Abstract:
There is disclosed an antibody drug conjugate (ADC) having an IgG antibody that binds to a c-Met target conjugated at both Cys sites in the hinge region of an IgG antibody. There is further disclosed a method for treating a breast cancer comprising providing an effective amount of a c-Met ADC.

Description:
TECHNICAL FIELD 
       [0001]    The present disclosure provides an antibody drug conjugate (ADC) having an IgG antibody that binds to a c-Met target conjugated at both Cys sites in the hinge region of an IgG antibody. The present disclosure further provides a method for treating a breast cancer comprising providing an effective amount of a c-Met ADC. 
       CROSS REFERENCE TO RELATED APPLICATION 
       [0002]    This patent application claims priority from U.S. provisional patent application 62/089,203 filed 8 Dec. 2014. 
       BACKGROUND 
       [0003]    HGF is a mesenchyme-derived pleiotrophic factor with mitogenic, motogenic and morphogenic activities on a number of different cell types. HGF effects are mediated through a specific tyrosine kinase, c-Met, and aberrant HGF and c-Met expression are frequently observed in a variety of tumors. (Maulik et al.,  Cytokine  &amp;  Growth Factor Reviews  (2002), 13:41-59; Danilkovitch-Miagkova &amp; Zbar,  J. Clin. Invest.  (2002), 109(7):863-867). Regulation of the HGF/c-Met signaling pathway is implicated in tumor progression and metastasis. (Trusolino &amp; Comoglio,  Nature Rev.  (2002), 2:289-300). 
         [0004]    HGF binds the extracellular domain of the Met receptor tyrosine kinase (RTK) and regulates diverse biological processes such as cell scattering, proliferation, and survival. HGF-Met signaling is essential for normal embryonic development especially in migration of muscle progenitor cells and development of the liver and nervous system (Bladt et al.,  Nature  376, 768-771. 1995; Hamanoue et al.  J. Neurosci. Res.  43, 554-564. 1996; Schmidt et al.,  Proc. Natl. Acad. Sci. USA  94, 11445-11450, 1995; Uehara et al.,  Nature  373, 702-705, 1995). Developmental phenotypes of Met and HGF knockout mice are very similar suggesting that HGF is the cognate ligand for the Met receptor (Schmidt et al.,  Proc. Natl. Acad. Sci. USA  94, 11445-11450, 1995; Uehara et al.,  Nature  373, 702-705, 1995). HGF-Met also plays a role in liver regeneration, angiogenesis, and wound healing (Bussolino et al.,  J. Cell Biol.  119, 629-641 1992; Nusrat et al.,  J. Clin. Invest.  93, 2056-2065 1994). The precursor Met receptor undergoes proteolytic cleavage into an extracellular subunit and membrane spanning subunit linked by disulfide bonds (Tempest et al.,  Br. J. Cancer  58, 3-7 1988). The subunit contains the cytoplasmic kinase domain and harbors a multi-substrate docking site at the C-terminus where adapter proteins bind and initiate signaling. Upon HGF binding, activation of Met leads to tyrosine phosphorylation and downstream signaling through Gab1 and Grb2/Sos mediated PI3-kinase and Ras/MAPK activation respectively, which drives cell motility and proliferation (Furge et al.,  Oncogene  19, 5582-5589 2000; Hartmann et al.,  J. Biol. Chem.  269, 21936-21939 1994; Ponzetto et al.,  Cell  87, 531-542 1996; and Royal and Park,  J. Biol. Chem.  270, 27780-27787 1995). 
         [0005]    Met overexpression or gene-amplification has been observed in a variety of human cancers. For example, Met protein is overexpressed at least 5-fold in colorectal cancers and reported to be gene-amplified in liver metastasis (Di Renzo et al., Clin.  Cancer Res.  1, 147-154, 1995; Liu et al.,  Oncogene  7, 181-185 1992). Met protein is also reported to be overexpressed in oral squamous cell carcinoma, hepatocellular carcinoma, renal cell carcinoma, breast carcinoma, and lung carcinoma (Jin et al.,  Cancer  79, 749-760 1997; Morello et al.,  J. Cell Physiol.  189, 285-290 2001; Natali et al.,  Int. J. Cancer  69, 212-217. 1996; Olivero et al.,  Br. J. Cancer  74, 1862-1868 1996; Suzuki et al.,  Hepatology  20, 1231-1236 1994). In addition, overexpression of mRNA has been observed in hepatocellular carcinoma, gastric carcinoma, and colorectal carcinoma (Boix et al.,  Hepatology  19, 88-91 1994; Kuniyasu et al.,  Int. J. Cancer  55, 72-75 1993; Liu et al.,  Oncogene  7, 181-185 1992). 
         [0006]    A number of mutations in the kinase domain of Met have been found in renal papillary carcinoma which leads to constitutive receptor activation (Olivero et al.,  Int. J. Cancer  82, 640-643 1999; Schmidt et al.,  Nat. Genet.  16, 68-73 1997; Schmidt et al., Oncogene 18, 2343-2350 1999). These activating mutations confer constitutive Met tyrosine phosphorylation and result in MAPK activation, focus formation, and tumorigenesis (Jeffers et al.,  Proc. Natl. Acad. Sci. USA  94, 11445-11450 1997). In addition, these mutations enhance cell motility and invasion (Giordano et al., 2000; Lorenzato et al.,  Cancer Res.  62, 7025-7030 2002). HGF-dependent Met activation in transformed cells mediates increased motility, scattering, and migration which eventually leads to invasive tumor growth and metastasis (Jeffers et al.,  Mol. Cell Biol.  16, 1115-1125 1996; Meiners et al.,  Oncogene  16, 9-20 1998). 
         [0007]    Met is a member of the subfamily of RTKs which include Ron and Sea (Maulik et al.,  Cytokine Growth Factor Rev.  13, 41-59 2002). Prediction of the extracellular domain structure of Met suggests shared homology with the semaphorins and plexins. The N-terminus of Met contains a Sema domain of approximately 500 amino acids that is conserved in all semaphorins and plexins. The semaphorins and plexins belong to a large family of secreted and membrane-bound proteins first described for their role in neural development (Van Vactor and Lorenz,  Curr. Biol.  9, R201-204 1999). However, semaphorin overexpression has been correlated with tumor invasion and metastasis. A cysteine-rich PSI domain (also referred to as a Met Related Sequence domain) found in plexins, semaphorins, and integrins lies adjacent to the Sema domain followed by four IPT repeats that are immunoglobulin-like regions found in plexins and transcription factors. A recent study suggests that the Met Sema domain is sufficient for HGF and heparin binding (Gherardi et al., (2003). Functional map and domain structure of Met, the product of the c-Met protooncogene and receptor for hepatocyte growth factor/scatter factor.  Proc. Natl. Acad. Sci. USA  2003). Furthermore, Kong-Beltran et al. ( Cancer Cell  (2004), 6:61-73) have reported that the Sema domain of Met is necessary for receptor dimerization and activation. 
         [0008]    C-Met, a transmembrane receptor tyrosine kinase, plays a key role in malignant transformation of epithelial cells by activating signal transduction pathways essential for cellular proliferation, survival, migration and invasion. C-Met overexpression, with or without gene amplification, has been reported in primary breast cancers and correlate with poor prognosis. C-Met signaling inhibition, such as tyrosine kinase inhibitors (TKIs), usually not sufficient for sustained treatment efficacy. Therefore, we believe that antibody drug conjugates (ADCs) offer the promise and potential of delivering potent anti-tumor activity with the advantage of reduced side effects. 
       SUMMARY 
       [0009]    The present disclosure provides and antibody drug conjugate (ADC) having an IgG antibody that binds to a c-Met target conjugated at both Cys sites in the hinge region of an IgG antibody. The present disclosure further provides a method for treating a breast cancer comprising providing an effective amount of a c-Met ADC. 
         [0010]    We generated antibody drug conjugates containing a novel human anti-c-Met antibody (STI-0602) (described in U.S. patent application Ser. No. 13/924,492 filed 21 Jun. 2013, the disclosure of which is incorporated by reference herein) with either a tubulin inhibitor or DNA damaging agent, such as doxorubicin analogs. The ADC conjugates retained binding affinity and showed potent cell killing in a variety of c-Met positive cell lines. 
         [0011]    The present disclosure provides an antibody drug conjugate (ADC) composition comprising an IgG antibody that binds to c-Met, a conjugation linker moiety that binds to both Cys residues in the hinge region of an IgG antibody and a toxin moiety. Preferably, the toxin moiety is a tubulin inhibitor or a doxorubicin analog. Preferably, the antibody is an IgG antibody from the H8 (heavy/light SEQ ID NOs 19/20) family or is a B12 (heavy/light SEQ ID NOs 7/8), wherein the H8 antibody family is selected from the group consisting of H8-A2, H8-9, H8-9EE8L3, H8-C1, H8-D4, H8-D5, H8-D6, H8-D10, H8-E5, H8-G7, H8-H6, H8-2A2, H8-2B1, H8-2B2, H8-2B4, H8-2B7, H8-A7P, H8-9EH11L, H8-9EH11L, and H8-6AG2H3. Preferably, the conjugated toxin is 
         [0000]    
       
