO: 59) 
               
               
                 Sh24C05 
                 DYAMS 
                 
                   TISDGGTYTYYPDNVKG 
                 
                 EWGDYDGFDY 
               
               
                 Hv3-30 
                 (SEQ ID NO: 57) 
                 (SEQ ID NO: 58) 
                 (SEQ ID NO: 59) 
               
               
                 Hu24C05 
                 DYAMS 
                 
                   TISDGGTYTYYPDNVKG 
                 
                 EWGDYDGFDY 
               
               
                 HvA 
                 (SEQ ID NO: 57) 
                 (SEQ ID NO: 58) 
                 (SEQ ID NO: 59) 
               
               
                   
               
             
          
           
               
                 
                   Chothia 
                 
               
             
          
           
               
                 24C05 
                 
                   GFTFSDY 
                 
                 SDGGTY 
                 EWGDYDGFDY 
               
               
                   
                 (SEQ ID NO: 75) 
                 (SEQ ID NO: 76) 
                 (SEQ ID NO: 59) 
               
               
                 Sh24C05 
                 
                   GFTFSDY 
                 
                 SDGGTY 
                 EWGDYDGFDY 
               
               
                 Hv3-7 
                 (SEQ ID NO: 75) 
                 (SEQ ID NO: 76) 
                 (SEQ ID NO: 59) 
               
               
                 Sh24C05 
                 
                   GFTFSDY 
                 
                 SDGGTY 
                 EWGDYDGFDY 
               
               
                 Hv3-11 
                 (SEQ ID NO: 75) 
                 (SEQ ID NO: 76) 
                 (SEQ ID NO: 59) 
               
               
                 Sh24C05 
                 
                   GFTFSDY 
                 
                 SDGGTY 
                 EWGDYDGFDY 
               
               
                 Hv3-11 N62S 
                 (SEQ ID NO: 75) 
                 (SEQ ID NO: 76) 
                 (SEQ ID NO: 59) 
               
               
                 Sh24C05 
                 
                   GFTFSDY 
                 
                 SDGGTY 
                 EWGDYDGFDY 
               
               
                 Hv3-21 
                 (SEQ ID NO: 75) 
                 (SEQ ID NO: 76) 
                 (SEQ ID NO: 59) 
               
               
                 Sh24C05 
                 
                   GFTFSDY 
                 
                 SDGGTY 
                 EWGDYDGFDY 
               
               
                 Hv3-23 
                 (SEQ ID NO: 75) 
                 (SEQ ID NO: 76) 
                 (SEQ ID NO: 59) 
               
               
                 Sh24C05 
                 
                   GFTFSDY 
                 
                 SDGGTY 
                 EWGDYDGFDY 
               
               
                 Hv3-30 
                 (SEQ ID NO: 75) 
                 (SEQ ID NO: 76) 
                 (SEQ ID NO: 59) 
               
               
                 Hu24C05 
                 
                   GFTFSDY 
                 
                 SDGGTY 
                 EWGDYDGFDY 
               
               
                 HvA 
                 (SEQ ID NO: 75) 
                 (SEQ ID NO: 76) 
                 (SEQ ID NO: 59) 
               
               
                   
               
             
          
           
               
                 IMGT 
               
             
          
           
               
                 24C05 
                 GFTFSDYA 
                 ISDGGTYT 
                 
                   AREWGDYDGFDY 
                 
               
               
                   
                 (SEQ ID NO: 94) 
                 (SEQ ID NO: 95) 
                 (SEQ ID NO: 96) 
               
               
                 Sh24C05 
                 GFTFSDYA 
                 ISDGGTYT 
                 
                   AREWGDYDGFDY 
                 
               
               
                 Hv3-7 
                 (SEQ ID NO: 94) 
                 (SEQ ID NO: 95) 
                 (SEQ ID NO: 96) 
               
               
                 Sh24C05 
                 GFTFSDYA 
                 ISDGGTYT 
                 
                   AREWGDYDGFDY 
                 
               
               
                 Hv3-11 
                 (SEQ ID NO: 94) 
                 (SEQ ID NO: 95) 
                 (SEQ ID NO: 96) 
               
               
                 Sh24C05 
                 GFTFSDYA 
                 ISDGGTYT 
                 
                   AREWGDYDGFDY 
                 
               
               
                 Hv3-11 N62S 
                 (SEQ ID NO: 94) 
                 (SEQ ID NO: 95) 
                 (SEQ ID NO: 96) 
               
               
                 Sh24C05 
                 GFTFSDYA 
                 ISDGGTYT 
                 
                   AREWGDYDGFDY 
                 
               
               
                 Hv3-21 
                 (SEQ ID NO: 94) 
                 (SEQ ID NO: 95) 
                 (SEQ ID NO: 96) 
               
               
                 Sh24C05 
                 GFTFSDYA 
                 ISDGGTYT 
                 
                   AREWGDYDGFDY 
                 
               
               
                 Hv3-23 
                 (SEQ ID NO: 94) 
                 (SEQ ID NO: 95) 
                 (SEQ ID NO: 96) 
               
               
                 Sh24C05 
                 GFTFSDYA 
                 ISDGGTYT 
                 
                   AREWGDYDGFDY 
                 
               
               
                 Hv3-30 
                 (SEQ ID NO: 94) 
                 (SEQ ID NO: 95) 
                 (SEQ ID NO: 96) 
               
               
                 Hu24C05 
                 GFTFSDYA 
                 ISDGGTYT 
                 
                   AREWGDYDGFDY 
                 
               
               
                 HvA 
                 (SEQ ID NO: 94) 
                 (SEQ ID NO: 95) 
                 (SEQ ID NO: 96) 
               
               
                   
               
             
          
         
       
     
         [0182]    Humanized monoclonal antibody Kappa light chain CDR sequences (Kabat, Chothia, and IMGT definitions) are shown in Table 12. 
         [0000]    
       
         
               
               
               
               
             
               
             
               
               
               
               
             
               
             
               
               
               
               
             
           
               
                 TABLE 12 
               
               
                   
               
               
                   
                 CDR1 
                 CDR2 
                 CDR3 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Kabat/Chothia 
               
             
          
           
               
                 24C05 
                 
                   RASQEISGYLS 
                 
                 
                   AASTLDS 
                 
                 
                   LQYDSYPYT 
                 
               
               
                   
                 (SEQ ID NO: 60) 
                 (SEQ ID NO: 61) 
                 (SEQ ID NO: 62) 
               
               
                 Sh24C05 Kv1-9 
                 
                   RASQEISGYLS 
                 
                 
                   AASTLDS 
                 
                 
                   LQYDSYPYT 
                 
               
               
                   
                 (SEQ ID NO: 60) 
                 (SEQ ID NO: 61) 
                 (SEQ ID NO: 62) 
               
               
                 Sh24C05 Kv1-16 
                 
                   RASQEISGYLS 
                 
                 
                   AASTLDS 
                 
                 
                   LQYDSYPYT 
                 
               
               
                   
                 (SEQ ID NO: 60) 
                 (SEQ ID NO: 61) 
                 (SEQ ID NO: 62) 
               
               
                 Sh24C05 Kv1-17 
                 
                   RASQEISGYLS 
                 
                 
                   AASTLDS 
                 
                 
                   LQYDSYPYT 
                 
               
               
                   
                 (SEQ ID NO: 60) 
                 (SEQ ID NO: 61) 
                 (SEQ ID NO: 62) 
               
               
                 Sh24C05 Kv1-33 
                 
                   RASQEISGYLS 
                 
                 
                   AASTLDS 
                 
                 
                   LQYDSYPYT 
                 
               
               
                   
                 (SEQ ID NO: 60) 
                 (SEQ ID NO: 61) 
                 (SEQ ID NO: 62) 
               
               
                 Sh24C05 Kv1-39 
                 
                   RASQEISGYLS 
                 
                 
                   AASTLDS 
                 
                 
                   LQYDSYPYT 
                 
               
               
                   
                 (SEQ ID NO: 60) 
                 (SEQ ID NO: 61) 
                 (SEQ ID NO: 62) 
               
               
                 Hu24C05  
                 
                   RASQEISGYLS 
                 
                 
                   AASTLDS 
                 
                 
                   LQYDSYPYT 
                 
               
               
                 KvA 
                 (SEQ ID NO: 60) 
                 (SEQ ID NO: 61) 
                 (SEQ ID NO: 62) 
               
               
                   
               
             
          
           
               
                 IMGT 
               
             
          
           
               
                 24C05 
                 QEISGY 
                 AAS 
                 LQYDSYPYT 
               
               
                   
                 (SEQ ID NO: 101) 
                   
                 (SEQ ID NO: 62) 
               
               
                 Sh24C05 
                 QEISGY 
                 AAS 
                 LQYDSYPYT 
               
               
                 Kv1-9 
                 (SEQ ID NO: 101) 
                   
                 (SEQ ID NO: 62) 
               
               
                 Sh24C05 
                 QEISGY 
                 AAS 
                 LQYDSYPYT 
               
               
                 Kv1-16 
                 (SEQ ID NO: 101) 
                   
                 (SEQ ID NO: 62) 
               
               
                 Sh24C05 
                 QEISGY 
                 AAS 
                 LQYDSYPYT 
               
               
                 Kv1-17 
                 (SEQ ID NO: 101) 
                   
                 (SEQ ID NO: 62) 
               
               
                 Sh24C05 
                 QEISGY 
                 AAS 
                 LQYDSYPYT 
               
               
                 Kv1-33 
                 (SEQ ID NO: 101) 
                   
                 (SEQ ID NO: 62) 
               
               
                 Sh24C05 
                 QEISGY 
                 AAS 
                 LQYDSYPYT 
               
               
                 Kv1-39 
                 (SEQ ID NO: 101) 
                   
                 (SEQ ID NO: 62) 
               
               
                 Hu24C05 
                 QEISGY 
                 AAS 
                 LQYDSYPYT 
               
               
                 KvA 
                 (SEQ ID NO: 101) 
                   
                 (SEQ ID NO: 62) 
               
               
                   
               
             
          
         
       
     
         [0183]    In Tables 11 and 12, the longest CDR sequences for the immunoglobulin heavy chain and light chain are shown in bold. 
         [0184]    To create the complete chimeric and humanized heavy or kappa chain antibody sequences, each variable sequence above is combined with its respective human constant region. For example, a complete heavy chain comprises a heavy variable sequence followed by a human IgG1 heavy chain constant sequence or a human IgG2 heavy chain constant sequence. A complete kappa chain comprises a kappa variable sequence followed by the human kappa light chain constant sequence. 
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
           
               
                 Nucleic Acid Sequence Encoding the Human IgG1 Heavy Chain Constant Region 
                   
               
               
                 (SEQ ID NO: 175) 
                   
               
             
          
           
               
                 1 
                 gcctcaacaa aaggaccaag tgtgttccca ctcgccccta gcagcaagag tacatccggg 
                   
               
               
                 61 
                 ggcactgcag cactcggctg cctcgtcaag gattattttc cagagccagt aaccgtgagc 
               
               
                 121 
                 tggaacagtg gagcactcac ttctggtgtc catacttttc ctgctgtcct gcaaagctct 
               
               
                 181 
                 ggcctgtact cactcagctc cgtcgtgacc gtgccatctt catctctggg cactcagacc 
               
               
                 241 
                 tacatctgta atgtaaacca caagcctagc aatactaagg tcgataagcg ggtggaaccc 
               
               
                 301 
                 aagagctgcg acaagactca cacttgtccc ccatgccctg cccctgaact tctgggcggt 
               
               
                 361 
                 cccagcgtct ttttgttccc accaaagcct aaagatactc tgatgataag tagaacaccc 
               
               
                 421 
                 gaggtgacat gtgttgttgt agacgtttcc cacgaggacc cagaggttaa gttcaactgg 
               
               
                 481 
                 tacgttgatg gagtcgaagt acataatgct aagaccaagc ctagagagga gcagtataat 
               
               
                 541 
                 agtacatacc gtgtagtcag tgttctcaca gtgctgcacc aagactggct caacggcaaa 
               
               
                 601 
                 gaatacaaat gcaaagtgtc caacaaagca ctcccagccc ctatcgagaa gactattagt 
               
               
                 661 
                 aaggcaaagg ggcagcctcg tgaaccacag gtgtacactc tgccacccag tagagaggaa 
               
               
                 721 
                 atgacaaaga accaagtctc attgacctgc ctggtgaaag gcttctaccc cagcgacatc 
               
               
                 781 
                 gccgttgagt gggagagtaa cggtcagcct gagaacaatt acaagacaac ccccccagtg 
               
               
                 841 
                 ctggatagtg acgggtcttt ctttctgtac agtaagctga ctgtggacaa gtcccgctgg 
               
               
                 901 
                 cagcagggta acgtcttcag ctgttccgtg atgcacgagg cattgcacaa ccactacacc 
               
               
                 961 
                 cagaagtcac tgagcctgag cccagggaag 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Human IgG1 Heavy Chain Constant Region 
                   
               
               
                 (SEQ ID NO: 176) 
                   
               
             
          
           
               
                 1 
                 astkgpsvfp lapsskstsg gtaalgclvk dyfpepvtvs wnsgaltsgv htfpavlqss 
                   
               
               
                 61 
                 glyslssvvt vpssslgtqt yicnvnhkps ntkvdkrvep kscdkthtcp pcpapellgg 
               
               
                 121 
                 psvflfppkp kdtlmisrtp evtcvvvdvs hedpevkfnw yvdgvevhna ktkpreeqyn 
               
               
                 181 
                 styrvvsvlt vlhqdwlngk eykckvsnka 1papiektis kakgqprepq vytlppsree 
               
               
                 241 
                 mtknqvsltc lvkgfypsdi avewesngqp ennykttppv ldsdgsffly skltvdksrw 
               
               
                 301 
                 qqgnvfscsv mhealhnhyt qkslslspgk 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Human IgG2 Heavy Chain Constant Region 
                   
               
               
                 (SEQ ID NO: 177) 
                   
               
             
          
           
               
                 1 
                 gcctccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 
                   
               
               
                 61 
                 agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 
               
               
                 121 
                 tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 
               
               
                 181 
                 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 
               
               
                 241 
                 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 
               
               
                 301 
                 aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 
               
               
                 361 
                 ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 
               
               
                 421 
                 gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 
               
               
                 481 
                 gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt 
               
               
                 541 
                 gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc 
               
               
                 601 
                 aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 
               
               
                 661 
                 cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 
               
               
                 721 
                 caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 
               
               
                 781 
                 gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 
               
               
                 841 
                 ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 
               
               
                 901 
                 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 
               
               
                 961 
                 tccctgtctc cgggtaaa 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Human IgG2 Heavy Chain Constant Region 
                   
               
               
                 (SEQ ID NO: 178) 
                   
               
             
          
           
               
                 1 
                 astkgpsvfp lapcsrstse staalgclvk dyfpepvtvs wnsgaltsgv htfpavlqss 
                   
               
               
                 61 
                 glyslssvvt vpssnfgtqt ytcnvdhkps ntkvdktver kccvecppcp appvagpsvf 
               
               
                 121 
                 lfppkpkdtl misrtpevtc vvvdvshedp evqfnwyvdg vevhnaktkp reeqfnstfr 
               
               
                 181 
                 vvsvltvvhq dwlngkeykc kvsnkglpap iektisktkg qprepqvytl ppsreemtkn 
               
               
                 241 
                 qvsltclvkg fypsdiavew esngqpenny kttppmldsd gsfflysklt vdksrwqqgn 
               
               
                 301 
                 vfscsvmhea lhnhytqksl slspgk 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Human Kappa Light Chain Constant Region 
                   
               
               
                 (SEQ ID NO: 179) 
                   
               
             
          
           
               
                 1 
                 cgcacagttg ctgcccccag cgtgttcatt ttcccaccta gcgatgagca gctgaaaagc 
                   
               
               
                 61 
                 ggtactgcct ctgtcgtatg cttgctcaac aacttttacc cacgtgaggc taaggtgcag 
               
               
                 121 
                 tggaaagtgg ataatgcact tcaatctgga aacagtcaag agtccgtgac agaacaggac 
               
               
                 181 
                 agcaaagact caacttattc actctcttcc accctgactc tgtccaaggc agactatgaa 
               
               
                 241 
                 aaacacaagg tatacgcctg cgaggttaca caccagggtt tgtctagtcc tgtcaccaag 
               
               
                 301 
                 tccttcaata ggggcgaatg t 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Human Kappa Light Chain Constant Region 
                   
               
               
                 (SEQ ID NO: 180) 
                   
               
             
          
           
               
                 1 
                 rtvaapsvfi fppsdeqlks gtasvvclln nfypreakvq wkvdnalqsg nsqesvteqd 
                   
               
               