                 
         
             
             
         
       
     
         [0012]    The present disclosure provides a method for treating breast cancer, comprising administering an effective amount of an antibody drug conjugate (ADC) composition comprising an IgG antibody that binds to c-Met, a conjugation linker moiety that binds to both Cys residues in the hinge region of an IgG antibody and a toxin moiety. Preferably, the toxin moiety is a tubulin inhibitor or a doxorubicin analog. Preferably, the antibody is an IgG antibody from the H8 (heavy/light SEQ ID NOs 19/20) family or is a B12 (heavy/light SEQ ID NOs 7/8), wherein the H8 antibody family is selected from the group consisting of H8-A2, H8-9, H8-9EE8L3, H8-C1, H8-D4, H8-D5, H8-D6, H8-D10, H8-E5, H8-G7, H8-H6, H8-2A2, H8-2B1, H8-2B2, H8-2B4, H8-2B7, H8-A7P, H8-9EH11L, H8-9EH11L, and H8-6AG2H3. Preferably, the conjugated toxin is 
         [0000]    or 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    Structure for conjugation and drug 
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         [0000]    Structure for conjugation and drug. 
     
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         [0013]      FIG. 1  shows the effects of treatment with anti-cMet IgG1 antibody STI-0602 described herein with MDA-MB-231 and HS578T cells. The cells were plated at 10K cells/well overnight in complete RPMI and then treated with STI-0602 antibody in serum-free RPMI for 4 hours, starting at an initial concentration of 10 μg/ml, and the serially diluted 1:5 for a total of 8 different concentrations. After 4 hours, cells were stimulated with 50 ng/ml HGF diluted in serum-free RPMI for 15 minutes (media controls were left unstimulated). Cells were then lysed and frozen at −80 ° C. freezer overnight and phosphorylated c-Met levels were determined using a Cell Signaling ELISA kit. 
           [0014]      FIG. 2  shows a comparison of in vivo results achieved comparing 2 c-Met ADC doses (3 mg/kg and 10 mg/kg) to the c-Met antibody alone (STI-0602, also called H8-A2 and disclosed herein as heavy chain SEG ID NO.25 and light chain SEQ ID NO. 26) and control ADC The experimental detail is described in Example 1. 
           [0015]      FIG. 3  shows a comparison of in vivo results achieved comparing 2 c-Met ADC doses (3 mg/kg and 10 mg/kg) to the c-Met antibody alone and control ADC. The experimental detail is described in Example 1. 
           [0016]      FIG. 4  is a table showing the experimental detail described in Example 1.  FIGS. 2 and 3  show the in vivo results. 
           [0017]      FIG. 5  shows a graph of three different ADC&#39;s, each with the STI 0602 anti c-Met IgG1 antibody and different toxins retain their binding affinities to c-Met TNBC cells. Mice were given a single iv dose at 10 mg/kg. Mean concentrations of total antibody and ADC in serum were determined by ELISA. 
           [0018]      FIG. 6  shows a graph of an ADC and a control STI 0602 anti c-Met IgG1 antibody have similar pharmacokinetic properties in mice. Mice were given a single iv dose at 10 mg/kg. Mean concentrations of total antibody and ADC in serum were determined by ELISA. 
           [0019]      FIGS. 7A and 7B  show anti-c-Met ADC&#39;s specifically inhibit c-Met TNBC cell proliferation.  FIG. 7A  shows inhibition of cell proliferation in HS578T and  FIG. 7B  shows inhibition of cell proliferation in-T47D. Cells were plated at 4000 per well and treated with one of the three ADC&#39;s. After incubation for 4 days, proliferation was measured using a Cell Titer Glo assay. 
           [0020]      FIG. 8  shows that the anti-c-Met IgG1 antibody was internalized in a triple negative breast cancer cell line. Internalization of anti c-Met antibody IgG1 H8-A2 (also called STI-0602 SEQ ID NO. 25/SEQ ID NO. 26) in MDA-MB468. MDA-MB468 were plated overnight and incubated with 1 μg/ml anti-C-Met H8A2 antibody for 180 min at 37° C. Cells were stained with anti-AF488. 
           [0021]      FIG. 9  shows an in vivo comparison of two doses of c-Met 0174 ADC at 3 mg/kg and 10 mg/kg and vehicle control with a c-Met antibody. 
           [0022]      FIG. 10  shows a single 1 mg/kg much lower dose of c-Met 0276 ADC and vehicle control. Tumor volume was measured twice weekly in all of the mice.  FIG. 10  provides these comparative data and it shows a significant effect for the lower 1 mg/kg dose when measuring tumor volume. 
           [0023]      FIGS. 11A and 11B  show that there was no significant weight change for these mice with either c-Met 0276 ADC ( FIG. 11A ) or c-Met 0174 ADC ( FIG. 1  IB), compared to vehicle controls. These data suggest that there was no observed toxicity from either ADC tested. 
       
    
    
     DETAILED DESCRIPTION 
     Antibody Component 
       [0024]    The present disclosure provides a fully human antibody of an IgG class that binds to a c-Met epitope with a binding affinity of at least 10 −6 M, which has a heavy chain variable domain sequence that is at least 95% identical to the amino acid sequences selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO. 37, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO. 74, SEQ ID NO. 75, SEQ ID NO. 76, SEQ ID NO. 79, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, and combinations thereof, and that has a light chain variable domain sequence that is at least 95% identical to the amino acid sequences selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 35, SEQ ID NO. 38, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 67, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 73, SEQ ID NO. 77, SEQ ID NO. 78, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, and combinations thereof. Preferably, the fully human antibody has both a heavy chain and a light chain wherein the antibody has a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2 (called Al herein), SEQ ID NO. 3/SEQ ID NO. 4 (called A2 herein), SEQ ID NO. 5/SEQ ID NO. 6 (called A8 herein), SEQ ID NO. 7/SEQ ID NO. 8 (called B12 herein), SEQ ID NO. 9/SEQ ID NO. 10 (called D6 herein), SEQ ID NO. 11/SEQ ID NO. 12 (called El herein), SEQ ID NO. 13/SEQ ID NO. 14 (called E6 herein), SEQ ID NO. 15/SEQ ID NO. 16 (called F3 herein), SEQ ID NO. 17/SEQ ID NO. 18 (called H6 herein), SEQ ID NO. 19/SEQ ID NO. 20 (called H8 herein), SEQ ID NO. 21/SEQ ID NO. 22 (called H8-9 herein), SEQ ID NO. 21/SEQ ID NO. 23 (called H8-9EE8L3 herein), SEQ ID NO. 24/SEQ ID NO. 22 (called H8-G3S herein), SEQ ID NO. 25/SEQ ID NO. 26 (called H8-A2 herein), SEQ ID NO. 27/SEQ ID NO. 28 (called H8-B6 herein), SEQ ID NO. 29/SEQ ID NO. 23 (called H8-C1 herein), SEQ ID NO. 24/SEQ ID NO. 30 (called H8-D4 herein), SEQ ID NO. 31/SEQ ID NO. 23 (called H8-D5 herein), SEQ ID NO. 24/SEQ ID NO. 23 (called H8-D6 herein), SEQ ID NO. 32/SEQ ID NO. 23 (called H8-D10 herein), SEQ ID NO. 33/SEQ ID NO. 22 (called H8-E5 herein), SEQ ID NO. 34/SEQ ID NO. 22 (called H8-G7 herein), SEQ ID NO. 24/SEQ ID NO. 35 (called H8-G9 herein), SEQ ID NO. 36/SEQ ID NO. 26 (called H8-H6 herein), SEQ ID NO. 29/SEQ ID NO. 22 (called H8-2A2 herein), SEQ ID NO. 37/SEQ ID NO. 38 (called H8-2B1 herein), SEQ ID NO. 34/SEQ ID NO. 23 (called H8-2B2 herein), SEQ ID NO. 37/SEQ ID NO. 23 (called H8-2B4 herein), SEQ ID NO. 32/SEQ ID NO. 39 (called H8-2B7 herein), SEQ ID NO. 32/SEQ ID NO. 22 (called H8-A7P herein), SEQ ID NO. 40/SEQ ID NO. 41 (called GCE-A10 herein), SEQ ID NO. 42/SEQ ID NO. 43 (called GCE-A11 herein), SEQ ID NO. 44/SEQ ID NO. 41 (called GCE-A13 herein), SEQ ID NO. 45/SEQ ID NO. 46 (called GCE-A14 herein), SEQ ID NO. 47/SEQ ID NO. 48 (called GCE-A16 herein), SEQ ID NO. 49/SEQ ID NO. 50 (called GCE-A18 herein), SEQ ID NO. 51/SEQ ID NO. 52 (called GCE-B2 herein), SEQ ID NO. 53/SEQ ID NO. 54 (called GCE-B9 herein), SEQ ID NO. 45/SEQ ID NO. 55 (called GCE-B11 herein), SEQ ID NO. 56/SEQ ID NO. 57 (called GCE-B13 herein), SEQ ID NO. 58/SEQ ID NO. 57 (called GCE-B19 herein), SEQ ID NO. 59/SEQ ID NO. 60 (called GCE-BR1 herein), SEQ ID NO. 61/SEQ ID NO. 62 (called GCE-B20 herein), SEQ ID NO. 63/SEQ ID NO. 64 (called GCE-A19 herein), SEQ ID NO. 65/SEQ ID NO. 66 (called GCE-B10 herein), SEQ ID NO. 58/SEQ ID NO. 67 (called GCE-B5 herein), SEQ ID NO. 61/SEQ ID NO. 68 (called GCE-B4 herein), SEQ ID NO. 69/SEQ ID NO. 70 (called GCE-A26 herein), SEQ ID NO. 71/SEQ ID NO. 72 (called GCE-L1A-9 herein), SEQ ID NO. 49/SEQ ID NO. 73 (called GCE-H34-36 herein), SEQ ID NO. 74/SEQ ID NO. 73 (called GCE-H13-1 herein), SEQ ID NO. 61/SEQ ID NO. 73 (called GCE-H13-2 herein), SEQ ID NO. 44/SEQ ID NO. 73 (called GCE-H13-3 herein), SEQ ID NO. 40/SEQ ID NO. 73 (called GCE-H13-4 herein), SEQ ID NO. 75/SEQ ID NO. 73 (called GCE-H13-5 herein), SEQ ID NO. 69/SEQ ID NO. 73 (called GCE-H13-6 herein), SEQ ID NO. 76/SEQ ID NO. 73 (called GCE-H13-8 herein), SEQ ID NO. 21/SEQ ID NO. 77 (called H8-9EH11L herein), SEQ ID NO. 21/SEQ ID NO. 78 (called H8-9EG11L herein), SEQ ID NO. 79/SEQ ID NO. 20 (called H8-6AG2H3 herein), SEQ ID NO. 80/SEQ ID NO. 81 (called A1-2 herein), SEQ ID NO. 82/SEQ ID NO. 83 (called A1-4 herein), SEQ ID NO. 84/SEQ ID NO. 85 (called A1-6 herein), SEQ ID NO. 86/SEQ ID NO. 87 (called A1-8 herein), SEQ ID NO. 88/SEQ ID NO. 89 (called A1-9 herein), SEQ ID NO. 90/SEQ ID NO. 91 (called A1-24 herein), SEQ ID NO. 92/SEQ ID NO. 93 (called A1-32 herein), and combinations thereof. 
         [0025]    The present disclosure provides a fully human antibody Fab fragment, having a variable domain region from a heavy chain and a variable domain region from a light chain, wherein the heavy chain variable domain sequence that is at least 95% identical to the amino acid sequences selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO. 37, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO. 74, SEQ ID NO. 75, SEQ ID NO. 76, SEQ ID NO. 79, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, and combinations thereof, and that has a light chain variable domain sequence that is at least 95% identical to the amino acid sequences selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 35, SEQ ID NO. 38, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 67, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 73, SEQ ID NO. 77, SEQ ID NO. 78, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, and combinations thereof. Preferably, the fully human antibody Fab fragment has both a heavy chain variable domain region and a light chain variable domain region wherein the antibody has a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 21/SEQ ID NO. 23, SEQ ID NO. 24/SEQ ID NO. 22, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID NO. 23, SEQ ID NO. 24/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 23, SEQ ID NO. 24/SEQ ID NO. 23, SEQ ID NO. 32/SEQ ID NO. 23, SEQ ID NO. 33/SEQ ID NO. 22, SEQ ID NO. 34/SEQ ID NO. 22, SEQ ID NO. 24/SEQ ID NO. 35, SEQ ID NO. 36/SEQ ID NO. 26, SEQ ID NO. 29/SEQ ID NO. 22, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 34/SEQ ID NO. 23, SEQ ID NO. 37/SEQ ID NO. 23, SEQ ID NO. 32/SEQ ID NO. 39, SEQ ID NO. 32/SEQ ID NO. 22, SEQ ID NO. 40/SEQ ID NO. 41, SEQ ID NO. 42/SEQ ID NO. 43, SEQ ID NO. 44/SEQ ID NO. 41, SEQ ID NO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID NO. 45/SEQ ID NO. 55, SEQ ID NO. 56/SEQ ID NO. 57, SEQ ID NO. 58/SEQ ID NO. 57, SEQ ID NO. 59/SEQ ID NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 58/SEQ ID NO. 67, SEQ ID NO. 61/SEQ ID NO. 68, SEQ ID NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID NO. 49/SEQ ID NO. 73, SEQ ID NO. 74/SEQ ID NO. 73, SEQ ID NO. 61/SEQ ID NO. 73, SEQ ID NO. 44/SEQ ID NO. 73, SEQ ID NO. 40/SEQ ID NO. 73, SEQ ID NO. 75/SEQ ID NO. 73, SEQ ID NO. 69/SEQ ID NO. 73, SEQ ID NO. 76/SEQ ID NO. 73, SEQ ID NO. 21/SEQ ID NO. 77, SEQ ID NO. 21/SEQ ID NO. 78, SEQ ID NO. 79/SEQ ID NO. 20, SEQ ID NO. 80/SEQ ID NO. 81, SEQ ID NO. 82/SEQ ID NO. 83, SEQ ID NO. 84/SEQ ID NO. 85, SEQ ID NO. 86/SEQ ID NO. 87, SEQ ID NO. 88/SEQ ID NO. 89, SEQ ID NO. 90/SEQ ID NO. 91, SEQ ID NO. 92/SEQ ID NO. 93, and combinations thereof. 
         [0026]    The present disclosure provides a single chain human antibody, having a variable domain region from a heavy chain and a variable domain region from a light chain and a peptide linker connection the heavy chain and light chain variable domain regions, wherein the heavy chain variable domain sequence that is at least 95% identical to the amino acid sequences selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO. 37, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO. 74, SEQ ID NO. 75, SEQ ID NO. 76, SEQ ID NO. 79, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, and combinations thereof, and that has a light chain variable domain sequence that is at least 95% identical to the amino acid sequences selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 35, SEQ ID NO. 38, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 67, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 73, SEQ ID NO. 77, SEQ ID NO. 78, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, and combinations thereof. Preferably, the fully human single chain antibody has both a heavy chain variable domain region and a light chain variable domain region, wherein the single chain fully human antibody has a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 21/SEQ ID NO. 23, SEQ ID NO. 24/SEQ ID NO. 22, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID NO. 23, SEQ ID NO. 24/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 23, SEQ ID NO. 24/SEQ ID NO. 23, SEQ ID NO. 32/SEQ ID NO. 23, SEQ ID NO. 33/SEQ ID NO. 22, SEQ ID NO. 34/SEQ ID NO. 22, SEQ ID NO. 24/SEQ ID NO. 35, SEQ ID NO. 36/SEQ ID NO. 26, SEQ ID NO. 29/SEQ ID NO. 22, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 34/SEQ ID NO. 23, SEQ ID NO. 37/SEQ ID NO. 23, SEQ ID NO. 32/SEQ ID NO. 39, SEQ ID NO. 32/SEQ ID NO. 22, SEQ ID NO. 40/SEQ ID NO. 41, SEQ ID NO. 42/SEQ ID NO. 43, SEQ ID NO. 44/SEQ ID NO. 41, SEQ ID NO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID NO. 45/SEQ ID NO. 55, SEQ ID NO. 56/SEQ ID NO. 57, SEQ ID NO. 58/SEQ ID NO. 57, SEQ ID NO. 59/SEQ ID NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 58/SEQ ID NO. 67, SEQ ID NO. 61/SEQ ID NO. 68, SEQ ID NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID NO. 49/SEQ ID NO. 73, SEQ ID NO. 74/SEQ ID NO. 73, SEQ ID NO. 61/SEQ ID NO. 73, SEQ ID NO. 44/SEQ ID NO. 73, SEQ ID NO. 40/SEQ ID NO. 73, SEQ ID NO. 75/SEQ ID NO. 73, SEQ ID NO. 69/SEQ ID NO. 73, SEQ ID NO. 76/SEQ ID NO. 73, SEQ ID NO. 21/SEQ ID NO. 77, SEQ ID NO. 21/SEQ ID NO. 78, SEQ ID NO. 79/SEQ ID NO. 20, SEQ ID NO. 80/SEQ ID NO. 81, SEQ ID NO. 82/SEQ ID NO. 83, SEQ ID NO. 84/SEQ ID NO. 85, SEQ ID NO. 86/SEQ ID NO. 87, SEQ ID NO. 88/SEQ ID NO. 89, SEQ ID NO. 90/SEQ ID NO. 91, SEQ ID NO. 92/SEQ ID NO. 93, and combinations thereof. 
         [0000]    Preparation of cMet—DM1 ADC 
         [0027]    Anti-c-Met antibody was buffer exchanged to phosphate buffer, pH from 6.5 to 7.5. Toxin-linker, SMCC-DM1 was dissolved in DMA (Dimethylacetamide) solution and added to antibody solution with Toxin/Antibody ratio from 7 to 10. The antibody-toxin solution was incubated at room temperature overnight. The unconjugated antibody was removed either gel-filtration chromatography or centrifugation filtration. The cMet-DM1 was characterized by HPLC. The drug antibody ratio (DAR) was calculated based on UV-VIS of cMet-DM1. 
         [0000]    Preparation of cMet-Duo3 
         [0028]    Anti-cMet antibody was reduced by TCEP (tris(2-carboxyethyl)phosphine), up to 20 mM. The excess of TCEP was removed by gel-filtration chromatography or centrifugal filtration. Toxin-Duo3-linker was dissolved in DMA solution and added to the reduced antibody with Toxin/antibody ratio from 4.5 to 6. After few hours&#39; incubation at room temperature, the unconjugated Duo3-linker was removed by gel-filtration chromatography or centrifugal filtration. The cMet-Duo3 was characterized by HPLC. The drug antibody ratio (DAR) was calculated based on UV-VIS or HIC-HPLC. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    Structure of compound 030-0260 and preparation as follows: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0029]    To a solution of compound 50 (18 mg, 0.02 mmol) in DCM (2 mL) was added compound 65 (15 mg), followed by DIEA (5 μL). The mixture was stirred at room temperature for 10 min. The reaction was then diluted with DCM (30 mL) and washed with aq. saturated NaHCO 3 . The organic layer was concentrated and residue was purified by RP-HPLC to give compound 14 as a red solid after lyophilization (7 mg, 29%). MS m/z 1231.3 (M+H). 
         [0000]    Structure of compound 030-0174 
         [0000]    
       