                 61 
                 skdstyslss tltlskadye khkvyacevt hqglsspvtk sfnrgec 
               
             
          
         
       
     
         [0185]    The following sequences represent the actual or contemplated full length heavy and light chain sequences (i.e., containing both the variable and constant regions sequences) for each antibody described in this Example. Signal sequences for proper secretion of the antibodies are also included at the 5′ end of the DNA sequences or the amino terminal end of the protein sequences. It is also contemplated herein that the variable region sequences can be ligated to other constant region sequences to produce active full length IgG heavy and light chains. 
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
           
               
                 Nucleic Acid Sequence Encoding the Full Length Chimeric 24C05 Heavy Chain 
                   
               
               
                 (Mouse Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 181) 
                   
               
             
          
           
               
                 1 
                 atgaacttcg ggctcagctt gatgttcctt gtccttgtct taaaaggtgt ccagtgtgag 
                   
               
               
                 61 
                 gtgcagctgg tggaatctgg gggaggctta gtgaagcctg gagggtccct gaaactctcc 
               
               
                 121 
                 tgtgcagcct ctggattcac tttcagtgac tatgccatgt cttgggttcg ccagactccg 
               
               
                 181 
                 gaaaagaggc tggagtgggt cgcaaccatt agtgatggtg gtacttacac ctactatcca 
               
               
                 241 
                 gacaatgtaa agggccgatt caccatctcc agagacaatg ccaagaacaa cctgtacctg 
               
               
                 301 
                 caaatgagcc atctgaagtc tgaggacaca gccatgtatt actgtgcaag agaatggggt 
               
               
                 361 
                 gattacgacg gatttgacta ctggggccaa ggcaccactc tcacagtctc ctcggcctca 
               
               
                 421 
                 acaaaaggac caagtgtgtt cccactcgcc cctagcagca agagtacatc cgggggcact 
               
               
                 481 
                 gcagcactcg gctgcctcgt caaggattat tttccagagc cagtaaccgt gagctggaac 
               
               
                 541 
                 agtggagcac tcacttctgg tgtccatact tttcctgctg tcctgcaaag ctctggcctg 
               
               
                 601 
                 tactcactca gctccgtcgt gaccgtgcca tcttcatctc tgggcactca gacctacatc 
               
               
                 661 
                 tgtaatgtaa accacaagcc tagcaatact aaggtcgata agcgggtgga acccaagagc 
               
               
                 721 
                 tgcgacaaga ctcacacttg tcccccatgc cctgcccctg aacttctggg cggtcccagc 
               
               
                 781 
                 gtctttttgt tcccaccaaa gcctaaagat actctgatga taagtagaac acccgaggtg 
               
               
                 841 
                 acatgtgttg ttgtagacgt ttcccacgag gacccagagg ttaagttcaa ctggtacgtt 
               
               
                 901 
                 gatggagtcg aagtacataa tgctaagacc aagcctagag aggagcagta taatagtaca 
               
               
                 961 
                 taccgtgtag tcagtgttct cacagtgctg caccaagact ggctcaacgg caaagaatac 
               
               
                 1021 
                 aaatgcaaag tgtccaacaa agcactccca gcccctatcg agaagactat tagtaaggca 
               
               
                 1081 
                 aaggggcagc ctcgtgaacc acaggtgtac actctgccac ccagtagaga ggaaatgaca 
               
               
                 1141 
                 aagaaccaag tctcattgac ctgcctggtg aaaggcttct accccagcga catcgccgtt 
               
               
                 1201 
                 gagtgggaga gtaacggtca gcctgagaac aattacaaga caaccccccc agtgctggat 
               
               
                 1261 
                 agtgacgggt ctttctttct gtacagtaag ctgactgtgg acaagtcccg ctggcagcag 
               
               
                 1321 
                 ggtaacgtct tcagctgttc cgtgatgcac gaggcattgc acaaccacta cacccagaag 
               
               
                 1381 
                 tcactgagcc tgagcccagg gaag 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Chimeric 24C05 Heavy Chain (Mouse 
                   
               
               
                 Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 182) 
                   
               
             
          
           
               
                 1 
                 mnfglslmfl vlvlkgvqce vqlvesgggl vkpggslkls caasgftfsd yamswvrqtp 
                   
               
               
                 61 
                 ekrlewvati sdggtytyyp dnvkgrftis rdnaknnlyl qmshlksedt amyycarewg 
               
               
                 121 
                 dydgfdywgq gttltvssas tkgpsvfpla psskstsggt aalgclvkdy fpepvtvswn 
               
               
                 181 
                 sgaltsgvht fpavlqssgl yslssvvtvp ssslgtqtyi cnvnhkpsnt kvdkrvepks 
               
               
                 241 
                 cdkthtcppc papellggps vflfppkpkd tlmisrtpev tcvvvdvshe dpevkfnwyv 
               
               
                 301 
                 dgvevhnakt kpreeqynst yrvvsvltvl hqdwlngkey kckvsnkalp apiektiska 
               
               
                 361 
                 kgqprepqvy tlppsreemt knqvsltclv kgfypsdiav ewesngqpen nykttppvld 
               
               
                 421 
                 sdgsfflysk ltvdksrwqq gnvfscsvmh ealhnhytqk slslspgk 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Chimeric 24C05 Light Chain 
                   
               
               
                 (Mouse Kappa Chain Variable Region and Human Kappa Constant Region) 
               
               
                 (SEQ ID NO: 183) 
                   
               
             
          
           
               
                 1 
                 atggacatga gggttcctgc tcacgttttt ggcttcttgt tgctctggtt tccaggtacc 
                   
               
               
                 61 
                 agatgtgaca tccagatgac ccagtctcca tcctccttat ctgcctctct gggagaaaga 
               
               
                 121 
                 gtcagtctca cttgtcgggc aagtcaggaa attagtggtt acttaagctg gcttcagcag 
               
               
                 181 
                 aaaccagatg gaactattaa acgcctgatc tacgccgcat ccactttaga ttctggtgtc 
               
               
                 241 
                 ccaaaaaggt tcagtggcag taggtctggg tcagattatt ctctcaccat cggcagcctt 
               
               
                 301 
                 gagtctgaag atcttgcaga ctattactgt ctacaatatg atagttatcc gtacacgttc 
               
               
                 361 
                 ggagggggga ccaagctgga aataaaacgc acagtcgccg ctccctccgt gttcatcttt 
               
               
                 421 
                 ccaccaagtg atgagcaact gaagtctggt actgcttcag tcgtgtgtct gctgaacaat 
               
               
                 481 
                 ttctaccctc gagaagccaa agtccaatgg aaggtagaca acgcactgca gtccggcaat 
               
               
                 541 
                 agccaagaat cagttaccga acaggattca aaggacagta catattccct gagcagcact 
               
               
                 601 
                 ctgaccctgt caaaggccga ttacgagaaa cacaaggtct atgcttgcga agtgacacat 
               
               
                 661 
                 cagggactgt ccagcccagt gacaaaatct tttaaccgtg gggagtgt 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Chimeric 24C05 Light Chain (Mouse 
                   
               
               
                 Kappa Chain Variable Region and Human Kappa Constant Region) 
               
               
                 (SEQ ID NO: 184) 
                   
               
             
          
           
               
                 1 
                 mdmrvpahvf gflllwfpgt rcdiqmtqsp sslsaslger vsltcrasqe isgylswlqq 
                   
               
               
                 61 
                 kpdgtikrli yaastldsgv pkrfsgsrsg sdysltigsl esedladyyc lqydsypytf 
               
               
                 121 
                 gggtkleikr tvaapsvfif ppsdeqlksg tasvvcllnn fypreakvqw kvdnalqsgn 
               
               
                 181 
                 sqesvteqds kdstyslsst ltlskadyek hkvyacevth qglsspvtks fnrgec 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Humanized sh24C05 Hv3-7 Heavy 
                   
               
               
                 Chain (Humanized Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 185) 
                   
               
             
          
           
               
                 1 
                 atggacatga gagttcctgc tcagctgctc gggttgctgt tgctttggct ccggggtgct 
                   
               
               
                 61 
                 aggtgcgagg ttcagctggt ggaatctggc ggtgggcttg tacaaccagg aggctccctc 
               
               
                 121 
                 agactgagtt gtgccgcttc agggttcaca ttctccgact atgcgatgtc atgggtgcgc 
               
               
                 181 
                 caagcacccg ggaaaggact ggagtgggtt gccactatca gcgatggcgg aacgtatacc 
               
               
                 241 
                 tattaccctg acaatgtgaa gggtcggttc accatttcca gggataacgc aaagaacagt 
               
               
                 301 
                 ctctacctgc agatgaacag cctgagggct gaggacaccg ccgtctacta ctgcgcccga 
               
               
                 361 
                 gaatggggag attatgatgg gtttgactat tggggccagg gcactttggt gacagtcagt 
               
               
                 421 
                 tctgcctcaa caaaaggacc aagtgtgttc ccactcgccc ctagcagcaa gagtacatcc 
               
               
                 481 
                 gggggcactg cagcactcgg ctgcctcgtc aaggattatt ttccagagcc agtaaccgtg 
               
               
                 541 
                 agctggaaca gtggagcact cacttctggt gtccatactt ttcctgctgt cctgcaaagc 
               
               
                 601 
                 tctggcctgt actcactcag ctccgtcgtg accgtgccat cttcatctct gggcactcag 
               
               
                 661 
                 acctacatct gtaatgtaaa ccacaagcct agcaatacta aggtcgataa gcgggtggaa 
               
               
                 721 
                 cccaagagct gcgacaagac tcacacttgt cccccatgcc ctgcccctga acttctgggc 
               
               
                 781 
                 ggtcccagcg tctttttgtt cccaccaaag cctaaagata ctctgatgat aagtagaaca 
               
               
                 841 
                 cccgaggtga catgtgttgt tgtagacgtt tcccacgagg acccagaggt taagttcaac 
               
               
                 901 
                 tggtacgttg atggagtcga agtacataat gctaagacca agcctagaga ggagcagtat 
               
               
                 961 
                 aatagtacat accgtgtagt cagtgttctc acagtgctgc accaagactg gctcaacggc 
               
               
                 1021 
                 aaagaataca aatgcaaagt gtccaacaaa gcactcccag cccctatcga gaagactatt 
               
               
                 1081 
                 agtaaggcaa aggggcagcc tcgtgaacca caggtgtaca ctctgccacc cagtagagag 
               
               
                 1141 
                 gaaatgacaa agaaccaagt ctcattgacc tgcctggtga aaggcttcta ccccagcgac 
               
               
                 1201 
                 atcgccgttg agtgggagag taacggtcag cctgagaaca attacaagac aaccccccca 
               
               
                 1261 
                 gtgctggata gtgacgggtc tttctttctg tacagtaagc tgactgtgga caagtcccgc 
               
               
                 1321 
                 tggcagcagg gtaacgtctt cagctgttcc gtgatgcacg aggcattgca caaccactac 
               
               
                 1381 
                 acccagaagt cactgagcct gagcccaggg aag 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Humanized Sh24C05 Hv3-7 Heavy Chain 
                   
               
               
                 (Humanized Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 186) 
                   
               
             
          
           
               
                 1 
                 mdmrvpaqll gllllwlrga rcevqlvesg gglvqpggsl rlscaasgft fsdyamswvr 
                   
               
               
                 61 
                 qapgkglewv atisdggtyt yypdnvkgrf tisrdnakns lylqmnslra edtavyycar 
               
               
                 121 
                 ewgdydgfdy wgqgtivtvs sastkgpsvf plapssksts ggtaalgclv kdyfpepvtv 
               
               
                 181 
                 swnsgaltsg vhtfpavlqs sglyslssvv tvpssslgtq tyicnvnhkp sntkvdkrve 
               
               
                 241 
                 pkscdkthtc ppcpapellg gpsvflfppk pkdtlmisrt pevtcvvvdv shedpevkfn 
               
               
                 301 
                 wyvdgvevhn aktkpreeqy nstyrvvsvl tvlhqdwlng keykckvsnk alpapiekti 
               
               
                 361 
                 skakgqprep qvytlppsre emtknqvslt clvkgfypsd iavewesngq pennykttpp 
               
               
                 421 
                 vldsdgsffl yskltvdksr wqqgnvfscs vmhealhnhy tqkslslspg k 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Humanized Sh24C05 Hv3-11 
                   
               
               
                 Heavy Chain (Humanized Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 187) 
                   
               
             
          
           
               
                 1 
                 atggacatga gagttcctgc tcagctgctc gggttgctgt tgctttggct ccggggtgct 
                   
               
               
                 61 
                 aggtgccaag ttcagctggt ggaatctggc ggtgggcttg taaagccagg aggctccctc 
               
               
                 121 
                 agactgagtt gtgccgcttc agggttcaca ttctccgact atgcgatgtc atggatcagg 
               
               
                 181 
                 caagcacccg ggaaaggact ggagtgggtt agcactatca gcgatggcgg aacgtatacc 
               
               
                 241 
                 tattaccctg acaatgtgaa gggtcggttc accatttcca gggataacgc aaagaacagt 
               
               
                 301 
                 ctctaccttc agatgaacag cctgagggct gaggacaccg ccgtctacta ctgcgcccga 
               
               
                 361 
                 gaatggggag attatgatgg gtttgactat tggggccagg gcactttggt gacagtcagt 
               
               
                 421 
                 tctgcctcaa caaaaggacc aagtgtgttc ccactcgccc ctagcagcaa gagtacatcc 
               
               
                 481 
                 gggggcactg cagcactcgg ctgcctcgtc aaggattatt ttccagagcc agtaaccgtg 
               
               
                 541 
                 agctggaaca gtggagcact cacttctggt gtccatactt ttcctgctgt cctgcaaagc 
               
               
                 601 
                 tctggcctgt actcactcag ctccgtcgtg accgtgccat cttcatctct gggcactcag 
               
               
                 661 
                 acctacatct gtaatgtaaa ccacaagcct agcaatacta aggtcgataa gcgggtggaa 
               
               
                 721 
                 cccaagagct gcgacaagac tcacacttgt cccccatgcc ctgcccctga acttctgggc 
               
               
                 781 
                 ggtcccagcg tctttttgtt cccaccaaag cctaaagata ctctgatgat aagtagaaca 
               
               
                 841 
                 cccgaggtga catgtgttgt tgtagacgtt tcccacgagg acccagaggt taagttcaac 
               
               
                 901 
                 tggtacgttg atggagtcga agtacataat gctaagacca agcctagaga ggagcagtat 
               
               
                 961 
                 aatagtacat accgtgtagt cagtgttctc acagtgctgc accaagactg gctcaacggc 
               
               
                 1021 
                 aaagaataca aatgcaaagt gtccaacaaa gcactcccag cccctatcga gaagactatt 
               
               
                 1081 
                 agtaaggcaa aggggcagcc tcgtgaacca caggtgtaca ctctgccacc cagtagagag 
               
               
                 1141 
                 gaaatgacaa agaaccaagt ctcattgacc tgcctggtga aaggcttcta ccccagcgac 
               
               
                 1201 
                 atcgccgttg agtgggagag taacggtcag cctgagaaca attacaagac aaccccccca 
               
               
                 1261 
                 gtgctggata gtgacgggtc tttctttctg tacagtaagc tgactgtgga caagtcccgc 
               
               
                 1321 
                 tggcagcagg gtaacgtctt cagctgttcc gtgatgcacg aggcattgca caaccactac 
               
               
                 1381 
                 acccagaagt cactgagcct gagcccaggg aag 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Humanized Sh24C05 Hv3-11 Heavy 
                   
               
               
                 Chain (Humanized Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 188) 
                   
               
             
          
           
               
                 1 
                 mdmrvpaqll gllllwlrga rcqvqlvesg gglvkpggsl rlscaasgft fsdyamswir 
                   
               
               
                 61 
                 qapgkglewv stisdggtyt yypdnvkgrf tisrdnakns lylqmnslra edtavyycar 
               
               
                 121 
                 ewgdydgfdy wgqgtivtvs sastkgpsvf plapssksts ggtaalgclv kdyfpepvtv 
               
               
                 181 
                 swnsgaltsg vhtfpavlqs sglyslssvv tvpssslgtq tyicnvnhkp sntkvdkrve 
               
               
                 241 
                 pkscdkthtc ppcpapellg gpsvflfppk pkdtlmisrt pevtcvvvdv shedpevkfn 
               
               
                 301 
                 wyvdgvevhn aktkpreeqy nstyrvvsvl tvlhqdwlng keykckvsnk alpapiekti 
               
               
                 361 
                 skakgqprep qvytlppsre emtknqvslt clvkgfypsd iavewesngq pennykttpp 
               
               
                 421 
                 vldsdgsffl yskltvdksr wqqgnvfscs vmhealhnhy tqkslslspg k 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Humanized Sh24C05 Hv3-11 
                   