                 
         
             
             
         
       
     
         [0030]    The synthesis of this compound was described as compound 8. 
         [0000]    Preparation of compound 8 
         [0000]    
       
                 
         
             
             
         
       
     
         [0031]    To compound 41 (72 mg, 0.10 mmol) in 3 mL of DMF was added DIEA (75 μL), and amine TFA 63 (86 mg, 0.12 mmol). The mixture was stirred at room temperature for 3 h, then diluted with DCM (40 mL). The mixture was washed with brine. The organic layer was dried and evaporated to dryness. The residue was purified by column (silica gel, DCM:MeOH, 9:1) to give compound 8 (63 mg, 52%). MS m/z 1214.5 (M+H). 
       EXAMPLE 1 
       [0032]    Upon receipt, animals were housed 5 mice per cage in a room with a controlled environment. Animals were provided rodent chow and water ad libitum. Acclimation of the mice to laboratory conditions was at least 72 hours prior to the start of cell administration and dosing. During the acclimation period, the animals&#39; health status was determined. Only animals that are observed to be healthy prior to study initiation were used. 
         [0033]    This example provides an in vivo experiment comparing treatment of mice with control (PBS), anti-c-Met IgG1 antibody (STI-0602 and STI-0607) and an ADC variant of both antibodies. The procedure first does a tumor cell inoculation &amp; establishment of tumors:
   a. U87 cells were cultured with 10% FBS U87 medium (EMEM) and harvested with 0.05% trypsin. Cells were washed 2 times with serum-free EMEM, counted, and resuspended at 5 x10 6  cells in 0.2 mL or, 25 x10 6  cells/mL in a 1:1 mix of serum-free EMEM and matrigel and injected subcutaneously into the upper right flank of each mouse.   b. Tumor growth was monitored by tumor volume measurement using a digital caliper starting   
 
         [0036]    Day 6-9 after inoculation, 2 times per week thereafter and prior to study termination.
   c. Tumors were measured with digital calipers. The length (the longest dimension) and the width (the distance perpendicular to and in the same plane as the length) were measured. The formula for calculating tumor volume was TV (mm3)=1/2×L×W2.   Treatments:   a. Once tumors were staged to the desired volume (average from 200 to 300 mm3), animals were randomized and mice with very large or small tumors culled. Mice were divided into 8 groups of 10 mice each, randomized by tumor volume.   b. Mice were treated with either vehicle or Test Article according to  FIG. 4 . Mice received a total of 5 doses.   c. Tumor responses were monitored and study terminated once clear treatment trends are established and/or when tumor load in vehicle-treated mice reaches IACUC protocol limits (2000 mm 3 ).   
 
       EXAMPLE 2 
       [0042]    This example is an in vivo experiment comparing two disclosed c-Met ADCs in vivo with mice having (H292 non-small cell lung cancer line). ADC or vehicle control was administered iv to the tail in three weekly doses.  FIG. 9  shows two different doses of c-Met 0174 ADC at 3 mg/kg and 10 mg/kg and vehicle control. Tumor volume was measured twice weekly in all of the mice. 
         [0043]      FIG. 9  provides these comparative data and it shows a significant dose-dependent effect when measuring tumor volume.  FIG. 11B  shows that there was no significant weight change for these mice, compared to vehicle control. These data suggest that there was no observed toxicity from the ADC. 
         [0044]      FIG. 10  shows a single 1 mg/kg much lower dose of c-Met 0276 ADC at and vehicle control. Tumor volume was measured twice weekly in all of the mice.  FIG. 10  provides these comparative data and it shows a significant effect for the lower 1 mg/kg dose when measuring tumor volume.  FIG. 11A  shows that there was no significant weight change for these mice, compared to vehicle control. These data suggest that there was no observed toxicity from this ADC. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Sequence Listing 
               
             
          
           
               
                   
                 Heavy chain variable domain region 
                 Light chain variable domain region 
               
               
                   
               
               
                 A1 
                 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSG 
                 LPVLTQPASVSGSPGQSITISCTGTSSD 
               
               
                   
                 GYYWSWIRQHPGKGLEWIGEINHSGSTNYNP 
                 VGGYNYVSWYQQHPGKAPKLMIYDVS 
               
               
                   
                 SLKSRVTISVDTSKNQFSLKLSSVTAADTAVYY 
                 DRPSGVSTRFSGSKSGNTASLTISGLQ 
               
               
                   
                 CARGRDGYDFDPWGQGTLVTVSS SEQ ID 
                 AEDEADYYCSSYRSSSALVVFGGGTK 
               
               
                   
                 NO. 1 
                 LTVL SEQ ID NO. 2 
               
               
                   
               
               
                 A2 
                 QVQLQESGPGLVKPSGTLSLTCAVSGGSISRS 
                 LPVLTQPASVSGSPGQSITISCTGTSSD 
               
               
                   
                 NWWSWVRQPPGKGLEWIGEVYHSGSTNYNP 
                 VGGYKYVSWYQQHPGKAPKLLIYDVT 
               
               
                   
                 SLKSRVTISVDKSKNQFSLKVNSVTAADTAVY 
                 DRPSGVSNRFSGSQSGNTASLTISGLQ 
               
               
                   
                 YCARDSDGGYYFDYWGQGTLVTVSS SEQ 
                 TEDEADYYCSSYTDNGALVVFGGGTK 
               
               
                   
                 ID NO. 3 
                 LTVL SEQ ID NO. 4 
               
               
                   
               
               
                 A8 
                 QITLKESGAEVKKPGSSVKVSCKASGGTFSSY 
                 SYELMQPASVSGSPGQSITISCTGTSS 
               
               
                   
                 GISWVRQAPGQGLEWMGGIIPMFGTANYAQK 
                 DVGGYDHVSWYQQHPGKAPKLMIYAV 
               
               
                   
                 FQGRVTITADESTSTAYMELSSLRSEDTAVYY 
                 RNRPSGVPDRFSGSKSGNTASLTISGL 
               
               
                   
                 CARDEVAPDYYGSGPSYGMDVWGQGTMVT 
                 QAEDEADYYCSSYTSSLTYVFGTGTKV 
               
               
                   
                 VSS SEQ ID NO. 5 
                 TVL SEQ ID NO. 6 
               
               
                   
               
               
                 B12 
                 QVQLVESGAEVKKPGASVKVSCKASGYTFTG 
                 QAVLTQPPSVSGSPGQSITISCTGTSS 
               
               
                   
                 YYMHWVRQAPGQGLEWMGWINPNSGNTGY 
                 DVGTFNLVSWYQQHPGKAPKLIIYEVS 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 KRPSDVSPRYSGSKSGTTASLTISVLQ 
               
               
                   
                 VYYCARRGTTVSFDYVVGQGTTVTVSS SEQ 
                 TEDEADYYCCSYTTSSSYVFGIGTKVT 
               
               
                   
                 ID NO. 7 
                 VL SEQ ID NO. 8 
               
               
                   
               
               
                 D6 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSG 
                 QSVLTQPPSASGSPGQSVTISCTGTSS 
               
               
                   
                 YYWSWIRQPPGKGLEWIGEINHSGSTNYNPS 
                 DVGGYNYVSWYQQHPGKAPKLMIYEV 
               
               
                   
                 LKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC 
                 SKRPSGVPDRFSGSKSGNTASLTVSG 
               
               
                   
                 ARGRDGYDFDPWGQGTLVTVSS SEQ ID 
                 LQAEDEADYYCSSYAGSNNLVVFGGG 
               
               
                   
                 NO. 9 
                 TQLTVL SEQ ID NO. 10 
               
               
                   
               
               
                 E1 
                 QVQLVQSGAEVKKPGASVKVSCKTSGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCTGSS 
               
               
                   
                 DYMHWVRQAPGQGLEWMGWINPNSGGTNY 
                 SNIGAGYDVHWYQQLPGTVPKLLIYGN 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 SNRPSGVPDRFSGSKSGTSASLAITGL 
               
               
                   
                 AVYYCAREPGRDYYYYDGMDVWGQGTTVTV 
                 QAEDEADYYCQSYDSSLSAYVFGTGT 
               
               
                   
                 SS SEQ ID NO. 11 
                 KVTVL SEQ ID NO. 12 
               
               
                   
               
               
                 E6 
                 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSG 
                 QAVLTQPASVSGSPGQSITISCTGTRS 
               
               
                   
                 YYWSWIRQPPGKGLEWIGEINHSGSTNYNPS 
                 DVGGYNYVSWYQQHPGKAPKLLVYDV 
               
               
                   
                 LKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC 
                 SNRPSGVSNRFSGSQSGNTASLTISGL 
               
               
                   
                 ARGGRVYSNYYMDVWGKGTTVTVSS SEQ 
                 QTEDEADYYCSSYTDNSALVVFGGGT 
               
               
                   
                 ID NO. 13 
                 KVTVL SEQ ID NO. 14 
               
               
                   
               
               
                 F3 
                 QVQLVESGPGLVKPSGTLSLTCAVSGGSISSS 
                 QSVLTQPASVSGSPGQSITISCTGTSS 
               
               
                   
                 NWWSWVRQPPGKGLEWIGEIYHSGSTNYNP 
                 DVGGYNYVSWYQQHPGKAPKLLIYDV 
               
               
                   
                 SLKSRVTISVDKSKNQFSLKLSSVTAADTAVYY 
                 DSRPSGVSNRFSGSKSGNTASLTISGL 
               
               
                   
                 CARSAYGDYFLDYWGQGTLVTVSS SEQ ID 
                 QAEDEADYYCSSFTSSSTLVVFGGGT 
               
               
                   
                 NO. 15 
                 KVTVL SEQ ID NO. 16 
               
               
                   
               
               
                 H6 
                 EVQLLESGGGLVQPGGSLRLSCAASGFTFSS 
                 AIRMTQSPAFMSATPGDKVNISYKASQ 
               
               
                   
                 YEMNWVRQAPGKGLEWVSYISSSGSTIYYAD 
                 DVDDDMTWCQEKPGEAAIFIFQEAATL 
               
               
                   
                 SVKGRFTISRDNAKNSLYLQMNSLRAEDTAVY 
                 VPGIPPRLSGSGNGTDFTLTINNMESE 
               
               
                   
                 YCARDGAATGDOIDYVVGQGTLVTVSS SEQ 
                 DAAYYFCLQQDNFPLTFGQGTKVDIK 
               
               
                   
                 ID NO. 17 
                 SEQ ID NO. 18 
               
               
                   
               
               
                 H8 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFSS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 YYMHWVRQAPGQGLEWMGWINPNSGNTGY 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDYVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAGVFGGGTKL 
               
               
                   
                 ID NO. 19 
                 TVL SEQ ID NO. 20 
               
               
                   
               
               
                 H8-9 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 YYMHWVRQAPGQGLEWMGWINPNSGNTGY 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWVFGGGTK 
               
               
                   
                 ID NO. 21 
                 LTVL SEQ ID NO. 22 
               
               
                   
               
               
                 H8-9EE8L3 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 YYMHWVRQAPGQGLEWMGWINPNSGNTGY 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWLFGGGTKL 
               
               
                   
                 ID NO. 21 
                 TVL SEQ ID NO. 23 
               
               
                   
               
               
                 H8-G35 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 EYMHWVRQAPGQGLEWMGWINPNSGNTGY 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWVFGGGTK 
               
               
                   
                 ID NO. 24 
                 LTVL SEQ ID NO. 22 
               
               
                   
               
               
                 H8-A2 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 EYMHWVRQAPGQGLEWMGWINPNSGNTGV 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 APKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWAFGGGTK 
               
               
                   
                 ID NO. 25 
                 LTVL SEQ ID NO. 26 
               
               
                   
               
               
                 H8-B6 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 EYMHWVRQAPGQGLEWMGWINPNSGNTGY 
                 FTDNTYVSWYHHLPGTAPKLLIYDTNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWVFGGGTK 
               
               
                   
                 ID NO. 27 
                 LTVL SEQ ID NO. 28 
               
               
                   
               
               
                 H8-C1 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 EYMHWVRQAPGQGLEWMGWINPNSGNTGL 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 APKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWLFGGGTKL 
               
               
                   
                 ID NO. 29 
                 TVL SEQ ID NO. 23 
               
               
                   
               
               
                 H8-D4 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 EYMHWVRQAPGQGLEWMGWINPNSGNTGY 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RQSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWVFGGGTK 
               
               
                   
                 ID NO. 24 
                 LTVL SEQ ID NO. 30 
               
               
                   
               
               
                 H8-D5 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 YYMHWVRQAPGQGLEWMGWINPNSGNTGV 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWLFGGGTKL 
               
               
                   
                 ID NO. 31 
                 TVL SEQ ID NO. 23 
               
               
                   
               
               
                 H8-D6 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 EYMHWVRQAPGQGLEWMGWINPNSGNTGY 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWLFGGGTKL 
               
               
                   
                 ID NO. 24 
                 TVL SEQ ID NO. 23 
               
               
                   
               
               
                 H8-D10 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 EYMHWVRQAPGQGLEWMGWINPNSGNTGL 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWLFGGGTKL 
               
               
                   
                 ID NO. 32 
                 TVL SEQ ID NO. 23 
               
               
                   
               
               