               
               
                 N62S IgG1 Heavy Chain (Humanized Heavy Chain Variable Region and Human IgG1 Constant 
               
               
                 Region) 
               
               
                 (SEQ ID NO: 189) 
                   
               
             
          
           
               
                 1 
                 atggacatga gagttcctgc tcagctgctc gggttgctgt tgctttggct ccggggtgct 
                   
               
               
                 61 
                 aggtgccaag ttcagctggt ggaatctggc ggtgggcttg taaagccagg aggctccctc 
               
               
                 121 
                 agactgagtt gtgccgcttc agggttcaca ttctccgact atgcgatgtc atggatcagg 
               
               
                 181 
                 caagcacccg ggaaaggact ggagtgggtt agcactatca gcgatggcgg aacgtatacc 
               
               
                 241 
                 tattaccctg actccgtgaa gggtcggttc accatttcca gggataacgc aaagaacagt 
               
               
                 301 
                 ctctaccttc agatgaacag cctgagggct gaggacaccg ccgtctacta ctgcgcccga 
               
               
                 361 
                 gaatggggag attatgatgg gtttgactat tggggccagg gcactttggt gacagtcagt 
               
               
                 421 
                 tctgcctcaa caaaaggacc aagtgtgttc ccactcgccc ctagcagcaa gagtacatcc 
               
               
                 481 
                 gggggcactg cagcactcgg ctgcctcgtc aaggattatt ttccagagcc agtaaccgtg 
               
               
                 541 
                 agctggaaca gtggagcact cacttctggt gtccatactt ttcctgctgt cctgcaaagc 
               
               
                 601 
                 tctggcctgt actcactcag ctccgtcgtg accgtgccat cttcatctct gggcactcag 
               
               
                 661 
                 acctacatct gtaatgtaaa ccacaagcct agcaatacta aggtcgataa gcgggtggaa 
               
               
                 721 
                 cccaagagct gcgacaagac tcacacttgt cccccatgcc ctgcccctga acttctgggc 
               
               
                 781 
                 ggtcccagcg tctttttgtt cccaccaaag cctaaagata ctctgatgat aagtagaaca 
               
               
                 841 
                 cccgaggtga catgtgttgt tgtagacgtt tcccacgagg acccagaggt taagttcaac 
               
               
                 901 
                 tggtacgttg atggagtcga agtacataat gctaagacca agcctagaga ggagcagtat 
               
               
                 961 
                 aatagtacat accgtgtagt cagtgttctc acagtgctgc accaagactg gctcaacggc 
               
               
                 1021 
                 aaagaataca aatgcaaagt gtccaacaaa gcactcccag cccctatcga gaagactatt 
               
               
                 1081 
                 agtaaggcaa aggggcagcc tcgtgaacca caggtgtaca ctctgccacc cagtagagag 
               
               
                 1141 
                 gaaatgacaa agaaccaagt ctcattgacc tgcctggtga aaggcttcta ccccagcgac 
               
               
                 1201 
                 atcgccgttg agtgggagag taacggtcag cctgagaaca attacaagac aaccccccca 
               
               
                 1261 
                 gtgctggata gtgacgggtc tttctttctg tacagtaagc tgactgtgga caagtcccgc 
               
               
                 1321 
                 tggcagcagg gtaacgtctt cagctgttcc gtgatgcacg aggcattgca caaccactac 
               
               
                 1381 
                 acccagaagt cactgagcct gagcccaggg aag 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Humanized Sh24C05 Hv3-11 N62S IgG1 
                   
               
               
                 Heavy Chain (Humanized Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 190) 
                   
               
             
          
           
               
                 1 
                 mdmrvpaqll gllllwlrga rcqvqlvesg gglvkpggsl rlscaasgft fsdyamswir 
                   
               
               
                 61 
                 qapgkglewv stisdggtyt yypdsvkgrf tisrdnakns lylqmnslra edtavyycar 
               
               
                 121 
                 ewgdydgfdy wgqgtivtvs sastkgpsvf plapssksts ggtaalgclv kdyfpepvtv 
               
               
                 181 
                 swnsgaltsg vhtfpavlqs sglyslssvv tvpssslgtq tyicnvnhkp sntkvdkrve 
               
               
                 241 
                 pkscdkthtc ppcpapellg gpsvflfppk pkdtlmisrt pevtcvvvdv shedpevkfn 
               
               
                 301 
                 wyvdgvevhn aktkpreeqy nstyrvvsvl tvlhqdwlng keykckvsnk alpapiekti 
               
               
                 361 
                 skakgqprep qvytlppsre emtknqvslt clvkgfypsd iavewesngq pennykttpp 
               
               
                 421 
                 vldsdgsffl yskltvdksr wqqgnvfscs vmhealhnhy tqkslslspg k 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Humanized Sh24C05 Hv3-11 
                   
               
               
                 N62S IgG2 Heavy Chain (Humanized Heavy Chain Variable Region and Human IgG2 
               
               
                 Constant Region) 
               
               
                 (SEQ ID NO: 191) 
                   
               
             
          
           
               
                 1 
                 atggacatga gagttcctgc tcagctgctc gggttgctgt tgctttggct ccggggtgct 
                   
               
               
                 61 
                 aggtgccaag ttcagctggt ggaatctggc ggtgggcttg taaagccagg aggctccctc 
               
               
                 121 
                 agactgagtt gtgccgcttc agggttcaca ttctccgact atgcgatgtc atggatcagg 
               
               
                 181 
                 caagcacccg ggaaaggact ggagtgggtt agcactatca gcgatggcgg aacgtatacc 
               
               
                 241 
                 tattaccctg actccgtgaa gggtcggttc accatttcca gggataacgc aaagaacagt 
               
               
                 301 
                 ctctaccttc agatgaacag cctgagggct gaggacaccg ccgtctacta ctgcgcccga 
               
               
                 361 
                 gaatggggag attatgatgg gtttgactat tggggccagg gcactttggt gacagtcagt 
               
               
                 421 
                 tctgcctcca ccaagggccc atcggtcttc cccctggcgc cctgctccag gagcacctcc 
               
               
                 481 
                 gagagcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 
               
               
                 541 
                 tcgtggaact caggcgctct gaccagcggc gtgcacacct tcccagctgt cctacagtcc 
               
               
                 601 
                 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcaactt cggcacccag 
               
               
                 661 
                 acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gacagttgag 
               
               
                 721 
                 cgcaaatgtt gtgtcgagtg cccaccgtgc ccagcaccac ctgtggcagg accgtcagtc 
               
               
                 781 
                 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcacg 
               
               
                 841 
                 tgcgtggtgg tggacgtgag ccacgaagac cccgaggtcc agttcaactg gtacgtggac 
               
               
                 901 
                 ggcgtggagg tgcataatgc caagacaaag ccacgggagg agcagttcaa cagcacgttc 
               
               
                 961 
                 cgtgtggtca gcgtcctcac cgttgtgcac caggactggc tgaacggcaa ggagtacaag 
               
               
                 1021 
                 tgcaaggtct ccaacaaagg cctcccagcc cccatcgaga aaaccatctc caaaaccaaa 
               
               
                 1081 
                 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 
               
               
                 1141 
                 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 
               
               
                 1201 
                 tgggagagca atgggcagcc ggagaacaac tacaagacca cacctcccat gctggactcc 
               
               
                 1261 
                 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 
               
               
                 1321 
                 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 
               
               
                 1381 
                 ctctccctgt ctccgggtaa a 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Humanized Sh24C05 Hv3-11 N62S IgG2 
                   
               
               
                 Heavy Chain (Humanized Heavy Chain Variable Region and Human IgG2 Constant Region) 
               
               
                 (SEQ ID NO: 192) 
                   
               
             
          
           
               
                 1 
                 mdmrvpaqll gllllwlrga rcqvqlvesg gglvkpggsl rlscaasgft fsdyamswir 
                   
               
               
                 61 
                 qapgkglewv stisdggtyt yypdsvkgrf tisrdnakns lylqmnslra edtavyycar 
               
               
                 121 
                 ewgdydgfdy wgqgtivtvs sastkgpsvf plapcsrsts estaalgclv kdyfpepvtv 
               
               
                 181 
                 swnsgaltsg vhtfpavlqs sglyslssvv tvpssnfgtq tytcnvdhkp sntkvdktve 
               
               
                 241 
                 rkccvecppc pappvagpsv flfppkpkdt lmisrtpevt cvvvdvshed pevqfnwyvd 
               
               
                 301 
                 gvevhnaktk preeqfnstf rvvsvltvvh qdwlngkeyk ckvsnkglpa piektisktk 
               
               
                 361 
                 gqprepqvyt lppsreemtk nqvsltclvk gfypsdiave wesngqpenn ykttppmlds 
               
               
                 421 
                 dgsfflyskl tvdksrwqqg nvfscsvmhe alhnhytqks lslspgk 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Humanized Sh24C05 Hv3-21 
                   
               
               
                 Heavy Chain (Humanized Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 193) 
                   
               
             
          
           
               
                 1 
                 atggacatga gagttcctgc tcagctgctc gggttgctgt tgctttggct ccggggtgct 
                   
               
               
                 61 
                 aggtgcgagg ttcagctggt ggaatctggc ggtgggcttg taaagccagg aggctccctc 
               
               
                 121 
                 agactgagtt gtgccgcttc agggttcaca ttctccgact atgcgatgtc atgggtgcgc 
               
               
                 181 
                 caagcacccg ggaaaggact ggagtgggtt agcactatca gcgatggcgg aacgtatacc 
               
               
                 241 
                 tattaccctg acaatgtgaa gggtcggttc accatttcca gggataacgc aaagaacagt 
               
               
                 301 
                 ctctatttgc agatgaacag cctgagggct gaggacaccg ccgtctacta ctgcgcccga 
               
               
                 361 
                 gaatggggag attatgatgg gtttgactat tggggccagg gcactttggt gacagtcagt 
               
               
                 421 
                 tctgcctcaa caaaaggacc aagtgtgttc ccactcgccc ctagcagcaa gagtacatcc 
               
               
                 481 
                 gggggcactg cagcactcgg ctgcctcgtc aaggattatt ttccagagcc agtaaccgtg 
               
               
                 541 
                 agctggaaca gtggagcact cacttctggt gtccatactt ttcctgctgt cctgcaaagc 
               
               
                 601 
                 tctggcctgt actcactcag ctccgtcgtg accgtgccat cttcatctct gggcactcag 
               
               
                 661 
                 acctacatct gtaatgtaaa ccacaagcct agcaatacta aggtcgataa gcgggtggaa 
               
               
                 721 
                 cccaagagct gcgacaagac tcacacttgt cccccatgcc ctgcccctga acttctgggc 
               
               
                 781 
                 ggtcccagcg tctttttgtt cccaccaaag cctaaagata ctctgatgat aagtagaaca 
               
               
                 841 
                 cccgaggtga catgtgttgt tgtagacgtt tcccacgagg acccagaggt taagttcaac 
               
               
                 901 
                 tggtacgttg atggagtcga agtacataat gctaagacca agcctagaga ggagcagtat 
               
               
                 961 
                 aatagtacat accgtgtagt cagtgttctc acagtgctgc accaagactg gctcaacggc 
               
               
                 1021 
                 aaagaataca aatgcaaagt gtccaacaaa gcactcccag cccctatcga gaagactatt 
               
               
                 1081 
                 agtaaggcaa aggggcagcc tcgtgaacca caggtgtaca ctctgccacc cagtagagag 
               
               
                 1141 
                 gaaatgacaa agaaccaagt ctcattgacc tgcctggtga aaggcttcta ccccagcgac 
               
               
                 1201 
                 atcgccgttg agtgggagag taacggtcag cctgagaaca attacaagac aaccccccca 
               
               
                 1261 
                 gtgctggata gtgacgggtc tttctttctg tacagtaagc tgactgtgga caagtcccgc 
               
               
                 1321 
                 tggcagcagg gtaacgtctt cagctgttcc gtgatgcacg aggcattgca caaccactac 
               
               
                 1381 
                 acccagaagt cactgagcct gagcccaggg aag 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Humanized 24C05 Hv3-21 Heavy Chain 
                   
               
               
                 (Humanized Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 194) 
                   
               
             
          
           
               
                 1 
                 mdmrvpaqll gllllwlrga rcevqlvesg gglvkpggsl rlscaasgft fsdyamswvr 
                   
               
               
                 61 
                 qapgkglewv stisdggtyt yypdnvkgrf tisrdnakns lylqmnslra edtavyycar 
               
               
                 121 
                 ewgdydgfdy wgqgtivtvs sastkgpsvf plapssksts ggtaalgclv kdyfpepvtv 
               
               
                 181 
                 swnsgaltsg vhtfpavlqs sglyslssvv tvpssslgtq tyicnvnhkp sntkvdkrve 
               
               
                 241 
                 pkscdkthtc ppcpapellg gpsvflfppk pkdtlmisrt pevtcvvvdv shedpevkfn 
               
               
                 301 
                 wyvdgvevhn aktkpreeqy nstyrvvsvl tvlhqdwlng keykckvsnk alpapiekti 
               
               
                 361 
                 skakgqprep qvytlppsre emtknqvslt clvkgfypsd iavewesngq pennykttpp 
               
               
                 421 
                 vldsdgsffl yskltvdksr wqqgnvfscs vmhealhnhy tqkslslspg k 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Humanized Sh24C05 Hv3-23 
                   
               
               
                 Heavy Chain (Humanized Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 195) 
                   
               
             
          
           
               
                 1 
                 atggacatga gagttcctgc tcagctgctc gggttgctgt tgctttggct ccggggtgct 
                   
               
               
                 61 
                 aggtgcgagg ttcagcttct ggaatctggc ggtgggcttg tacagccagg aggctccctc 
               
               
                 121 
                 agactgagtt gtgccgcttc agggttcaca ttctccgact atgcgatgtc atgggtgcgc 
               
               
                 181 
                 caagcacccg ggaaaggact ggagtgggtt tcaactatca gcgatggcgg aacgtatacc 
               
               
                 241 
                 tattaccctg acaatgtgaa gggtcggttc accatttcca gggataacag caagaacaca 
               
               
                 301 
                 ctctatctcc agatgaacag cctgagggct gaggacaccg ccgtctacta ctgcgcccga 
               
               
                 361 
                 gaatggggag attatgatgg gtttgactat tggggccagg gcactttggt gacagtcagt 
               
               
                 421 
                 tctgcctcaa caaaaggacc aagtgtgttc ccactcgccc ctagcagcaa gagtacatcc 
               
               
                 481 
                 gggggcactg cagcactcgg ctgcctcgtc aaggattatt ttccagagcc agtaaccgtg 
               
               
                 541 
                 agctggaaca gtggagcact cacttctggt gtccatactt ttcctgctgt cctgcaaagc 
               
               
                 601 
                 tctggcctgt actcactcag ctccgtcgtg accgtgccat cttcatctct gggcactcag 
               
               
                 661 
                 acctacatct gtaatgtaaa ccacaagcct agcaatacta aggtcgataa gcgggtggaa 
               
               
                 721 
                 cccaagagct gcgacaagac tcacacttgt cccccatgcc ctgcccctga acttctgggc 
               
               
                 781 
                 ggtcccagcg tctttttgtt cccaccaaag cctaaagata ctctgatgat aagtagaaca 
               
               
                 841 
                 cccgaggtga catgtgttgt tgtagacgtt tcccacgagg acccagaggt taagttcaac 
               
               
                 901 
                 tggtacgttg atggagtcga agtacataat gctaagacca agcctagaga ggagcagtat 
               
               
                 961 
                 aatagtacat accgtgtagt cagtgttctc acagtgctgc accaagactg gctcaacggc 
               
               
                 1021 
                 aaagaataca aatgcaaagt gtccaacaaa gcactcccag cccctatcga gaagactatt 
               
               
                 1081 
                 agtaaggcaa aggggcagcc tcgtgaacca caggtgtaca ctctgccacc cagtagagag 
               
               
                 1141 
                 gaaatgacaa agaaccaagt ctcattgacc tgcctggtga aaggcttcta ccccagcgac 
               
               
                 1201 
                 atcgccgttg agtgggagag taacggtcag cctgagaaca attacaagac aaccccccca 
               
               
                 1261 
                 gtgctggata gtgacgggtc tttctttctg tacagtaagc tgactgtgga caagtcccgc 
               
               
                 1321 
                 tggcagcagg gtaacgtctt cagctgttcc gtgatgcacg aggcattgca caaccactac 
               
               
                 1381 
                 acccagaagt cactgagcct gagcccaggg aag 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Humanized Sh24C05 Hv3-23 Heavy 
                   
               
               
                 Chain (Humanized Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 196) 
                   
               
             
          
           
               
                 1 
                 mdmrvpaqll gllllwlrga rcevqllesg gglvqpggsl rlscaasgft fsdyamswvr 
                   
               
               
                 61 
                 qapgkglewv stisdggtyt yypdnvkgrf tisrdnsknt lylqmnslra edtavyycar 
               
               
                 121 
                 ewgdydgfdy wgqgtivtvs sastkgpsvf plapssksts ggtaalgclv kdyfpepvtv 
               
               
                 181 
                 swnsgaltsg vhtfpavlqs sglyslssvv tvpssslgtq tyicnvnhkp sntkvdkrve 
               
               
                 241 
                 pkscdkthtc ppcpapellg gpsvflfppk pkdtlmisrt pevtcvvvdv shedpevkfn 
               
               
                 301 
                 wyvdgvevhn aktkpreeqy nstyrvvsvl tvlhqdwlng keykckvsnk alpapiekti 
               
               
                 361 
                 skakgqprep qvytlppsre emtknqvslt clvkgfypsd iavewesngq pennykttpp 
               
               
                 421 
                 vldsdgsffl yskltvdksr wqqgnvfscs vmhealhnhy tqkslslspg k 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Humanized Sh24C05 Hv3-30 
                   
               
               
                 Heavy Chain (Humanized Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 197) 
                   
               
             
          
           
               
                 1 
                 atggacatga gagttcctgc tcagctgctc gggttgctgt tgctttggct ccggggtgct 
                   
               
               
                 61 
                 aggtgccagg ttcagctggt ggaatctggc ggtggggtag tacaaccagg acggtccctc 
               
               
                 121 
                 agactgagtt gtgccgcttc agggttcaca ttctccgact atgcgatgtc atgggtgcgc 
               
               
                 181 
                 caagcacccg ggaaaggact ggagtgggtt gccactatca gcgatggcgg aacgtatacc 
               
               
                 241 
                 tattaccctg acaatgtgaa gggtcggttc accatttcca gggataactc aaagaacacc 
               
               
                 301 
                 ctctatctcc aaatgagtag cctgagggct gaggacaccg ccgtctacta ctgcgcccga 
               
               
                 361 
                 gaatggggag attatgatgg gtttgactat tggggccagg gcactttggt gacagtcagt 
               
               
                 421 
                 tctgcctcaa caaaaggacc aagtgtgttc ccactcgccc ctagcagcaa gagtacatcc 
               
               
                 481 
                 gggggcactg cagcactcgg ctgcctcgtc aaggattatt ttccagagcc agtaaccgtg 
               
               
                 541 
                 agctggaaca gtggagcact cacttctggt gtccatactt ttcctgctgt cctgcaaagc 
               
               
                 601 
                 tctggcctgt actcactcag ctccgtcgtg accgtgccat cttcatctct gggcactcag 
               
               
                 661 
                 acctacatct gtaatgtaaa ccacaagcct agcaatacta aggtcgataa gcgggtggaa 
               
               
                 721 
                 cccaagagct gcgacaagac tcacacttgt cccccatgcc ctgcccctga acttctgggc 
               
               
                 781 
                 ggtcccagcg tctttttgtt cccaccaaag cctaaagata ctctgatgat aagtagaaca 
               
               
                 841 
                 cccgaggtga catgtgttgt tgtagacgtt tcccacgagg acccagaggt taagttcaac 
               
               
                 901 
                 tggtacgttg atggagtcga agtacataat gctaagacca agcctagaga ggagcagtat 
               
               
                 961 
                 aatagtacat accgtgtagt cagtgttctc acagtgctgc accaagactg gctcaacggc 
               
               
                 1021 
                 aaagaataca aatgcaaagt gtccaacaaa gcactcccag cccctatcga gaagactatt 
               
               
                 1081 
                 agtaaggcaa aggggcagcc tcgtgaacca caggtgtaca ctctgccacc cagtagagag 
               
               
                 1141 
                 gaaatgacaa agaaccaagt ctcattgacc tgcctggtga aaggcttcta ccccagcgac 
               
               
                 1201 
                 atcgccgttg agtgggagag taacggtcag cctgagaaca attacaagac aaccccccca 
               
               
                 1261 
                 gtgctggata gtgacgggtc tttctttctg tacagtaagc tgactgtgga caagtcccgc 
               
               
                 1321 
                 tggcagcagg gtaacgtctt cagctgttcc gtgatgcacg aggcattgca caaccactac 
               
               
                 1381 
                 acccagaagt cactgagcct gagcccaggg aag 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Humanized of Sh24C05 Hv3-30 Heavy 
                   
               
               
                 Chain (Humanized Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 198) 
                   
               
             
          
           
               
                 1 
                 mdmrvpaqll gllllwlrga rcqvqlvesg ggvvqpgrsl rlscaasgft fsdyamswvr 
                   
               
               
                 61 
                 qapgkglewv atisdggtyt yypdnvkgrf tisrdnsknt lylqmsslra edtavyycar 
               
               
                 121 
                 ewgdydgfdy wgqgtivtvs sastkgpsvf plapssksts ggtaalgclv kdyfpepvtv 
               
               
                 181 
                 swnsgaltsg vhtfpavlqs sglyslssvv tvpssslgtq tyicnvnhkp sntkvdkrve 
               
               
                 241 
                 pkscdkthtc ppcpapellg gpsvflfppk pkdtlmisrt pevtcvvvdv shedpevkfn 
               
               
                 301 
                 wyvdgvevhn aktkpreeqy nstyrvvsvl tvlhqdwlng keykckvsnk alpapiekti 
               
               
                 361 
                 skakgqprep qvytlppsre emtknqvslt clvkgfypsd iavewesngq pennykttpp 
               
               
                 421 
                 vldsdgsffl yskltvdksr wqqgnvfscs vmhealhnhy tqkslslspg k 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Humanized Hu24C05 HvA Heavy 
                   
               
               
                 Chain (Humanized Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 199) 
                   
               
             
          
           
               
                 1 
                 atggacatga gagttcctgc tcagctgctc gggttgctgt tgctttggct ccggggtgct 
                   
               
               
                 61 
                 aggtgcgagg ttcagctggt ggaatctggc ggtgggcttg taaagccagg aggctccctc 
               
               
                 121 
                 agactgagtt gtgccgcttc agggttcaca ttctccgact atgcgatgtc atgggtgcgc 
               
               
                 181 
                 caagcacccg ggaaaggact ggagtgggtt gccactatca gcgatggcgg aacgtatacc 
               
               
                 241 
                 tattaccctg acaatgtgaa gggtcggttc accatttcca gggataacgc aaagaacagt 
               
               
                 301 
                 ctctaccttc agatgaacag cctgagggct gaggacaccg ccgtctacta ctgcgcccga 
               
               
                 361 
                 gaatggggag attatgatgg gtttgactat tggggccagg gcactttggt gacagtcagt 
               
               
                 421 
                 tctgcctcaa caaaaggacc aagtgtgttc ccactcgccc ctagcagcaa gagtacatcc 
               
               
                 481 
                 gggggcactg cagcactcgg ctgcctcgtc aaggattatt ttccagagcc agtaaccgtg 
               
               
                 541 
                 agctggaaca gtggagcact cacttctggt gtccatactt ttcctgctgt cctgcaaagc 
               
               
                 601 
                 tctggcctgt actcactcag ctccgtcgtg accgtgccat cttcatctct gggcactcag 
               
               
                 661 
                 acctacatct gtaatgtaaa ccacaagcct agcaatacta aggtcgataa gcgggtggaa 
               
               
                 721 
                 cccaagagct gcgacaagac tcacacttgt cccccatgcc ctgcccctga acttctgggc 
               
               
                 781 
                 ggtcccagcg tctttttgtt cccaccaaag cctaaagata ctctgatgat aagtagaaca 
               
               
                 841 
                 cccgaggtga catgtgttgt tgtagacgtt tcccacgagg acccagaggt taagttcaac 
               
               
                 901 
                 tggtacgttg atggagtcga agtacataat gctaagacca agcctagaga ggagcagtat 
               
               
                 961 
                 aatagtacat accgtgtagt cagtgttctc acagtgctgc accaagactg gctcaacggc 
               
               
                 1021 
                 aaagaataca aatgcaaagt gtccaacaaa gcactcccag cccctatcga gaagactatt 
               
               
                 1081 
                 agtaaggcaa aggggcagcc tcgtgaacca caggtgtaca ctctgccacc cagtagagag 
               
               
                 1141 
                 gaaatgacaa agaaccaagt ctcattgacc tgcctggtga aaggcttcta ccccagcgac 
               
               
                 1201 
                 atcgccgttg agtgggagag taacggtcag cctgagaaca attacaagac aaccccccca 
               
               
                 1261 
                 gtgctggata gtgacgggtc tttctttctg tacagtaagc tgactgtgga caagtcccgc 
               
               
                 1321 
                 tggcagcagg gtaacgtctt cagctgttcc gtgatgcacg aggcattgca caaccactac 
               
               
                 1381 
                 acccagaagt cactgagcct gagcccaggg aag 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Humanized Hu24C05 HvA Heavy Chain 
                   
               
               
                 (Humanized Heavy Chain Variable Region and Human IgG1 Constant Region) 
               
               
                 (SEQ ID NO: 200) 
                   
               
             
          
           
               
                 1 
                 mdmrvpaqll gllllwlrga rcevqlvesg gglvkpggsl rlscaasgft fsdyamswvr 
                   
               
               
                 61 
                 qapgkglewv atisdggtyt yypdnvkgrf tisrdnakns lylqmnslra edtavyycar 
               
               
                 121 
                 ewgdydgfdy wgqgtivtvs sastkgpsvf plapssksts ggtaalgclv kdyfpepvtv 
               
               
                 181 
                 swnsgaltsg vhtfpavlqs sglyslssvv tvpssslgtq tyicnvnhkp sntkvdkrve 
               
               
                 241 
                 pkscdkthtc ppcpapellg gpsvflfppk pkdtlmisrt pevtcvvvdv shedpevkfn 
               
               
                 301 
                 wyvdgvevhn aktkpreeqy nstyrvvsvl tvlhqdwlng keykckvsnk alpapiekti 
               
               
                 361 
                 skakgqprep qvytlppsre emtknqvslt clvkgfypsd iavewesngq pennykttpp 
               
               
                 421 
                 vldsdgsffl yskltvdksr wqqgnvfscs vmhealhnhy tqkslslspg k 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Humanized Sh24C05 Kv1-9 Light 
                   
               
               
                 Chain (Humanized Kappa Chain Variable Region and Human Constant Region) 
               
               
                 (SEQ ID NO: 201) 
                   
               
             
          
           
               
                 1 
                 atggacatga gggtgcccgc tcaactgctg gggctgctgc tgctgtggct gagaggagct 
                   
               
               
                 61 
                 cgttgcgata ttcagttgac ccaatcacct agcttcctct cagcttccgt gggcgacaga 
               
               
                 121 
                 gttaccataa cctgtcgggc aagccaggag atttctgggt acctgtcctg gtaccaacag 
               
               
                 181 
                 aagcccggaa aagcccctaa gctgttgatc tatgctgcgt caaccttgga tagcggtgtc 
               
               
                 241 
                 ccgagtcgat tctccggttc tggctccgga acagagttca ctctgacaat ttctagcctt 
               
               
                 301 
                 cagccagaag atttcgccac gtactattgc ctccagtacg acagctatcc ctatacattt 
               
               
                 361 
                 gggcagggca ctaaactgga gatcaaacgc acagttgctg cccccagcgt gttcattttc 
               
               
                 421 
                 ccacctagcg atgagcagct gaaaagcggt actgcctctg tcgtatgctt gctcaacaac 
               
               
                 481 
                 ttttacccac gtgaggctaa ggtgcagtgg aaagtggata atgcacttca atctggaaac 
               
               
                 541 
                 agtcaagagt ccgtgacaga acaggacagc aaagactcaa cttattcact ctcttccacc 
               
               
                 601 
                 ctgactctgt ccaaggcaga ctatgaaaaa cacaaggtat acgcctgcga ggttacacac 
               
               
                 661 
                 cagggtttgt ctagtcctgt caccaagtcc ttcaataggg gcgaatgt 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Humanized Sh24C05 Kv1-9 Light Chain 
                   
               
               
                 (Humanized Kappa Chain Variable Region and Human Constant Region) 
               
               
                 (SEQ ID NO: 202) 
                   
               
             
          
           
               
                 1 
                 mdmrvpaqll gllllwlrga rcdiqltqsp sflsasvgdr vtitcrasqe isgylswyqq 
                   
               
               
                 61 
                 kpgkapklli yaastldsgv psrfsgsgsg teftltissl qpedfatyyc lqydsypytf 
               
               
                 121 
                 gqgtkleikr tvaapsvfif ppsdeqlksg tasvvcllnn fypreakvqw kvdnalqsgn 
               
               
                 181 
                 sqesvteqds kdstyslsst ltlskadyek hkvyacevth qglsspvtks fnrgec 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Humanized Sh24C05 Kv1-16 Light 
                   
               
               
                 Chain (Humanized Kappa Chain Variable Region and Human Constant Region) 
               
               
                 (SEQ ID NO: 203) 
                   
               
             
          
           
               
                 1 
                 atggacatga gggtgcccgc tcaactgctg gggctgctgc tgctgtggct gagaggagct 
                   
               
               
                 61 
                 cgttgcgata ttcagatgac ccaatcacct agcagtctct cagcttccgt gggcgacaga 
               
               
                 121 
                 gttaccataa cctgtcgggc aagccaggag atttctgggt acctgtcctg gtttcaacag 
               
               
                 181 
                 aagcccggaa aggccccgaa gagcttgatc tatgctgcgt caaccttgga tagcggtgtc 
               
               
                 241 
                 ccgagtcgat tctccggttc tggctccgga accgacttta ctctgacaat ttctagcctt 
               
               
                 301 
                 cagccagaag atttcgccac gtactattgc ctccagtacg acagctatcc ctatacattt 
               
               
                 361 
                 gggcagggca ctaaactgga gatcaaacgc acagttgctg cccccagcgt gttcattttc 
               
               
                 421 
                 ccacctagcg atgagcagct gaaaagcggt actgcctctg tcgtatgctt gctcaacaac 
               
               
                 481 
                 ttttacccac gtgaggctaa ggtgcagtgg aaagtggata atgcacttca atctggaaac 
               
               
                 541 
                 agtcaagagt ccgtgacaga acaggacagc aaagactcaa cttattcact ctcttccacc 
               
               
                 601 
                 ctgactctgt ccaaggcaga ctatgaaaaa cacaaggtat acgcctgcga ggttacacac 
               
               
                 661 
                 cagggtttgt ctagtcctgt caccaagtcc ttcaataggg gcgaatgt 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Humanized Sh24C05 Kv1-16 Light Chain 
                   
               
               
                 (Humanized Kappa Chain Variable Region and Human Constant Region) 
               
               
                 (SEQ ID NO: 204) 
                   
               
             
          
           
               
                 1 
                 mdmrvpaqll gllllwlrga rcdiqmtqsp sslsasvgdr vtitcrasqe isgylswfqq 
                   
               
               
                 61 
                 kpgkapksli yaastldsgv psrfsgsgsg tdftltissl qpedfatyyc lqydsypytf 
               
               
                 121 
                 gqgtkleikr tvaapsvfif ppsdeqlksg tasvvcllnn fypreakvqw kvdnalqsgn 
               
               
                 181 
                 sqesvteqds kdstyslsst ltlskadyek hkvyacevth qglsspvtks fnrgec 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Humanized Sh24C05 Kv1-17 Light 
                   
               
               
                 Chain (Humanized Kappa Chain Variable Region and Human Constant Region) 
               
               
                 (SEQ ID NO: 205) 
                   
               
             
          
           
               
                 1 
                 atggacatga gggtgcccgc tcaactgctg gggctgctgc tgctgtggct gagaggagct 
                   
               
               
                 61 
                 cgttgcgata ttcagatgac ccaatcacct agcagtctct cagcttccgt gggcgacaga 
               
               
                 121 
                 gttaccataa cctgtcgggc aagccaggag atttctgggt acctgtcctg gtatcaacag 
               
               
                 181 
                 aagcccggaa aagccccaaa gaggttgatc tatgctgcgt caaccttgga tagcggtgtc 
               
               
                 241 
                 ccgagtcgat tctccggttc tggctccgga accgagttca ctctgacaat ttctagcctt 
               
               
                 301 
                 cagccagaag atttcgccac gtactattgc ctccagtacg acagctatcc ctatacattt 
               
               
                 361 
                 gggcagggca ctaaactgga gatcaaacgc acagttgctg cccccagcgt gttcattttc 
               
               
                 421 
                 ccacctagcg atgagcagct gaaaagcggt actgcctctg tcgtatgctt gctcaacaac 
               