                 H8-E5 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 EYMHWVRQAPGQGLEWMGWINPNSGNTGY 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 APKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWVFGGGTK 
               
               
                   
                 ID NO. 33 
                 LTVL SEQ ID NO. 22 
               
               
                   
               
               
                 H8-G7 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 EYMHWVRQAPGQGLEWMGWINPNSGNTGV 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWVFGGGTK 
               
               
                   
                 ID NO. 34 
                 LTVL SEQ ID NO. 22 
               
               
                   
               
               
                 H8-G9 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 EYMHWVRQAPGQGLEWMGWINPNSGNTGY 
                 FSSNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWVFGGGTK 
               
               
                   
                 ID NO. 24 
                 LTVL SEQ ID NO. 35 
               
               
                   
               
               
                 H8-H6 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 YYMHWVRQAPGQGLEWMGWINPNSGNTGL 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWAFGGGTK 
               
               
                   
                 IDNO.36 
                 LTVLSEQIDNO.26 
               
               
                   
               
               
                 H8-2A2 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 EYMHWVRQAPGQGLEWMGWINPNSGNTGL 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 APKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWVFGGGTK 
               
               
                   
                 ID NO. 29 
                 LTVL SEQ ID NO. 22 
               
               
                   
               
               
                 H8-2B1 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 YYMHWVRQAPGQGLEWMGWINPNSGNTGL 
                 NIGNNYVSWYHHLPGTAPKLLIYDTNK 
               
               
                   
                 APKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWAFGGGTK 
               
               
                   
                 ID NO. 37 
                 LTVL SEQ ID NO. 38 
               
               
                   
               
               
                 H8-2B2 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 EYMHWVRQAPGQGLEWMGWINPNSGNTGV 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWLFGGGTKL 
               
               
                   
                 ID NO. 34 
                 TVL SEQ ID NO. 23 
               
               
                   
               
               
                 H8-2B4 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 YYMHWVRQAPGQGLEWMGWINPNSGNTGL 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 APKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWLFGGGTKL 
               
               
                   
                 ID NO. 37 
                 TVL SEQ ID NO. 23 
               
               
                   
               
               
                 H8-2B7 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSASNS 
               
               
                   
                 EYMHWVRQAPGQGLEWMGWINPNSGNTGL 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWVFGGGTK 
               
               
                   
                 ID NO. 32 
                 LTVL SEQ ID NO. 39 
               
               
                   
               
               
                 H8-A7P 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 EYMHWVRQAPGQGLEWMGWINPNSGNTGL 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSSSEQ 
                 GDEAHYYCGTWDSTLSAWVFGGGTK 
               
               
                   
                 ID NO. 32 
                 LTVL SEQ ID NO. 22 
               
               
                   
               
               
                 GCE-A10 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCLGSAS 
               
               
                   
                 DYMHWVRQAPGQGLEWMGWINPNSGGTNY 
                 NIGAGHDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 NRPSGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 AVYYCAREPARDYYYYDGLDVWGQGTTVTV 
                 AEDEADYYCQSYSSSLSAYVFGTGTK 
               
               
                   
                 SS SEQ ID NO. 40 
                 VTVL SEQ ID NO. 41 
               
               
                   
               
               
                 GCE-A11 
                 QVQLVQSGAEVKKPGASVKVSCKASGFTFSG 
                 QSVVTQPPSVSGAPGQRVTISCLGSSS 
               
               
                   
                 DYIHWVRQAPGQGLEWMGWINPNSGGTNYA 
                 NIGAGHDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 QKFQGRVTMTRDTSISTAYMELSRLRSDDTA 
                 NRISGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 VYYCAREPARDYYYYDGLDVWGQGTTVTVS 
                 AEDEADYYCQSYSSSLSAYLFGTGTKV 
               
               
                   
                 S SEQ ID NO. 42 
                 TVL SEQ ID NO. 43 
               
               
                   
               
               
                 GCE-A13 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCLGSAS 
               
               
                   
                 DYLHWVRQAPGQGLEWMGWINPNSGGTNY 
                 NIGAGHDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 NRPSGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 AVYYCAREPARDYYYYDGLDVWGQGTTVTV 
                 AEDEADYYCQSYSSSLSAYVFGTGTK 
               
               
                   
                 SS SEQ ID NO. 44 
                 VTVL SEQ ID NO. 41 
               
               
                   
               
               
                 GCE-A14 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCIGSSS 
               
               
                   
                 DYIHWVRQAPGQGLEWMGWINPNSGGTNYA 
                 NIGAGHDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 QKFQGRVTMTRDTSISTAYMELSRLRSDDTA 
                 NRPSGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 VYYCAREPARDYYYYDGLDVWGQGTTVTVS 
                 AEDEADYYCQSYSSSLSAYVFGTGTK 
               
               
                   
                 S SEQ ID NO. 45 
                 VTVL SEQ ID NO. 46 
               
               
                   
               
               
                 GCE-A16 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCIGSSS 
               
               
                   
                 DYLHWVRQAPGQGLEWMGWINPNTGGTNYA 
                 NIGAGYDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 QKFQGRVTMTRDTSISTAYMELSRLRSDDTA 
                 NLPSGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 VYYCAREPARDYYYYDGLDVWGQGTTVTVS 
                 AEDEADYYCQSYESSLSAYVFGTGTK 
               
               
                   
                 S SEQ ID NO. 47 
                 VTVL SEQ ID NO. 48 
               
               
                   
               
               
                 GCE-A18 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCIGSAS 
               
               
                   
                 DYMHWVRQAPGQGLEWMGWINPNSGGTNY 
                 NIGAGHDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 NRPSGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 AVYYCAREPGRDYYYYDGLDVWGQGTTVTV 
                 AEDEADYYCQSYSSSLSAYVFGTGTK 
               
               
                   
                 SS SEQ ID NO. 49 
                 VTVL SEQ ID NO. 50 
               
               
                   
               
               
                 GCE-B2 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCLGSAS 
               
               
                   
                 DYMHWVRQAPGQGLEWMGWINPNTGGTNY 
                 NIGAGYDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 NRPSGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 AVYYCAREPARDYYYYDGLDVWGQGTTVTV 
                 AEDEADYYCQSYSSSLSAYVFGTGTK 
               
               
                   
                 SS SEQ ID NO. 51 
                 VTVL SEQ ID NO. 52 
               
               
                   
               
               
                 GCE-B9 
                 QVQLVQSGAEVKKPGASVKVSCKASGFTFSG 
                 QSVVTQPPSVSGAPGQRVTISCLGSSS 
               
               
                   
                 DYMHWVRQAPGQGLEWMGWINPNSGGTNY 
                 NIGAGHDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 NLPSGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 AVYYCAREPARDYYYYDGLDVWGQGTTVTV 
                 AEDEADYYCQSYSSSLSAVLFGTGTKV 
               
               
                   
                 SS SEQ ID NO. 53 
                 TVL SEQ ID NO. 54 
               
               
                   
               
               
                 GCE-B11 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCIGSSS 
               
               
                   
                 DYIHWVRQAPGQGLEWMGWINPNSGGTNYA 
                 NIGAGYDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 QKFQGRVTMTRDTSISTAYMELSRLRSDDTA 
                 NRISGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 VYYCAREPARDYYYYDGLDVWGQGTTVTVS 
                 AEDEADYYCQSYSSSLSAVLFGTGTKV 
               
               
                   
                 S SEQ ID NO. 45 
                 TVL SEQ ID NO. 55 
               
               
                   
               
               
                 GCE-B13 
                 QVQLVQSGAEVKKPGASVKVSCKASGSTFSG 
                 QSVVTQPPSVSGAPGQRVTISCLGSAS 
               
               
                   
                 DYIHWVRQAPGQGLEWMGWINPNSGGTNYA 
                 NIGAGHDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 QKFQGRVTMTRDTSISTAYMELSRLRSDDTA 
                 NRPSGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 VYYCAREPARDYYYYDGLDVWGQGTTVTVS 
                 AEDEADYYCQSYSSSLSAVLFGTGTKV 
               
               
                   
                 S SEQ ID NO. 56 
                 TVL SEQ ID NO. 57 
               
               
                   
               
               
                 GCE-B19 
                 QVQLVQSGAEVKKPGASVKVSCKASGFTFSG 
                 QSVVTQPPSVSGAPGQRVTISCLGSAS 
               
               
                   