               
                 481 
                 ttttacccac gtgaggctaa ggtgcagtgg aaagtggata atgcacttca atctggaaac 
               
               
                 541 
                 agtcaagagt ccgtgacaga acaggacagc aaagactcaa cttattcact ctcttccacc 
               
               
                 601 
                 ctgactctgt ccaaggcaga ctatgaaaaa cacaaggtat acgcctgcga ggttacacac 
               
               
                 661 
                 cagggtttgt ctagtcctgt caccaagtcc ttcaataggg gcgaatgt 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Humanized Sh24C05 Kv1-17 Light Chain 
                   
               
               
                 (Humanized Kappa Chain Variable Region and Human Constant Region) 
               
               
                 (SEQ ID NO: 206) 
                   
               
             
          
           
               
                 1 
                 mdmrvpaqll gllllwlrga rcdiqmtqsp sslsasvgdr vtitcrasqe isgylswyqq 
                   
               
               
                 61 
                 kpgkapkrli yaastldsgv psrfsgsgsg teftltissl qpedfatyyc lqydsypytf 
               
               
                 121 
                 gqgtkleikr tvaapsvfif ppsdeqlksg tasvvcllnn fypreakvqw kvdnalqsgn 
               
               
                 181 
                 sqesvteqds kdstyslsst ltlskadyek hkvyacevth qglsspvtks fnrgec 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Humanized sh24C05 Kv1-33 Light 
                   
               
               
                 Chain (Humanized Kappa Chain Variable Region and Human Constant Region) 
               
               
                 (SEQ ID NO: 207) 
                   
               
             
          
           
               
                 1 
                 atggacatga gggtgcccgc tcaactgctg gggctgctgc tgctgtggct gagaggagct 
                   
               
               
                 61 
                 cgttgcgata ttcagatgac ccaatcacct agcagtctct cagcttccgt gggcgacaga 
               
               
                 121 
                 gttaccataa cctgtcgggc aagccaggag atttctgggt acctgtcctg gtaccaacag 
               
               
                 181 
                 aagcccggaa aggcccccaa gctgttgatc tatgctgcgt caaccttgga tagcggtgtc 
               
               
                 241 
                 ccgagtcgat tctccggttc tggctccgga acagacttta cttttacaat ttctagcctt 
               
               
                 301 
                 cagccagagg acatcgccac gtactattgc ctccagtacg acagctatcc ctatacattt 
               
               
                 361 
                 gggcagggca ctaaactgga gatcaaacgc acagttgctg cccccagcgt gttcattttc 
               
               
                 421 
                 ccacctagcg atgagcagct gaaaagcggt actgcctctg tcgtatgctt gctcaacaac 
               
               
                 481 
                 ttttacccac gtgaggctaa ggtgcagtgg aaagtggata atgcacttca atctggaaac 
               
               
                 541 
                 agtcaagagt ccgtgacaga acaggacagc aaagactcaa cttattcact ctcttccacc 
               
               
                 601 
                 ctgactctgt ccaaggcaga ctatgaaaaa cacaaggtat acgcctgcga ggttacacac 
               
               
                 661 
                 cagggtttgt ctagtcctgt caccaagtcc ttcaataggg gcgaatgt 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Humanized Sh24C05 Kv1-33 Light Chain 
                   
               
               
                 (Humanized Kappa Chain Variable Region and Human Constant Region) 
               
               
                 (SEQ ID NO: 208) 
                   
               
             
          
           
               
                 1 
                 mdmrvpaqll gllllwlrga rcdiqmtqsp sslsasvgdr vtitcrasqe isgylswyqq 
                   
               
               
                 61 
                 kpgkapklli yaastldsgv psrfsgsgsg tdftftissl qpediatyyc lqydsypytf 
               
               
                 121 
                 gqgtkleikr tvaapsvfif ppsdeqlksg tasvvcllnn fypreakvqw kvdnalqsgn 
               
               
                 181 
                 sqesvteqds kdstyslsst ltlskadyek hkvyacevth qglsspvtks fnrgec 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Humanzied Sh24C05 Kv1-39 Light 
                   
               
               
                 Chain (Humanized Kappa Chain Variable Region and Human Constant Region) 
               
               
                 (SEQ ID NO: 209) 
                   
               
             
          
           
               
                 1 
                 atggacatga gggtgcccgc tcaactgctg gggctgctgc tgctgtggct gagaggagct 
                   
               
               
                 61 
                 cgttgcgata ttcagatgac ccaatcacct agcagtctct cagcttccgt gggcgacaga 
               
               
                 121 
                 gttaccataa cctgtcgggc aagccaggag atttctgggt acctgtcctg gtatcaacag 
               
               
                 181 
                 aagcccggaa aagcccctaa gctgttgatc tatgctgcgt caaccttgga tagcggtgtc 
               
               
                 241 
                 ccgagtcgat tctccggttc tggctccgga actgacttca ctctgacaat ttctagcctt 
               
               
                 301 
                 cagccagaag atttcgccac gtactattgc ctccagtacg acagctatcc ctatacattt 
               
               
                 361 
                 gggcagggca ctaaactgga gatcaaacgc acagttgctg cccccagcgt gttcattttc 
               
               
                 421 
                 ccacctagcg atgagcagct gaaaagcggt actgcctctg tcgtatgctt gctcaacaac 
               
               
                 481 
                 ttttacccac gtgaggctaa ggtgcagtgg aaagtggata atgcacttca atctggaaac 
               
               
                 541 
                 agtcaagagt ccgtgacaga acaggacagc aaagactcaa cttattcact ctcttccacc 
               
               
                 601 
                 ctgactctgt ccaaggcaga ctatgaaaaa cacaaggtat acgcctgcga ggttacacac 
               
               
                 661 
                 cagggtttgt ctagtcctgt caccaagtcc ttcaataggg gcgaatgt 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Humanized Sh24C05 Kv1-39 Light Chain 
                   
               
               
                 (Humanized Kappa Chain Variable Region and Human Constant Region) 
               
               
                 (SEQ ID NO: 210) 
                   
               
             
          
           
               
                 1 
                 mdmrvpaqll gllllwlrga rcdiqmtqsp sslsasvgdr vtitcrasqe isgylswyqq 
                   
               
               
                 61 
                 kpgkapklli yaastldsgv psrfsgsgsg tdftltissl qpedfatyyc lqydsypytf 
               
               
                 121 
                 gqgtkleikr tvaapsvfif ppsdeqlksg tasvvcllnn fypreakvqw kvdnalqsgn 
               
               
                 181 
                 sqesvteqds kdstyslsst ltlskadyek hkvyacevth qglsspvtks fnrgec 
               
               
                   
               
             
          
           
               
                 Nucleic Acid Sequence Encoding the Full Length Humanized Hu24C05 KvA Light 
                   
               
               
                 Chain (Humanized Kappa Chain Variable Region and Human Constant Region) 
               
               
                 (SEQ ID NO: 211) 
                   
               
             
          
           
               
                 1 
                 atggacatga gggtgcccgc tcaactgctg gggctgctgc tgctgtggct gagaggagct 
                   
               
               
                 61 
                 cgttgcgata ttcagatgac ccaatcacct agcagtctct cagcttccgt gggcgacaga 
               
               
                 121 
                 gttaccataa cctgtcgggc aagccaggag atttctgggt acctgtcctg gctgcaacag 
               
               
                 181 
                 aagcccggag gcgccatcaa gaggttgatc tatgctgcgt caaccttgga tagcggtgtc 
               
               
                 241 
                 ccgagtcgat tctccggttc tggctccgga agtgactaca ctctgacaat ttctagcctt 
               
               
                 301 
                 cagccagaag atttcgccac gtactattgc ctccagtacg acagctatcc ctatacattt 
               
               
                 361 
                 gggcagggca ctaaactgga gatcaaacgc acagttgctg cccccagcgt gttcattttc 
               
               
                 421 
                 ccacctagcg atgagcagct gaaaagcggt actgcctctg tcgtatgctt gctcaacaac 
               
               
                 481 
                 ttttacccac gtgaggctaa ggtgcagtgg aaagtggata atgcacttca atctggaaac 
               
               
                 541 
                 agtcaagagt ccgtgacaga acaggacagc aaagactcaa cttattcact ctcttccacc 
               
               
                 601 
                 ctgactctgt ccaaggcaga ctatgaaaaa cacaaggtat acgcctgcga ggttacacac 
               
               
                 661 
                 cagggtttgt ctagtcctgt caccaagtcc ttcaataggg gcgaatgt 
               
               
                   
               
             
          
           
               
                 Protein Sequence Defining the Full Length Humanized Hu24C05 KvA Light Chain 
                   
               
               
                 (Humanized Kappa Chain Variable Region and Human Constant Region) 
               
               
                 (SEQ ID NO: 212) 
                   
               
             
          
           
               
                 1 
                 mdmrvpaqll gllllwlrga rcdiqmtqsp sslsasvgdr vtitcrasqe isgylswlqq 
                   
               
               
                 61 
                 kpggaikrli yaastldsgv psrfsgsgsg sdytltissl qpedfatyyc lqydsypytf 
               
               
                 121 
                 gqgtkleikr tvaapsvfif ppsdeqlksg tasvvcllnn fypreakvqw kvdnalqsgn 
               
               
                 181 
                 sqesvteqds kdstyslsst ltlskadyek hkvyacevth qglsspvtks fnrgec 
               
             
          
         
       
     
         [0186]    For convenience, Table 13 provides a concordance chart showing the SEQ ID NO. of each sequence discussed in this Example. 
         [0000]    
       
         
               
               
             
           
               
                 TABLE 13 
               
               
                   
               
               
                 SEQ ID 
                   
               
               
                 NO. 
                 Nucleic Acid or Protein 
               
               
                   
               
             
             
               
                 175 
                 Human IgG1 constant-nucleic acid 
               
               
                 176 
                 Human IgG1 constant-protein 
               
               
                 177 
                 Human IgG2 constant-nucleic acid 
               
               
                 178 
                 Human IgG2 constant-protein 
               
               
                 179 
                 Human Kappa constant-nucleic acid 
               
               
                 180 
                 Human Kappa constant-protein 
               
               
                 181 
                 Chimeric 24C05 Mouse Heavy Chain Variable + Human IgG1 
               
               
                   
                 constant-nucleic acid 
               
               
                 182 
                 Chimeric 24C05 Mouse Heavy Chain Variable + Human IgG1 
               
               
                   
                 constant-protein 
               
               
                 183 
                 Chimeric 24C05 Mouse Light Chain Variable + Human Kappa 
               
               
                   
                 constant-nucleic acid 
               
               
                 184 
                 Chimeric 24C05 Mouse Light Chain Variable + Human Kappa 
               
               
                   
                 constant-protein 
               
               
                 185 
                 Humanized Sh24C05 Hv3-7 Heavy Human Variable + Human 
               
               
                   
                 IgG1 constant-nucleic acid 
               
               
                 186 
                 Humanized Sh24C05 Hv3-7 Heavy Human Variable + Human 
               
               
                   
                 IgG1 constant-protein 
               
               
                 187 
                 Humanized Sh24C05 Hv3-11 Heavy Human Variable + Human 
               
               
                   
                 IgG1 constant-nucleic acid 
               
               
                 188 
                 Humanized Sh24C05 Hv3-11 Heavy Human Variable + Human 
               
               
                   
                 IgG1 constant-protein 
               
               
                 189 
                 Humanized Sh24C05 Hv3-11 N62S IgG1 Heavy Human 
               
               
                   
                 Variable + Human IgG1 constant-nucleic acid 
               
               
                 190 
                 Humanized Sh24C05 Hv3-11 N62S IgG1 Heavy Human 
               
               
                   
                 Variable + Human IgG1 constant-protein 
               
               
                 191 
                 Humanized Sh24C05 Hv3-11 N62S IgG2 Heavy Human 
               
               
                   
                 Variable + Human IgG2 constant-nucleic acid 
               
               
                 192 
                 Humanized Sh24C05 Hv3-11 N62S IgG2 Heavy Human 
               
               
                   
                 Variable + Human IgG2 constant-protein 
               
               
                 193 
                 Humanized Sh24C05 Hv3-21 Heavy Human Variable + Human 
               
               
                   
                 IgG1 constant-nucleic acid 
               
               
                 194 
                 Humanized Sh24C05 Hv3-21 Heavy Human Variable + Human 
               
               
                   
                 IgG1 constant-protein 
               
               
                 195 
                 Humanized Sh24C05 Hv3-23 Heavy Human Variable + Human 
               
               
                   
                 IgG1 constant-nucleic acid 
               
               
                 196 
                 Humanized Sh24C05 Hv3-23 Heavy Human Variable + Human 
               
               
                   
                 IgG1 constant-protein 
               
               
                 197 
                 Humanized Sh24C05 Hv3-30 Heavy Human Variable + Human 
               
               
                   
                 IgG1 constant-nucleic acid 
               
               
                 198 
                 Humanized Sh24C05 Hv3-30 Heavy Human Variable + Human 
               
               
                   
                 IgG1 constant-protein 
               
               
                 199 
                 Humanized Hu24C05 HvA Heavy Human Variable + Human 
               
               
                   
                 IgG1 constant-nucleic acid 
               
               
                 200 
                 Humanized Hu24C05 HvA Heavy Human Variable + Human 
               
               
                   
                 IgG1 constant-protein 
               
               
                 201 
                 Humanized Sh24C05 Kv1-9 Human Variable + Human Kappa 
               
               
                   
                 constant-nucleic acid 
               
               
                 202 
                 Humanized Sh24C05 Kv1-9 Human Variable + Human Kappa 
               
               
                   
                 constant-protein 
               
               
                 203 
                 Humanized Sh24C05 Kv1-16 Human Variable + Human Kappa 
               
               
                   
                 constant-nucleic acid 
               
               
                 204 
                 Humanized Sh24C05 Kv1-16 Human Variable + Human Kappa 
               
               
                   
                 constant-protein 
               
               
                 205 
                 Humanized Sh24C05 Kv1-17 Human Variable + Human Kappa 
               
               
                   
                 constant-nucleic acid 
               
               
                 206 
                 Humanized Sh24C05 Kv1-17 Human Variable + Human Kappa 
               
               
                   
                 constant-protein 
               
               
                 207 
                 Humanized Sh24C05 Kv1-33 Human Variable + Human Kappa 
               
               
                   
                 constant-nucleic acid 
               
               
                 208 
                 Humanized Sh24C05 Kv1-33 Human Variable + Human Kappa 
               
               
                   
                 constant-protein 
               
               
                 209 
                 Humanized Sh24C05 Kv1-39 Human Variable + Human Kappa 
               
               
                   
                 constant-nucleic acid 
               
               
                 210 
                 Humanized Sh24C05 Kv1-39 Human Variable + Human Kappa 
               
               
                   
                 constant-protein 
               
               
                 211 
                 Humanized Hu24C05 KvA Human Variable + Human Kappa 
               
               
                   
                 constant-nucleic acid 
               
               
                 212 
                 Humanized Hu24C05 KvA Human Variable + Human Kappa 
               
               
                   
                 constant-protein 
               
               
                   
               
             
          
         
       
     
         [0187]    Table 14 below shows antibodies containing chimeric immunoglobulin heavy and light chains and each of the possible combinations of the full-length humanized immunoglobulin heavy and light chains. 
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 14 
               
               
                   
               
               
                 Antibody 
                   
                   
               
               
                 Name 
                 Light Chain 
                 Heavy Chain 
               
               
                   
               
             
             
               
                 Sh24C05-1 
                 24C05 Chimeric Kappa 
                 GP203 24C05 Chimeric 
               
               
                   
                 (SEQ ID NO: 184) 
                 Heavy IgG1 
               
               
                   
                   
                 (SEQ ID NO: 182) 
               
               
                 Sh24C05-14 
                 Hu24C05 KvA Kappa 
                 Hu24C05 HvA IgG1 
               
               
                   
                 (SEQ ID NO: 212) 
                 (SEQ ID NO: 200) 
               
               
                 Sh24C05-15 
                 Hu24C05 KvA Kappa 
                 Sh24C05 Hv3-21 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 212) 
                 (SEQ ID NO: 194) 
               
               
                 Sh24C05-16 
                 Hu24C05 KvA Kappa 
                 Sh24C05 Hv3-23 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 212) 
                 (SEQ ID NO: 196) 
               
               
                 Sh24C05-17 
                 Hu24C05 KvA Kappa 
                 Sh24C05 Hv3-30 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 212) 
                 (SEQ ID NO: 198) 
               
               
                 Sh24C05-18 
                 Hu24C05 KvA Kappa 
                 Sh24C05 Hv3-7 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 212) 
                 (SEQ ID NO: 186) 
               
               
                 Sh24C05-19 
                 Hu24C05 KvA Kappa 
                 Sh24C05 Hv3-11 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 212) 
                 (SEQ ID NO: 188) 
               
               
                 Sh24C05-19 
                 Hu24C05 KvA Kappa 
                 Sh24C05 Hv3-11 N62S 
               
               
                 N62S IgG1 
                 (SEQ ID NO: 212) 
                 Heavy IgG1 
               
               
                   
                   
                 (SEQ ID NO: 190) 
               
               
                 Sh24C05-19 
                 Hu24C05 KvA Kappa 
                 Sh24C05 Hv3-11 N62S 
               
               
                 N62S IgG2 
                 (SEQ ID NO: 212) 
                 Heavy IgG2 
               
               
                   
                   
                 (SEQ ID NO: 192) 
               
               
                 Sh24C05-20 
                 Sh24C05 Kv1-16 Kappa 
                 Hu24C05 HvA IgG1 
               
               
                   
                 (SEQ ID NO: 204) 
                 (SEQ ID NO: 200) 
               
               
                 Sh24C05-21 
                 Sh24C05 Kv1-16 Kappa 
                 Sh24C05 Hv3-21 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 204) 
                 (SEQ ID NO: 194) 
               
               
                 Sh24C05-22 
                 Sh24C05 Kv1-16 Kappa 
                 Sh24C05 Hv3-23 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 204) 
                 (SEQ ID NO: 196) 
               
               
                 Sh24C05-23 
                 Sh24C05 Kv1-16 Kappa 
                 Sh24C05 Hv3-30 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 204) 
                 (SEQ ID NO: 198) 
               
               
                 Sh24C05-24 
                 Sh24C05 Kv1-16 Kappa 
                 Sh24C05 Hv3-7 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 204) 
                 (SEQ ID NO: 186) 
               
               
                 Sh24C05-25 
                 Sh24C05 Kv1-16 Kappa 
                 Sh24C05 Hv3-11 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 204) 
                 (SEQ ID NO: 188) 
               
               
                 Sh24C05-25 
                 Sh24C05 Kv1-16 Kappa 
                 Sh24C05 Hv3-11 N62S 
               
               
                 N62S IgG1 
                 (SEQ ID NO: 204) 
                 Heavy IgG1 
               
               
                   
                   
                 (SEQ ID NO: 190) 
               
               
                 Sh24C05-25 
                 Sh24C05 Kv1-16 Kappa 
                 Sh24C05 Hv3-11 N62S 
               
               
                 N62S IgG2 
                 (SEQ ID NO: 204) 
                 Heavy IgG2 
               
               
                   
                   
                 (SEQ ID NO: 192) 
               
               
                 Sh24C05-26 
                 Sh24C05 Kv1-17 Kappa 
                 Hu24C05 HvA IgG1 
               
               
                   
                 (SEQ ID NO: 206) 
                 (SEQ ID NO: 200) 
               
               
                 Sh24C05-27 
                 Sh24C05 Kv1-17 Kappa 
                 Sh24C05 Hv3-21 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 206) 
                 (SEQ ID NO: 194) 
               
               
                 Sh24C05-28 
                 Sh24C05 Kv1-17 Kappa 
                 Sh24C05 Hv3-23 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 206) 
                 (SEQ ID NO: 196) 
               
               
                 Sh24C05-29 
                 Sh24C05 Kv1-17 Kappa 
                 Sh24C05 Hv3-30 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 206) 
                 (SEQ ID NO: 198) 
               
               
                 Sh24C05-30 
                 Sh24C05 Kv1-17 Kappa 
                 Sh24C05 Hv3-7 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 206) 
                 (SEQ ID NO: 186) 
               
               
                 Sh24C05-31 
                 Sh24C05 Kv1-17 Kappa 
                 Sh24C05 Hv3-11 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 206) 
                 (SEQ ID NO: 188) 
               
               
                 Sh24C05-31 
                 Sh24C05 Kv1-17 Kappa 
                 Sh24C05 Hv3-11 N62S 
               
               
                 N62S IgG1 
                 (SEQ ID NO: 206) 
                 Heavy IgG1 
               
               
                   
                   
                 (SEQ ID NO: 190) 
               
               
                 Sh24C05-31 
                 Sh24C05 Kv1-17 Kappa 
                 Sh24C05 Hv3-11 N62S 
               
               
                 N62S IgG2 
                 (SEQ ID NO: 206) 
                 Heavy IgG2 
               
               
                   
                   
                 (SEQ ID NO: 192) 
               
               
                 Sh24C05-32 
                 Sh24C05 Kv1-33 Kappa 
                 Hu24C05 HvA IgG1 
               
               
                   
                 (SEQ ID NO: 208) 
                 (SEQ ID NO: 200) 
               
               
                 Sh24C05-33 
                 Sh24C05 Kv1-33 Kappa 
                 Sh24C05 Hv3-21 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 208) 
                 (SEQ ID NO: 194) 
               
               
                 Sh24C05-34 
                 Sh24C05 Kv1-33 Kappa 
                 Sh24C05 Hv3-23 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 208) 
                 (SEQ ID NO: 196) 
               
               
                 Sh24C05-35 
                 Sh24C05 Kv1-33 Kappa 
                 Sh24C05 Hv3-30 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 208) 
                 (SEQ ID NO: 198) 
               
               
                 Sh24C05-36 
                 Sh24C05 Kv1-33 Kappa 
                 Sh24C05 Hv3-7 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 208) 
                 (SEQ ID NO: 186) 
               
               
                 Sh24C05-37 
                 Sh24C05 Kv1-33 Kappa 
                 Sh24C05 Hv3-11 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 208) 
                 (SEQ ID NO: 188) 
               
               
                 Sh24C05-37 
                 Sh24C05 Kv1-33 Kappa 
                 Sh24C05 Hv3-11 N62S 
               
               
                 N62S IgG1 
                 (SEQ ID NO: 208) 
                 Heavy IgG1 
               
               
                   
                   
                 (SEQ ID NO: 190) 
               
               
                 Sh24C05-37 
                 Sh24C05 Kv1-33 Kappa 
                 Sh24C05 Hv3-11 N62S 
               
               
                 N62S IgG2 
                 (SEQ ID NO: 208) 
                 Heavy IgG2 
               
               
                   
                   
                 (SEQ ID NO: 192) 
               
               
                 Sh24C05-38 
                 Sh24C05 Kv1-9 Kappa 
                 Hu24C05 HvA IgG1 
               
               
                   
                 (SEQ ID NO: 202) 
                 (SEQ ID NO: 200) 
               
               
                 Sh24C05-39 
                 Sh24C05 Kv1-9 Kappa 
                 Sh24C05 Hv3-21 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 202) 
                 (SEQ ID NO: 194) 
               
               
                 Sh24C05-40 
                 Sh24C05 Kv1-9 Kappa 
                 Sh24C05 Hv3-23 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 202) 
                 (SEQ ID NO: 196) 
               
               
                 Sh24C05-41 
                 Sh24C05 Kv1-9 Kappa 
                 Sh24C05 Hv3-30 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 202) 
                 (SEQ ID NO: 198) 
               
               
                 Sh24C05-42 
                 Sh24C05 Kv1-9 Kappa 
                 Sh24C05 Hv3-7 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 202) 
                 (SEQ ID NO: 186) 
               
               
                 Sh24C05-43 
                 Sh24C05 Kv1-9 Kappa 
                 Sh24C05 Hv3-11 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 202) 
                 (SEQ ID NO: 188) 
               
               
                 Sh24C05-43 
                 Sh24C05 Kv1-9 Kappa 
                 Sh24C05 Hv3-11 N62S 
               
               
                 N62S IgG1 
                 (SEQ ID NO: 202) 
                 Heavy IgG1 
               
               
                   
                   
                 (SEQ ID NO: 190) 
               
               
                 Sh24C05-43 
                 Sh24C05 Kv1-9 Kappa 
                 Sh24C05 Hv3-11 N62S 
               
               
                 N62S IgG2 
                 (SEQ ID NO: 202) 
                 Heavy IgG2 
               
               
                   
                   
                 (SEQ ID NO: 192) 
               
               
                 Sh24C05-44 
                 Sh24C05 Kv1-39 Kappa 
                 Hu24C05 HvA IgG1 
               
               
                   
                 (SEQ ID NO: 210) 
                 (SEQ ID NO: 200) 
               
               
                 Sh24C05-45 
                 Sh24C05 Kv1-39 Kappa 
                 Sh24C05 Hv3-21 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 210) 
                 (SEQ ID NO: 194) 
               
               
                 Sh24C05-46 
                 Sh24C05 Kv1-39 Kappa 
                 Sh24C05 Hv3-23 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 210) 
                 (SEQ ID NO: 196) 
               
               
                 Sh24C05-47 
                 Sh24C05 Kv1-39 Kappa 
                 Sh24C05 Hv3-30 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 210) 
                 (SEQ ID NO: 198) 
               
               
                 Sh24C05-48 
                 Sh24C05 Kv1-39 Kappa 
                 Sh24C05 Hv3-7 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 210) 
                 (SEQ ID NO: 186) 
               
               
                 Sh24C05-49 
                 Sh24C05 Kv1-39 Kappa 
                 Sh24C05 Hv3-11 Heavy IgG1 
               
               
                   
                 (SEQ ID NO: 210) 
                 (SEQ ID NO: 188) 
               
               
                 Sh24C05-49 
                 Sh24C05 Kv1-39 Kappa 
                 Sh24C05 Hv3-11 N62S 
               
               
                 N62S IgG1 
                 (SEQ ID NO: 210) 
                 Heavy IgG1 
               
               
                   
                   
                 (SEQ ID NO: 190) 
               
               
                 Sh24C05-49 
                 Sh24C05 Kv1-39 Kappa 
                 Sh24C05 Hv3-11 N62S 
               
               
                 N62S IgG2 
                 (SEQ ID NO: 210) 
                 Heavy IgG2 
               
               
                   
                   
                 (SEQ ID NO: 192) 
               
               
                   
               
             
          
         
       
     
         [0188]    The antibody construct containing the full length chimeric heavy and light chains is designated below:
       Chimeric 24C05=Full Length Chimeric 24C05 Heavy Chain (Mouse Variable Region and Human IgG1 Constant Region) (SEQ ID NO: 182) plus Full Length Chimeric 24C05 Light Chain (Mouse Variable Region and Human Kappa Constant Region) (SEQ ID NO: 184)       
 
         [0190]    Four of the possible antibody constructs containing the full length immunoglobulin heavy and light chains containing humanized variable regions are designated below:
       Sh24C05-25 N62S IgG1=Humanized Sh24C05 Hv3-11 N62S Heavy Chain Variable Region and Human IgG1 Constant Region (SEQ ID NO: 190) plus Sh24C05 Kv1-16 Light Chain Variable Region and Human Kappa Constant Region (SEQ ID NO: 204)   Sh24C05-25 N62S IgG2=Humanized Sh24C05 Hv3-11 N62S Heavy Chain Variable Region and Human IgG2 Constant Region (SEQ ID NO: 192) plus Sh24C05 Kv1-16 Light Chain Variable Region and Human Kappa Constant Region (SEQ ID NO: 204)   Sh24C05-31 N62S IgG1=Humanized Sh24C05 Hv3-11 N62S Heavy Chain Variable Region and Human IgG1 Constant Region (SEQ ID NO: 190) plus Sh24C05 Kv1-17 Light Chain Variable Region and Human Kappa Constant Region (SEQ ID NO: 206)   Sh24C05-31 N62S IgG2=Humanized Sh24C05 Hv3-11 N62S Heavy Chain Variable Region and Human IgG2 Constant Region (SEQ ID NO: 192) plus Sh24C05 Kv1-17 Light Chain Variable Region and Human Kappa Constant Region (SEQ ID NO: 206)       
 
         [0195]    B. Binding Affinities of Humanized and Chimeric Anti-ErbB3 Monoclonal Antibodies 
         [0196]    The binding affinities and kinetics of interaction of monoclonal antibodies produced in Example 12 against recombinant human ErbB3 monomeric protein (cleaved rhErbB3) were measured by surface plasmon resonance using a Biacore® T100 (Biacore) instrument. Monomeric ErbB3 was obtained by protease cleavage of rhErbB3-Fc (R&amp;D Systems, Cat. No. 348-RB). 
         [0197]    Goat anti-human IgG Fc (Jackson ImmunoResearch, Catalog No. 109-005-098) was immobilized on carboxymethylated dextran CM4 sensor chips (Biacore, Catalog No. BR-1005-34) by amine coupling (Biacore, Catalog No. BR-1000-50) using a standard coupling protocol according to the vendor&#39;s instructions. The analyses were performed at 37° C. using PBS (Invitrogen, Catalog No. 14040-133) containing 0.05% surfactant P20 (Biacore, Catalog No. BR-1000-54) as running buffer. 
         [0198]    The antibodies were captured in individual flow cells at a flow rate of 60 μl/minute. Injection time was varied for each antibody to yield an R max  between 30 and 60 RU. Buffer or cleaved rhErbB3 diluted in running buffer was injected sequentially over a reference surface (no antibody captured) and the active surface (antibody to be tested) for 300 seconds at 60 μl/minute. The dissociation phase was monitored for up to 1200 seconds. The surface was then regenerated with two 60 second injections of Glycine pH 2.25 (made from Glycine pH 2.0 (Biacore, Catalog No. BR-1003-55) and pH 2.5 (Biacore, Catalog No. BR-1003-56)) at 60 μl/minute. For the initial screening, only one or two concentrations of cleaved rhErbB3 were tested, typically 5.0 and 1.25 nM (results are summarized in Table 15). 
         [0199]    Kinetic parameters were determined using the kinetic function of the BIAevaluation software (Biacore) with double reference subtraction. Kinetic parameters for each antibody, k a  (association rate constant), k d  (dissociation rate constant) and K D  (equilibrium dissociation constant) were determined. The initial monoclonal antibodies were screened using cell culture media supernatant containing secreted antibody, and kinetic values of the monoclonal antibodies on cleaved rhErbB3 at 37° C. are summarized in Table 15. 
         [0000]    
       
         
               
               
               
               
               
               
             
           
               
                   
                 TABLE 15 
               
               
                   
                   
               
               
                   
                 Antibody 
                 k a  (1/Ms) 
                 k d  (1/s) 
                 K D  (M) 
                 n 
               
               
                   
                   
               
             
             
               
                   
                 Sh24C05-1 
                 2.52E+06 
                 4.48E−04 
                 1.78E−10 
                 3 
               
               
                   
                 Sh24C05-14 
                 2.88E+06 
                 4.98E−04 
                 1.73E−10 
                 2 
               
               
                   
                 Sh24C05-15 
                 2.67E+06 
                 4.99E−04 
                 1.87E−10 
                 2 
               
               
                   
                 Sh24C05-16 
                 2.75E+06 
                 4.04E−04 
                 1.47E−10 
                 2 
               
               
                   
                 Sh24C05-17 
                 2.79E+06 
                 4.17E−04 
                 1.50E−10 
                 2 
               
               
                   
                 Sh24C05-18 
                 2.88E+06 
                 4.63E−04 
                 1.61E−10 
                 2 
               
               
                   
                 Sh24C05-19 
                 3.00E+06 
                 2.55E−04 
                 8.55E−11 
                 2 
               
               
                   
                 Sh24C05-20 
                 2.67E+06 
                 5.91E−04 
                 2.21E−10 
                 2 
               
               
                   
                 Sh24C05-21 
                 3.11E+06 
                 6.62E−04 
                 2.20E−10 
                 2 
               
               
                   
                 Sh24C05-22 
                 2.79E+06 
                 6.01E−04 
                 2.16E−10 
                 2 
               
               
                   
                 Sh24C05-23 
                 2.79E+06 
                 7.21E−04 
                 2.63E−10 
                 2 
               
               
                   
                 Sh24C05-24 
                 2.90E+06 
                 6.28E−04 
                 2.18E−10 
                 2 
               
               
                   
                 Sh24C05-25 
                 2.63E+06 
                 4.59E−04 
                 1.75E−10 
                 2 
               
               
                   
                 Sh24C05-26 
                 3.36E+06 
                 7.39E−04 
                 2.20E−10 
                 2 
               
               
                   
                 Sh24C05-27 
                 3.34E+06 
                 7.98E−04 
                 2.40E−10 
                 2 
               
               
                   
                 Sh24C05-28 
                 3.26E+06 
                 6.14E−04 
                 1.89E−10 
                 2 
               
               
                   
                 Sh24C05-29 
                 3.25E+06 
                 5.88E−04 
                 1.82E−10 
                 2 
               
               
                   
                 Sh24C05-30 
                 4.48E+06 
                 7.87E−04 
                 1.90E−10 
                 2 
               
               
                   