                 DYIHWVRQAPGQGLEWMGWINPNSGGTNYA 
                 NIGAGHDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 QKFQGRVTMTRDTSISTAYMELSRLRSDDTA 
                 NRPSGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 VYYCAREPGRDYYYYDGLDVWGQGTTVTVS 
                 AEDEADYYCQSYSSSLSAVLFGTGTKV 
               
               
                   
                 S SEQ ID NO. 58 
                 TVL SEQ ID NO. 57 
               
               
                   
               
               
                 GCE-BR1 
                 QVQLVQSGAEVKKPGASVKVSCKASGSTFSG 
                 QSVVTQPPSVSGAPGQRVTISCLGSAS 
               
               
                   
                 DYLHWVRQAPGQGLEWMGWINPNSGGTNY 
                 NIGAGYDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 NRPSGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 AVYYCAREPARDYYYYDGLDVWGQGTTVTV 
                 AEDEADYYCQSYSSSLSAVLFGTGTKV 
               
               
                   
                 SS SEQ ID NO. 59 
                 TVL SEQ ID NO. 60 
               
               
                   
               
               
                 GCE-B20 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCLGSAS 
               
               
                   
                 DYLHWVRQAPGQGLEWMGWINPNSGGTNY 
                 NIGAGHDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 NRISGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 AVYYCAREPARDYYYYDGMDVWGQGTTVTV 
                 AEDEADYYCQSYSSSLSAVLFGTGTKV 
               
               
                   
                 SS SEQ ID NO. 61 
                 TVL SEQ ID NO. 62 
               
               
                   
               
               
                 GCE-A19 
                 QVQLVQSGAEVKKPGASVKVSCKASGFTFSG 
                 QSVVTQPPSVSGAPGQRVTISCLGSSS 
               
               
                   
                 DYLHWVRQAPGQGLEWMGWINPNSGGTNY 
                 NIGAGHDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 NRISGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 AVYYCAREPARDYYYYYGLDVWGQGTTVTVS 
                 AEDEADYYCQSYSSSLSAYVFGTGTK 
               
               
                   
                 S SEQ ID NO. 63 
                 VTVL SEQ ID NO. 64 
               
               
                   
               
               
                 GCE-B10 
                 QVQLVQSGAEVKKPGASVKVSCKASGFTFSG 
                 QSVVTQPPSVSGAPGQRVTISCLGSSS 
               
               
                   
                 DYLHWVRQAPGQGLEWMGWINPNTGGTNYA 
                 NIGAGHDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 QKFQGRVTMTRDTSISTAYMELSRLKSDDTAV 
                 NLPSGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 YYCAREPARDYYYYDGLDVWGQGTTVTVSS 
                 AEDEADYYCQSYSSSLSAYVFGTGTK 
               
               
                   
                 SEQ ID NO. 65 
                 VTVL SEQ ID NO. 66 
               
               
                   
               
               
                 GCE-B5 
                 QVQLVQSGAEVKKPGASVKVSCKASGFTFSG 
                 QSVVTQPPSVSGAPGQRVTISCLGSAS 
               
               
                   
                 DYIHWVRQAPGQGLEWMGWINPNSGGTNYA 
                 NIGAGHDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 QKFQGRVTMTRDTSISTAYMELSRLRSDDTA 
                 NRPSGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 VYYCAREPGRDYYYYDGLDVWGQGTTVTVS 
                 AEDEADYYCQSYSSSLSAVVFGTGTK 
               
               
                   
                 S SEQ ID NO. 58 
                 VTVL SEQ ID NO. 67 
               
               
                   
               
               
                 GCE-B4 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCIGSAS 
               
               
                   
                 DYLHWVRQAPGQGLEWMGWINPNSGGTNY 
                 NIGAGHDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 NRISGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 AVYYCAREPARDYYYYDGMDVWGQGTTVTV 
                 AEDEADYYCQSYSSSLSAVLFGTGTKV 
               
               
                   
                 SS SEQ ID NO. 61 
                 TVL SEQ ID NO. 68 
               
               
                   
               
               
                 GCE-A26 
                 QVQLVQSGAEVKKPGASVKVSCKASGFTFSG 
                 QSVVTQPPSVSGAPGQRVTISCLGSSS 
               
               
                   
                 DYLHWVRQAPGQGLEWMGWINPNSGGTNY 
                 NIGAGHDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 NRPSGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 AVYYCAREPARDYYYYDGLDVWGQGTTVTV 
                 AEDEADYYCQSYSSSLSAYLFGTGTKV 
               
               
                   
                 SS SEQ ID NO. 69 
                 TVL SEQ ID NO. 70 
               
               
                   
               
               
                 GCE-L1A-9 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCLGSSS 
               
               
                   
                 DYMHWVRQAPGQGLEWMGWINPNSGGTNY 
                 NIGAGYDVHWYQQLPGTAPKLLIYGNS 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 NRPSGVPDRFSGSKSGTSASLAITGLQ 
               
               
                   
                 AVYYCAREPGRDYYYYDGMDVWGQGTTVTV 
                 AEDEADYYCQSYSSSLSAYVFGTGTK 
               
               
                   
                 SS SEQ ID NO. 71 
                 VTVL SEQ ID NO. 72 
               
               
                   
               
               
                 GCE-H3B-36 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCTGSS 
               
               
                   
                 DYMHWVRQAPGQGLEWMGWINPNSGGTNY 
                 SNIGAGYDVHWYQQLPGTAPKLLIYGN 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 SNRPSGVPDRFSGSKSGTSASLAITGL 
               
               
                   
                 AVYYCAREPGRDYYYYDGLDVWGQGTTVTV 
                 QAEDEADYYCQSYSSSLSAYVFGTGT 
               
               
                   
                 SS SEQ ID NO. 49 
                 KVTVL SEQ ID NO. 73 
               
               
                   
               
               
                 GCE-H13-1 
                 QVQLVQSGAEVKKPGASVKVSCKASGSTFSG 
                 QSVVTQPPSVSGAPGQRVTISCTGSS 
               
               
                   
                 DYLHWVRQAPGQGLEWMGWINPNSGGTNY 
                 SNIGAGYDVHWYQQLPGTAPKLLIYGN 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 SNRPSGVPDRFSGSKSGTSASLAITGL 
               
               
                   
                 AVYYCAREPGRDYYYYDGLDVWGQGTTVTV 
                 QAEDEADYYCQSYSSSLSAYVFGTGT 
               
               
                   
                 SS SEQ ID NO. 74 
                 KVTVL SEQ ID NO. 73 
               
               
                   
               
               
                 GCE-H13-2 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCTGSS 
               
               
                   
                 DYLHWVRQAPGQGLEWMGWINPNSGGTNY 
                 SNIGAGYDVHWYQQLPGTAPKLLIYGN 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 SNRPSGVPDRFSGSKSGTSASLAITGL 
               
               
                   
                 AVYYCAREPARDYYYYDGMDVWGQGTTVTV 
                 QAEDEADYYCQSYSSSLSAYVFGTGT 
               
               
                   
                 SS SEQ ID NO. 61 
                 KVTVL SEQ ID NO. 73 
               
               
                   
               
               
                 GCE-H13-3 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCTGSS 
               
               
                   
                 DYLHWVRQAPGQGLEWMGWINPNSGGTNY 
                 SNIGAGYDVHWYQQLPGTAPKLLIYGN 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 SNRPSGVPDRFSGSKSGTSASLAITGL 
               
               
                   
                 AVYYCAREPARDYYYYDGLDVWGQGTTVTV 
                 QAEDEADYYCQSYSSSLSAYVFGTGT 
               
               
                   
                 SS SEQ ID NO. 44 
                 KVTVL SEQ ID NO. 73 
               
               
                   
               
               
                 GCE-H13-4 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCTGSS 
               
               
                   
                 DYMHWVRQAPGQGLEWMGWINPNSGGTNY 
                 SNIGAGYDVHWYQQLPGTAPKLLIYGN 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 SNRPSGVPDRFSGSKSGTSASLAITGL 
               
               
                   
                 AVYYCAREPARDYYYYDGLDVWGQGTTVTV 
                 QAEDEADYYCQSYSSSLSAYVFGTGT 
               
               
                   
                 SS SEQ ID NO. 40 
                 KVTVL SEQ ID NO. 73 
               
               
                   
               
               
                 GCE-H13-5 
                 QVQLVQSGAEVKKPGASVKVSCKASGFTFSG 
                 QSVVTQPPSVSGAPGQRVTISCTGSS 
               
               
                   