                 Sh24C05-31 
                 3.47E+06 
                 2.92E−04 
                 8.65E−11 
                 2 
               
               
                   
                 Sh24C05-32 
                 9.98E+06 
                 6.02E−03 
                 6.03E−10 
                 1 
               
               
                   
                 Sh24C05-33 
                 4.02E+06 
                 4.33E−03 
                 1.08E−09 
                 1 
               
               
                   
                 Sh24C05-34 
                 1.09E+07 
                 6.00E−03 
                 5.52E−10 
                 1 
               
               
                   
                 Sh24C05-35 
                 8.44E+06 
                 5.53E−03 
                 6.55E−10 
                 1 
               
               
                   
                 Sh24C05-36 
                 5.18E+06 
                 4.34E−03 
                 8.37E−10 
                 1 
               
               
                   
                 Sh24C05-37 
                 5.94E+06 
                 2.00E−03 
                 3.74E−10 
                 2 
               
               
                   
                 Sh24C05-38 
                 2.71E+07 
                 1.54E−02 
                 5.67E−10 
                 1 
               
               
                   
                 Sh24C05-39 
                 1.18E+07 
                 9.67E−03 
                 8.19E−10 
                 1 
               
               
                   
                 Sh24C05-40 
                 2.11E+07 
                 1.06E−02 
                 5.03E−10 
                 1 
               
               
                   
                 Sh24C05-41 
                 1.81E+07 
                 1.21E−02 
                 6.69E−10 
                 1 
               
               
                   
                 Sh24C05-42 
                 7.35E+06 
                 6.82E−03 
                 9.27E−10 
                 1 
               
               
                   
                 Sh24C05-43 
                 6.16E+06 
                 3.58E−03 
                 5.82E−10 
                 1 
               
               
                   
                 Sh24C05-44 
                 7.96E+06 
                 5.12E−03 
                 6.44E−10 
                 1 
               
               
                   
                 Sh24C05-45 
                 8.57E+06 
                 6.06E−03 
                 7.07E−10 
                 1 
               
               
                   
                 Sh24C05-46 
                 7.99E+06 
                 4.40E−03 
                 5.51E−10 
                 1 
               
               
                   
                 Sh24C05-47 
                 7.98E+06 
                 4.41E−03 
                 5.53E−10 
                 1 
               
               
                   
                 Sh24C05-48 
                 8.72E+06 
                 4.90E−03 
                 5.62E−10 
                 1 
               
               
                   
                 Sh24C05-49 
                 4.08E+06 
                 1.70E−03 
                 4.16E−10 
                 2 
               
               
                   
                   
               
             
          
         
       
     
         [0200]    The results in Table 15 demonstrate that the chimeric and each of the humanized 24C05 antibodies have fast association rates (k a ), very slow disassociation rates (k d ) and very high affinities (K D ). In particular, the antibodies have affinities ranging from about 87 pM to about 1 nM. 
         [0201]    The binding affinities and kinetics of certain purified monoclonal antibodies were also determined. To further characterize certain antibodies, the surface plasmon resonance experiments described above were conducted using concentrations of cleaved rhErbB3 between 0.3125 nM and 5.0 nM (a 2-fold serial dilution). 
         [0202]    The kinetic values of certain purified monoclonal antibodies (i.e., Sh24C05-1, Sh24C05-25, Sh24C05-25 N62S IgG1, Sh24C05-25 N62S IgG2, Sh24C05-31, Sh24C05-31 N62S IgG1, and Sh24C05-31 N62S IgG2) on cleaved rhErbB3 at 37° C. are summarized in Table 16. 
         [0000]    
       
         
               
               
               
               
               
             
           
               
                 TABLE 16 
               
               
                   
               
               
                 Antibody 
                 k a  (1/Ms) 
                 k d  (1/s) 
                 K D  (M) 
                 n 
               
               
                   
               
             
             
               
                 Sh24C05-1 
                 3.5E+06 
                 4.4E−04 
                 1.4E−10 
                 3 
               
               
                 Sh24C05-25 
                 4.0E+06 
                 5.0E−04 
                 1.3E−10 
                 4 
               
               
                 Sh24C05-25 N62S IgG1 
                 2.9E+06 
                 4.5E−04 
                 1.6E−10 
                 4 
               
               
                 Sh24C05-25 N62S IgG2 
                 2.7E+06 
                 3.4E−04 
                 1.2E−10 
                 4 
               
               
                 Sh24C05-31 
                 4.7E+06 
                 2.8E−04 
                 6.3E−11 
                 3 
               
               
                 Sh24C05-31 N62S IgG1 
                 3.5E+06 
                 2.7E−04 
                 7.6E−11 
                 6 
               
               
                 Sh24C05-31 N62S IgG2 
                 3.2E+06 
                 2.4E−04 
                 7.4E−11 
                 3 
               
               
                   
               
             
          
         
       
     
         [0203]    The results in Table 16 demonstrate the purified antibodies have a have affinities ranging from about 63 pM to about 160 pM when tested at 37° C. 
         [0204]    C. Comparison of Other Anti-ErbB3 Antibodies 
         [0205]    Three human antibodies that inhibit the function of human ErbB3 were constructed and expressed using published information. One antibody, referred to as Ab #6, was constructed as a human IgG2/Lambda antibody based the disclosure of Schoeberl et al., US 2009/0291085 (Merrimack Pharmaceuticals, Inc.). Two additional antibodies, referred to as U1-53 and U1-59, were constructed as human IgG1/Kappa antibodies based on the disclosure of Rothe et al., US 2008/0124345 (U3 Pharma AG and Amgen, Inc.). 
         [0206]    Kinetic parameters for the Ab#6, U1-53, and U1-59 antibodies were determined by Biacore at 37° C. using cleaved rhErbB3 (monomer) as described above (See Section B. Binding Affinities of Humanized and Chimeric Anti-ErbB3 Monoclonal Antibodies). Both Biacore sensorgrams ( FIG. 17 ) and kinetic values (Table 17) are displayed for each antibody. 
         [0000]    
       
         
               
               
               
               
               
             
           
               
                 TABLE 17 
               
               
                   
               
               
                 Antibody 
                 k a  (1/Ms) 
                 k d  (1/s) 
                 K D  (M) 
                 n 
               
               
                   
               
             
             
               
                 Sh24C05-31 N62S IgG1 
                  3.5+06 
                 2.7E−04 
                 7.6E−11 
                 6 
               
               
                 Ab#6 
                 9.3E+05 
                 1.9E−04 
                 2.3E−10 
                 3 
               
               
                 U1-59 
                 1.8E+06 
                 9.4E−04 
                 5.3E−10 
                 3 
               
               
                 U1-53 
                 — 
                 — 
                 — 
                 — 
               
               
                   
               
             
          
         
       
     
         [0207]    The results in Table 17 demonstrate that the overall equilibrium dissociation constant (K D ) for the Sh24C05-31 N62S IgG1 (76 pM) was smaller (i.e., higher affinity) than the K D  for the Ab#6 and U1-59 antibodies (230 pM (p&lt;0.01) and 530 pM (p&lt;0.0005), respectively). The equilibrium dissociation constant (K D ) for U1-53 could not determined because of poor curve fits (see  FIG. 17 , which shows a fast K off  rate of U1-53). The K D  of Ab #6, U1-53, and U1-59 antibodies can also be compared with other humanized 24C05 variants by comparing Tables 16 and 17. 
         [0208]    Therefore, the affinity for Sh24C05-31 N62S IgG1 is significantly higher than the affinity of Ab#6 and U1-59 as disclosed herein. 
       Example 13 
     Neutralization Activity of the Humanized Anti-ErbB3 Antibodies 
       [0209]    In this example, the humanized antibodies produced in Example 12 were tested for their ability to inhibit rhErbB3 binding to NRG1-β1 by ECL assay. Multi-array 96-well standard binding plates (Meso Scale Discovery, Cat. No. L15XA-3) were coated with 50 μl of 0.5 μg/mL rhErbB3/Fc (R&amp;D systems, Cat. No. 348-RB) in PBS (Invitrogen, Cat. No. 14040-133) for one hour at room temperature with no agitation. The plates then were washed three times with PBS+0.1% Tween20 (Sigma P5927) and blocked with 200 μl of 100% Horse Serum, heat inactivated (GIBCO, Cat. No. 26050-088) for 1.5 hours at room temperature. After washing the plates three times with PBS+0.1% Tween, 25 μl of the antibody dilutions were added to the plates for another hour at room temperature with agitation. Ligand NRG1-β1 (R&amp;D Systems, Cat. No. 377-HB, 26 kDa) was added to the wells at a final concentration of 0.25 μg/ml. The plates were washed three times with PBS+0.1% Tween and incubated with 25 μl of 1 μg/mL biotinylated antibody against human NRG1-β1 (R&amp;D systems, Cat. No BAF377) preincubated for one hour with SULTO-TAG Streptavidin (Meso Scale Discovery, Cat. No R32AD-5) for one hour at room temperature with agitation. The plates then were washed three times with PBS+0.1% Tween, and 150 μl of 1× read buffer (Meso Scale Discovery, Cat. No. R92TC-1) was added to each well before the plates were analyzed on a Sector® Imager 2400 (Meso Scale Discovery) instrument. 
         [0210]    The interaction of NRG1-β1 with rhErbB3 was inhibited by antibodies Sh24C05-25 N62S-IgG1, Sh24C05-25 N62S-IgG2, Sh24C05-31 N62S-IgG1, and Sh24C05-31 N62S-IgG2 ( FIG. 18A ). The Ab#6 IgG2 antibody as described in Schoeberl et al. (supra) and the U1-53 and U1-59 antibodies as described in Rothe et al. (supra) were also tested for their ability to inhibit ErbB3 binding to NRG1-β1. As shown in  FIG. 18B , each of the Ab#6 IgG2, U1-53, and U1-59 antibodies inhibited ErbB3 binding to NRG1-β1. 
         [0211]    The IC 50  values for neutralization of NRG1-β1 binding to hErbB3 for the humanized 24C05 antibodies (i.e., Sh24C05-25 N62S-IgG1, Sh24C05-25 N62S-IgG2, Sh24C05-31 N62S-IgG1, and Sh24C05-31 N62S-IgG2) were calculated and are summarized in Table 18. The IC 50  values for the NRG1-β1 neutralization activity of the anti-ErbB3 human antibodies Ab#6 IgG2, U1-53 and U1-59 are also shown in Table 18. 
         [0000]    
       
         
               
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE 18 
               
             
             
               
                   
                   
               
               
                   
                 IC 50  (nM) 
                   
               
             
          
           
               
                 Antibody 
                 Average 
                 Standard Deviation 
                 n 
               
               
                   
               
               
                 Sh24C05-25 N62S-IgG1 
                 0.1219 
                 0.0173 
                 4 
               
               
                 Sh24C05-25 N62S-IgG2 
                 0.1117 
                 0.0154 
                 4 
               
               
                 Sh24C05-31 N62S-IgG1 
                 0.1242 
                 0.0391 
                 5 
               
               
                 Sh24C05-31 N62S-IgG2 
                 0.0860 
                 0.0588 
                 4 
               
               
                 U1-53 
                 0.1128 
                 0.0615 
                 3 
               
               
                 U1-59 
                 0.3181 
                 0.0274 
                 3 
               
               
                 Ab#6 IgG2 
                 1.5161 
                 0.5883 
                 5 
               
               
                   
               
             
          
         
       
     
         [0212]    The results in Table 18 demonstrate that antibodies Sh24C05-25 N62S-IgG1, Sh24C05-25 N62S-IgG2, Sh24C05-31 N62S-IgG1, and Sh24C05-31 N62S-IgG2 efficiently neutralized NRG1-β1 binding to rhErbB3. While the anti-ErbB3 human antibodies Ab#6 IgG2, U1-53 and U1-59 also showed neutralization activity, the humanized Sh24C05 antibodies (i.e., Sh24C05-25 N62S-IgG1, Sh24C05-25 N62S-IgG2, Sh24C05-31 N62S-IgG1, and Sh24C05-31 N62S-IgG2) had superior neutralization capacity than U1-59 or Ab#6 IgG2. 
       Example 14 
     Anti-Proliferative Activity 
       [0213]    In this example, the humanized antibodies produced in Example 12 were tested for their ability to inhibit NRG1-β1 dependent proliferation of cells in the BaF/3 cell system engineered to express both human Her2 and ErbB3. 
         [0214]    BaF/3 cells expressing Her2 and ErbB3 receptors as described in Example 6 were treated with anti-ErbB3 antibodies in the absence of WEHI conditioned media but in the presence of NRG1-β1 (100 ng/ml). Assays were conducted in a 96-well plate (5,000 cells/well) in the presence of NRG1-β1 (100 ng/ml) and various concentrations of antibodies (0.018-5000 ng/ml in 100 μl of final volume). MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays were conducted 3-4 days post NRG1-β1 stimulation. 
         [0215]    The results demonstrate that Sh24C05-25 N62S-IgG1, Sh24C05-25 N62S-IgG2, Sh24C05-31 N62S-IgG1, and Sh24C05-31 N62S-IgG2 inhibited NRG induced Her2/ErbB3-BaF/3 cell proliferation in a dose dependent manner ( FIG. 19A ). 
         [0216]    The IC 50  values for the inhibition of NRG1-β1 dependent Her2/ErbB3-BaF/3 cell line proliferation with the humanized 24C05 antibodies (i.e., Sh24C05-25 N62S-IgG1, Sh24C05-25 N62S-IgG2, Sh24C05-31 N62S-IgG1, Sh24C05-31 N62S-IgG2) were calculated and are summarized in Table 19. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 19 
               
             
             
               
                   
               
               
                 Her2/ErbB3-BaF/3, NRG1-β1 Dependent Proliferation 
               
             
          
           
               
                   
                 IC 50  (nM)- 
                   
                   
               
               
                 Antibody 
                 Average 
                 Standard deviation 
                 n 
               
               
                   
               
               
                 Sh24C05-25 N62S-IgG1 
                 0.0981 
                 0.0187 
                 2 
               
               
                 Sh24C05-25 N62S-IgG2 
                 0.2482 
                 0.0124 
                 2 
               
               
                 Sh24C05-31 N62S-IgG1 
                 0.1245 
                 0.0181 
                 5 
               
               
                 Sh24C05-31 N62S-IgG2 
                 0.2392 
                 0.0217 
                 2 
               
               
                 U1-53 
                 0.8128 
                 0.0268 
                 3 
               
               
                 U1-59 
                 0.8364 
                 0.0434 
                 5 
               
               
                 Ab#6 IgG2 
                 6.3015 
                 0.8577 
                 2 
               
               
                   
               
             
          
         
       
     