                 DYLHWVRQAPGQGLEWMGWINPNSGGTNY 
                 SNIGAGYDVHWYQQLPGTAPKLLIYGN 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 SNRPSGVPDRFSGSKSGTSASLAITGL 
               
               
                   
                 AVYYCAREPARDYYYYDGMDVWGQGTTVTV 
                 QAEDEADYYCQSYSSSLSAYVFGTGT 
               
               
                   
                 SS SEQ ID NO. 75 
                 KVTVL SEQ ID NO. 73 
               
               
                   
               
               
                 GCE-H13-6 
                 QVQLVQSGAEVKKPGASVKVSCKASGFTFSG 
                 QSVVTQPPSVSGAPGQRVTISCTGSS 
               
               
                   
                 DYLHWVRQAPGQGLEWMGWINPNSGGTNY 
                 SNIGAGYDVHWYQQLPGTAPKLLIYGN 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 SNRPSGVPDRFSGSKSGTSASLAITGL 
               
               
                   
                 AVYYCAREPARDYYYYDGLDVWGQGTTVTV 
                 QAEDEADYYCQSYSSSLSAYVFGTGT 
               
               
                   
                 SS SEQ ID NO. 69 
                 KVTVL SEQ ID NO. 73 
               
               
                   
               
               
                 GCE-H13-8 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSG 
                 QSVVTQPPSVSGAPGQRVTISCTGSS 
               
               
                   
                 DYLHWVRQAPGQGLEWMGWINPNSGGTNY 
                 SNIGAGYDVHWYQQLPGTAPKLLIYGN 
               
               
                   
                 AQKFQGRVTMTRDTSISTAYMELSRLRSDDT 
                 SNRPSGVPDRFSGSKSGTSASLAITGL 
               
               
                   
                 AVYYCAREPGRDYYYYDGLDVWGQGTTVTV 
                 QAEDEADYYCQSYSSSLSAYVFGTGT 
               
               
                   
                 SS SEQ ID NO. 76 
                 KVTVL SEQ ID NO. 73 
               
               
                   
               
               
                 H8-9EH11L 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 YYMHWVRQAPGQGLEWMGWINPNSGNTGY 
                 FIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWVFGGGTK 
               
               
                   
                 ID NO. 21 
                 LTVL SEQ ID NO. 77 
               
               
                   
               
               
                 H8-9EG11L 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFYS 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 YYMHWVRQAPGQGLEWMGWINPNSGNTGY 
                 NIGNTYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRGTTVSFDTVVGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAWVFGGGTK 
               
               
                   
                 ID NO. 21 
                 LTVL SEQ ID NO. 78 
               
               
                   
               
               
                 H8-6AG2H3 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFSD 
                 QLVLTQSPSVSVAPGQRVTISCSGSNS 
               
               
                   
                 YYMHWVRQAPGQGLEWMGWINPNSGNTGY 
                 NIGNNYVSWYHHLPGTAPKLLIYDNNK 
               
               
                   
                 AQKFQGRVTMTRNTSISTAYMELSSLRSEDTA 
                 RPSGIPDRFSGSKSGTSATLGITGLQP 
               
               
                   
                 VYYCARRATTVSFDYWGQGTLVTVSS SEQ 
                 GDEAHYYCGTWDSTLSAGVFGGGTKL 
               
               
                   
                 ID NO. 79 
                 TVL SEQ ID NO. 20 
               
               
                   
               
               
                 A1-2 
                 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSG 
                 LPVLTQPASVSGSPGQSITISCTGTSFD 
               
               
                   
                 GYYWSWIRQHPGKGLEWIGESTHSGSTNYN 
                 VGGYNYVSWYQQHPGKAPKLMIYDVS 
               
               
                   
                 PSLKSRVTISVDTSKNQFSLKLSSVTAADTAVY 
                 DRPSGVSTRFSGSKSGNTASLTISGLQ 
               
               
                   
                 YCARGRDGYDFDAWGQGTLVTVSS SEQ ID 
                 AEDEADYYCSSFRSSSALVVFGGGTKL 
               
               
                   
                 NO. 80 
                 TVL SEQ ID NO. 81 
               
               
                   
               
               
                 A1-4 
                 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSG 
                 LPVLTQPASVSGSPGQSITISCTGTSSD 
               
               
                   
                 GYYWSWIRQHPGKGLEWIGESSHSGSTNYN 
                 VGGYPYVSWYQQHPGKAPKLMIYVVS 
               
               
                   
                 PSLKSRVTISVDTSKNQFSLKLSSVTAADTAVY 
                 DRPSGVSTRFSGSKSGNTASLTISGLQ 
               
               
                   
                 YCARGRDGYYFDAWGQGTLVTVSS SEQ ID 
                 AEDEADYYCSSYRSSSALVVFGGGTQ 
               
               
                   
                 NO. 82 
                 LTVL SEQ ID NO. 83 
               
               
                   
               
               
                 A1-6 
                 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSG 
                 LPVLTQPASVSGSPGQSITISCTGTSW 
               
               
                   
                 GYYWSWIRQHPGKGLEWIGEITHSGSTNYNP 
                 DVGGYPYVSWYQQHPGKAPKLMIYDV 
               
               
                   
                 SLKSRVTISVDTSKNQFSLKLSSVTAADTAVYY 
                 SDRPSGVSTRFSGSKSGNTASLTISGL 
               
               
                   
                 CARGRDGYDIDAWGQGTLVTVSS SEQ ID 
                 QAEDEADYYCSSYRSVSALVVFGGGT 
               
               
                   
                 NO. 84 
                 KLTVL SEQ ID NO. 85 
               
               
                   
               
               
                 A1-8 
                 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSG 
                 LPVLTQPASVSGSPGQSITISCTGTSSD 
               
               
                   
                 GYYWSWIRQHPGKGLEWIGEISHSGSTNYNP 
                 VGGYPYVSWYQQHPGKAPKLMIYRVS 
               
               
                   
                 SLESRVTISVDTSKNQFSLKLSSVTAADTAVYY 
                 DRPSGVSTRFSGSKSGNTASLTISGLQ 
               
               
                   
                 CARGRDGYDLDRWGQGTLVTVSS SEQ ID 
                 AEDEADYYCSSYRSSAALVVFGGGTK 
               
               
                   
                 NO. 86 
                 LTVL SEQ ID NO. 87 
               
               
                   
               
               
                 A1-9 
                 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSG 
                 LPVLTQPASVSGSPGQSITISCTGTSSD 
               
               
                   
                 GYYWSWIRQHPGKGLEWIGEISHSGSTNYNP 
                 VGGYNYVSWYQQHPGKAPKLMIYNVS 
               
               
                   
                 SLKSRVTISVDTSKNQFSLKLSSVTAADTAVYY 
                 DRPSGVSTRFSGSKSGNTASLTISGLQ 
               
               
                   
                 CARGRDGYYLDQWGQGTLVTVSS SEQ ID 
                 AEDEADYYCSSFRSSSALVVFGGGTKL 
               
               
                   
                 NO. 88 
                 TVL SEQ ID NO. 89 
               
               
                   
               
               
                 A1-24 
                 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSG 
                 LPVLTQPASVSGSPGQSITISCTGTSFD 
               
               
                   
                 GYYWSWIRQHPGKGLEWIGESTHSGSTNYN 
                 VGGYNYVSWYQQHPGKAPKLMIYDVS 
               
               
                   
                 PSLESRVTISVDTSKNQFSLKLSSVTAADTAVY 
                 DRPSGVSTRFSGSKSGNTASLTISGLQ 
               
               
                   
                 YCARGRDSYDFDAWGQGTLVTVSS SEQ ID 
                 AEDEADYYCSSFRSSAALVVFGGGTKL 
               
               
                   
                 NO. 90 
                 TVL SEQ ID NO. 91 
               
               
                   
               
               
                 A1-32 
                 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSG 
                 LPVLTQPASVSGSPGQSITISCTGTSFD 
               
               
                   
                 GYYWSWIRQHPGKGLEWIGESTHSGSTNYN 
                 VGGYPYVSWYQQHPGKAPKLMIYDVS 
               
               
                   
                 PSLDSRVTISVDTSKNQFSLKLSSVTAADTAVY 
                 DRPSGVSTRFSGSKSGNTASLTISGLQ 
               
               
                   
                 YCARGRDGYYLDQWGQGTLVTVSS SEQ ID 
                 AEDEADYYCSSFRSSAALVVFGGGTKL 
               
               
                   
                 NO. 92 
                 TVL SEQ ID NO. 93