         [0217]    The results in Table 19 demonstrate that antibodies Sh24C05-25 N62S-IgG1, Sh24C05-25 N62S-IgG2, Sh24C05-31 N62S-IgG1, and Sh24C05-31 N62S-IgG2 strongly inhibited NRG1-β1-induced proliferation of BaF/3 cells expressing Her2/ErbB3. 
         [0218]    The inhibitory activity of anti-ErbB3 Ab#6 IgG2, U1-53 and U1-59 antibodies were also tested in the NRG1-β1 dependent Her2/ErbB3-BaF/3 cells proliferation assay. As shown in  FIG. 19B , the results demonstrate that the Ab#6 IgG2, U1-53 and U1-59 antibodies inhibited NRG induced Her2/ErbB3-BaF/3 cell proliferation in a dose dependent manner. Inhibition data of NRG1-β1 dependent Her2/ErbB3-BaF/3 cell proliferation with antibodies Ab#6 IgG2, U1-53 and U1-59 are summarized in Table 19. The results in Table 19 demonstrate that antibodies Ab#6 IgG2, U1-53, and U1-59 inhibited NRG1-β1-induced proliferation of Her2/ErbB3-BaF/3 cells. A comparison of the inhibitory activity of the tested anti-ErbB3 antibodies in the NRG1-β1 dependent Her2/ErbB3-BaF/3 cells proliferation assay indicates that the inhibitory activity of the humanized Sh24C05 antibodies is superior to the inhibitory activity of the Ab#6 IgG2, U1-53 and U1-59 antibodies (e.g., the IC 50  was 0.1245 nM for Sh24C05-31 N62S-IgG1 compared to 0.8128 nM for U1-53). 
       Example 15 
     Inhibition of Downstream Signaling in SKBR-3 Cells 
       [0219]    This example describes a characterization of the humanized antibodies produced in Example 12 for their ability to degrade total ErbB3 and inhibit phosphorylation of ErbB3 in exponentially growing SKBR-3 cells. 
         [0220]    The breast cancer SKBR-3 cells were maintained as recommended by ATCC. Cells maintained in full serum condition were treated for 1, 2, 4 or 6 hours with 40 μg/ml of anti-ErbB3 antibody (i.e., Sh24C05-25 N62S-IgG1, Sh24C05-25 N62S-IgG2, Sh24C05-31 N62S-IgG1, and Sh24C05-31 N62S-IgG2). Lysates were either analyzed by ELISA with the Total-ErbB3 and the Phospho-ErbB3 kit from R&amp;D Systems (Cat. No DYC234 and Cat. No DYC1769, respectively). 
         [0221]    The results demonstrate that anti-ErbB3 antibodies Sh24C05-25 N62S-IgG1, Sh24C05-25 N62S-IgG2, Sh24C05-31 N62S-IgG1, and Sh24C05-31 N62S-IgG2 inhibit at least 50% of the phosphorylation of ErbB3 in exponentially growing SKBR-3 cells ( FIG. 20 ). 
         [0222]    The results also demonstrate that anti-ErbB3 antibodies Sh24C05-25 N62S-IgG1, Sh24C05-25 N62S-IgG2, Sh24C05-31 N62S-IgG1, and Sh24C05-31 N62S-IgG2 degraded at least 50% of the total ErbB3 receptor present in exponentially growing SKBR-3 cells ( FIG. 21 ). 
       Example 16 
     Inhibition of B×PC3 Tumor Xenograft Growth 
       [0223]    The ability of the humanized monoclonal antibodies produced in Example 12 to inhibit tumor growth were tested in a B×PC3 pancreatic xenograft model. Human pancreatic B×PC3 cells were grown in culture in 37° C. in an atmosphere containing 5% CO2, using RMPI medium containing 10% fetal bovine serum. B×PC3 cells were inoculated subcutaneously into the flank of 8-week old female CB.17 SCID mice (Taconic Labs) with 10×10 6  cells per mouse in 50% matrigel (BD Biosciences, Cat No. 356237). Tumor measurements were taken twice weekly using vernier calipers. Tumor volume was calculated using the formula: width×width×length/2. When tumors reached approximately 200 mm 3 , the mice were randomized into 8 groups of 10 mice each. One group received PBS, another received huIgG control, and another received muIgG control. Each of the remaining five groups received one of the antibodies (i.e., murine 24C05, Sh24C05-25 N62S-IgG1, Sh24C05-25 N62S-IgG2, Sh24C05-31 N62S-IgG1 or Sh24C05-31 N62S-IgG2). All of the antibodies were dosed at 2 mg/kg body weight, twice per week, by intra-peritoneal injection for 7 weeks. Tumor volumes and mouse body weights were recorded twice per week. Tumor growth inhibition was analyzed using ANOVA and is expressed as percent inhibition compared to the PBS control. 
         [0224]    The tested humanized antibodies were active in vivo. All four humanized anti-ErbB3 antibodies had similar efficacy in the B×PC3 model when dosed at 2 mg/kg, ranging from 75-80% tumor growth inhibition (p&lt;0.001) (i.e., Sh24C05-25 N62S-IgG1, 75%; Sh24C05-25 N62S-IgG2, 76%; Sh24C05-31 N62S-IgG1, 79%; and Sh24C05-31 N62S-IgG2, 80%) at day 28 of the study ( FIG. 22 ). The murine antibody demonstrated 65% tumor growth inhibition in this study (p&lt;0.05). These results suggest similar potency and activity of the four humanized antibodies in this model. 
         [0225]    The ability of the humanized monoclonal antibodies U1-53, U1-59, and Ab#6 IgG2 to inhibit tumor growth were also tested in a B×PC3 xenograft model. Using the protocol described above, B×PC3 tumors were generated in CB.17 SCID mice. When tumors reached approximately 200 mm 3 , the mice were randomized into 11 groups of 10 mice each. One group received PBS and another received huIgG control. Each of the other nine groups received one of the humanized antibodies (i.e., Sh24C05-31 N62S-IgG1, U1-53, U1-59, or Ab#6 IgG2). The antibodies were dosed either at 0.5 mg/kg, 1 mg/kg, or 5 mg/kg body weight, twice per week, by intra-peritoneal injection for 7 weeks. Tumor volumes and mouse body weights were recorded twice per week. Tumor growth inhibition was analyzed using ANOVA and is expressed as percent inhibition compared to the PBS control. 
         [0226]    Tumor growth inhibition data determined at day 29 following treatment with one of the humanized antibodies (i.e., Sh24C05-31 N62S-IgG1, U1-59, or Ab#6 IgG2) is shown in Table 20. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
                 TABLE 20 
               
             
             
               
                   
                   
               
               
                   
                 Tumor 
                 ANOVA 
                 ANOVA 
               
               
                   
                 Growth 
                 Analysis 
                 Analysis 
               
             
          
           
               
                   
                 Treatment 
                 Inhibition 
                 (Compared 
                 (Compared 
               
             
          
           
               
                 Gr. 
                 Agent 
                 mg/kg 
                 (%) 
                 to PBS) 
                 to hIgG) 
               
               
                   
               
             
          
           
               
                 1 
                 PBS 
                 — 
                 NA 
                 NA 
                 NA 
               
               
                 2 
                 hIgG 
                 5 
                 29.2 
                 NS 
                 NS 
               
               
                 3 
                 Sh24C05-31 
                 0.5 
                 63.3 
                 P &lt; 0.001 
                 P &lt; 0.01  
               
               
                   
                 N62S-IgG1 
               
               
                 4 
                 Sh24C05-31 
                 1 
                 75.0 
                 P &lt; 0.001 
                 P &lt; 0.001 
               
               
                   
                 N62S-IgG1 
               
               
                 5 
                 Sh24C05-31 
                 5 
                 76.5 
                 P &lt; 0.001 
                 P &lt; 0.001 
               
               
                   
                 N62S-IgG1 
               
               
                 6 
                 Ab#6 IgG2 
                 0.5 
                 31.5 
                 P &lt; 0.05  
                 NS 
               
               
                 7 
                 Ab#6 IgG2 
                 1 
                 2.1 
                 NS 
                 NS 
               
               
                 8 
                 Ab#6 IgG2 
                 5 
                 40.6 
                 P &lt; 0.001 
                 NS 
               
               
                 9 
                 U1-59 
                 0.5 
                 32.6 
                 P &lt; 0.01  
                 NS 
               
               
                 10 
                 U1-59 
                 1 
                 52.9 
                 P &lt; 0.001 
                 NS 
               
               
                 11 
                 U1-59 
                 5 
                 60.3 
                 P &lt; 0.001 
                 P &lt; 0.05  
               
               
                   
               
             
          
         
       
     
         [0227]    The results demonstrate that Sh24C05-31 N62S-IgG1 showed the greatest tumor growth inhibition by day 29 (76.5%, p&lt;0.001) at a dose of 5 mg/kg in the B×PC3 pancreatic xenograft model. The U1-59 and Ab#6 IgG2 antibodies demonstrated approximately 60% and 41% tumor growth inhibition at a dose of 5 mg/kg in the B×PC3 model, respectively (P&lt;0.001). 
         [0228]    The results also demonstrate that Sh24C05-31 N62S-IgG1 showed the greatest tumor growth inhibition by day 29 at a dose of 0.5 mg/kg (63.3%, p&lt;0.001) and at a dose of 1 mg/kg (75.0%, p&lt;0.001) in the B×PC3 pancreatic xenograft model. The U1-59 and AB#6 IgG2 antibodies demonstrate approximately 33% (p&lt;0.01) and 31% (p&lt;0.05) tumor growth inhibition at a dose of 0.5 mg/kg in the B×PC3 model, respectively. The U1-59 and AB#6 IgG2 antibodies demonstrated approximately 53% (p&lt;0.001) and 2% (not significant) tumor growth inhibition at a dose of 1.0 mg/kg in the B×PC3 model, respectively. 
       Example 17 
     Inhibition of Calu-3 Tumor Xenograft Growth 
       [0229]    The ability of the humanized monoclonal antibodies produced in Example 12 to inhibit tumor growth was tested in a Calu-3 non-small cell lung cancer xenograft model. The ability of the humanized monoclonal antibodies U1-59 and Ab#6 IgG2, as described in Example 12, to inhibit tumor growth were also tested in the same model. 
         [0230]    Human Non-Small Cell Lung Cancer Calu-3 cells were grown in culture in 37° C. in an atmosphere containing 5% CO2, using EMEM medium containing 10% fetal bovine serum. Calu-3 cells were inoculated subcutaneously into the flank of 8-week old female NCR nude mice (Taconic Labs) with 10×10 6  cells per mouse in 50% matrigel (BD Biosciences, Cat No. 356237). Tumor measurements were taken twice weekly using vernier calipers. Tumor volume was calculated using the formula: width×width×length/2. 
         [0231]    When tumors reached approximately 200 mm 3 , the mice were randomized into 11 groups of 10 mice each. One group received PBS and another received muIgG control. Each of the other nine groups received one of the humanized antibodies (i.e., Sh24C05-31 N62S-IgG1, U1-59, or Ab#6 IgG2) at a dose of either 5 mg/kg, 10 mg/kg or 20 mg/kg body weight, twice per week, by intra-peritoneal injection for 4 weeks. Tumor volumes and mouse body weights were recorded twice per week. Tumor growth inhibition was analyzed using ANOVA and is expressed as percent inhibition compared to the PBS control. 
         [0232]    Tumor growth inhibition data determined at day 26 following treatment with one of the humanized antibodies (i.e., Sh24C05-31 N62S-IgG1, U1-59, or Ab#6 IgG2) is shown in Table 21. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
                 TABLE 21 
               
             
             
               
                   
                   
               
               
                   
                 Tumor 
                 ANOVA 
                 ANOVA 
               
               
                   
                 Growth 
                 Analysis 
                 Analysis 
               
             
          
           
               
                   
                 Treatment 
                 Inhibition 
                 (Compared 
                 (Compared 
               
             
          
           
               
                 Gr. 
                 Agent 
                 mg/kg 
                 (%) 
                 to PBS) 
                 to hIgG) 
               
               
                   
               
             
          
           
               
                 1 
                 PBS 
                 — 
                 NA 
                 NA 
                 NA 
               
               
                 2 
                 muIgG 
                 20 
                 −1.2 
                 NS 
                 NA 
               
               
                 3 
                 Sh24C05-31 
                 5 
                 62.3 
                 P &lt; 0.001 
                 P &lt; 0.001 
               
               
                   
                 N62S-IgG1 
               
               
                 4 
                 Sh24C05-31 
                 10 
                 62.0 
                 P &lt; 0.001 
                 P &lt; 0.001 
               
               
                   
                 N62S-IgG1 
               
               
                 5 
                 Sh24C05-31 
                 20 
                 69.0 
                 P &lt; 0.001 
                 P &lt; 0.001 
               
               
                   
                 N62S-IgG1 
               
               
                 6 
                 Ab#6 IgG2 
                 5 
                 24.7 
                 NS 
                 NS 
               
               
                 7 
                 Ab#6 IgG2 
                 10 
                 35.9 
                 P &lt; 0.01  
                 P &lt; 0.01  
               
               
                 8 
                 Ab#6 IgG2 
                 20 
                 48.4 
                 P &lt; 0.001 
                 P &lt; 0.001 
               
               
                 9 
                 U1-59 
                 5 
                 47.8 
                 P &lt; 0.001 
                 P &lt; 0.001 
               
               
                 10 
                 U1-59 
                 10 
                 56.7 
                 P &lt; 0.001 
                 P &lt; 0.001 
               
               
                 11 
                 U1-59 
                 20 
                 57.7 
                 P &lt; 0.001 
                 P &lt; 0.001 
               
               
                   
               
             
          
         
       
     
         [0233]    The results using the Calu-3 non-small cell lung cancer xenograft model demonstrate that Sh24C05-31 N62S-IgG1 showed the greatest tumor growth inhibition by day 26 at all doses tested (i.e., 5 mg/kg, 10 mg/kg, and 20 mg/kg of body weight). 
         [0234]    For example, at the 10 mg/kg dose, Sh24C05-31 N62S-IgG1 showed the greatest tumor growth inhibition by day 26 (62%, P&lt;0.001) when compared to Ab#6 IgG2 (36%, NS) or U1-59 (57%, P&lt;0.001). At the 20 mg/kg dose, Sh24C05-31 N62S-IgG1 also showed the greatest tumor growth inhibition by day 26 (69%, P&lt;0.001) when compared to Ab#6 IgG2 (48%, P&lt;0.001) or U1-59 (58%, P&lt;0.001). 
       Example 18 
     Inhibition of MDA-MB-453 Tumor Xenograft Growth 
       [0235]    The ability of the humanized monoclonal antibodies produced in Example 12 to inhibit tumor growth were tested in a MDA-MB-453 breast xenograft model (which is a HER2 positive breast model). The ability of the humanized monoclonal antibodies U1-59 and Ab#6 IgG2, as described in Example 12, to inhibit tumor growth were also tested in the same model. 
         [0236]    Human Breast MDA-MB-453 cells were grown in culture in 37° C. in an atmosphere containing 0% CO2, using Leibovitz ATCC medium (Cat No. 30-2008) containing 10% fetal bovine serum. MDA-MB-453 cells were inoculated subcutaneously into the flank of 8-week old female NOD SCID mice (Taconic Labs) with 20×10 6  cells per mouse in 50% matrigel (BD Biosciences, Cat No. 356237). Tumor measurements were taken twice weekly using vernier calipers. Tumor volume was calculated using the formula: width×width×length/2. 
         [0237]    When tumors reached approximately 200 mm 3 , the mice were randomized into 7 groups of 10 mice each. One group received PBS and another received huIgG control. Each of the other nine groups received one of the humanized antibodies (i.e., Sh24C05-31 N62S-IgG1, U1-59, or Ab#6 IgG2). Sh24C05-31 N62S-IgG1 was dosed either at 5 mg/kg, 10 mg/kg, or 20 mg/kg body weight, twice per week, by intra-peritoneal injection for more than 10 weeks; U1-59, or Ab#6 were dosed at 10 mg/kg with the same frequency. Tumor volumes and mouse body weights were recorded twice per week. Tumor growth inhibition was analyzed using ANOVA and is expressed as percent inhibition compared to the PBS control. 
         [0238]    Tumor growth inhibition data determined at day 71 following treatment with one of the humanized antibodies (i.e., Sh24C05-31 N62S-IgG1, U1-59, or Ab#6 IgG2) is shown in Table 22. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
                 TABLE 22 
               
             
             
               
                   
                   
               
               
                   
                   
                 Tumor 
                 ANOVA 
                 ANOVA 
               
               
                   
                   
                 Growth 
                 Analysis 
                 Analysis 
               
               
                   
                 Treatment 
                 Inhibition 
                 (Compared 
                 (Compared 
               
             
          
           
               
                 Gr. 
                 Agent 
                 mg/kg 
                 (%) 
                 to PBS) 
                 to hIgG) 
               
               
                   
               
               
                 1 
                 PBS 
                 — 
                 NA 
                 NA 
                 NA 
               
               
                 2 
                 hIgG 
                 20 
                 28.87 
                 p &lt; 0.001 
                 p &lt; 0.001 
               
               
                 3 
                 Sh24C05-31 
                 5 
                 86.57 
                 p &lt; 0.001 
                 p &lt; 0.001 
               
               
                   
                 N62S-IgG1 
               
               
                 4 
                 Sh24C05-31 
                 10 
                 84.09 
                 p &lt; 0.001 
                 p &lt; 0.001 
               
               
                   
                 N62S-IgG1 
               
               
                 5 
                 Sh24C05-31 
                 20 
                 85.26 
                 p &lt; 0.001 
                 p &lt; 0.001 
               
               
                   
                 N62S-IgG1 
               
               
                 6 
                 Ab#6 IgG2 
                 10 
                 62.48 
                 p &lt; 0.001 
                 p &lt; 0.001 
               
               
                 7 
                 U1-59 
                 10 
                 83.93 
                 p &lt; 0.001 
                 p &lt; 0.001 
               
               
                   
               
             
          
         
       
     
         [0239]    The results using the MDA-MB-453 xenograft model demonstrate that Sh24C05-31 N62S-IgG1 showed potent tumor growth inhibition by day 71 at all doses tested (i.e., 5 mg/kg, 10 mg/kg, and 20 mg/kg of body weight). 
         [0240]    The results also demonstrate that at the 10 mg/kg dose, Sh24C05-31 N62S-IgG1 showed greater tumor growth inhibition by day 71 (84%, P&lt;0.001) when compared to Ab#6 IgG2 (62%, P&lt;0.001). Sh24C05-31 N62S-IgG1 showed equivalent tumor growth inhibition as U1-59 at the same dose. 
       INCORPORATION BY REFERENCE 
       [0241]    The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. 
       EQUIVALENTS 
       [0242]    The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and the range of equivalency of the claims are intended to be embraced therein.