ANTI-cMET ANTIBODY

Abstract

The invention relates to a novel antibody capable of binding specifically to the human c-Met receptor and/or capable of specifically inhibiting the tyrosine kinase activity of said receptor, with an improved antagonistic activity, said antibody comprising a modified hinge region. The invention also relates to a composition comprising such an antibody antagonist to c-Met and its use as a medicament for treating cancer.

1 . A method for inhibiting the growth and/or the proliferation of tumor cells, the method comprising the administration to a subject in need thereof of a monoclonal antibody comprising: a heavy chain comprising complementarity determining regions (CDR) CDR-H1, CDR-H2, and CDR-H3 comprising amino acid sequences SEQ ID Nos. 1, 2, and 3, respectively; a light chain comprising CDR-L1, CDR-L2, and CDR-L3 comprising amino acid sequences SEQ ID Nos. 5, 6, and 7; and a modified hinge region comprising the amino acid sequence SEQ ID No. 26. 
     
     
         2 . The method of  claim 1 , wherein the antibody is a chimeric antibody. 
     
     
         3 . The method of  claim 1 , wherein the antibody is a human antibody. 
     
     
         4 . The method of  claim 1 , wherein the antibody is a humanized antibody. 
     
     
         5 . The method of  claim 1 , wherein the antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID No. 4; and a light chain variable domain comprising amino acid sequence SEQ ID No. 10. 
     
     
         6 . The method of  claim 5 , wherein the antibody comprises a human light chain constant region and a human heavy chain constant region. 
     
     
         7 . The method of  claim 6 , wherein the human light chain constant region is of the IgG1 kappa isotype. 
     
     
         8 . The method of  claim 1 , wherein the antibody comprises a human light chain constant region and a human heavy chain constant region. 
     
     
         9 . The method of  claim 8 , wherein the human light chain constant region is of the IgG1 kappa isotype. 
     
     
         10 . The method of  claim 6 , wherein the antibody is chemically coupled to a mitotic inhibitor. 
     
     
         11 . The method of  claim 8 , wherein the antibody is chemically coupled to a mitotic inhibitor. 
     
     
         12 . A method for treating cancer, the method comprising administering to a subject in need thereof a monoclonal antibody comprising: a heavy chain comprising complementarity determining regions (CDR) CDR-H1, CDR-H2, and CDR-H3 comprising amino acid sequences SEQ ID Nos. 1, 2, and 3, respectively; a light chain comprising CDR-L1, CDR-L2, and CDR-L3, comprising amino acid sequences SEQ ID Nos. 5, 6, and 7; and a modified hinge region comprising the amino acid sequence SEQ ID No. 26. 
     
     
         13 . The method of  claim 12 , wherein the antibody is a chimeric antibody. 
     
     
         14 . The method of  claim 12 , wherein the antibody is a human antibody. 
     
     
         15 . The method of  claim 12 , wherein the antibody is a humanized antibody. 
     
     
         16 . The method of  claim 12 , wherein the antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID No. 4; and a light chain variable domain comprising amino acid sequence SEQ ID No. 10. 
     
     
         17 . The method of  claim 16 , wherein the antibody comprises a human light chain constant region and a human heavy chain constant region. 
     
     
         18 . The method of  claim 17 , wherein the human light chain constant region is of the IgG1 kappa isotype. 
     
     
         19 . The method of  claim 12 , wherein the antibody comprises a human light chain constant region and a human heavy chain constant region. 
     
     
         20 . The method of  claim 19 , wherein the human light chain constant region is of the IgG1 kappa isotype. 
     
     
         21 . The method of  claim 17 , wherein the antibody is chemically coupled to a mitotic inhibitor. 
     
     
         22 . The method of  claim 19 , wherein the antibody is chemically coupled to a mitotic inhibitor. 
     
     
         23 . The method according to  claim 12 , wherein the cancer is chosen from prostate cancer, osteosarcoma, lung cancer, breast cancer, endometrial cancer, glyoblastoma, and colon cancer. 
     
     
         24 . The method according to  claim 12 , wherein the cancer is a c-Met-activation-related cancer chosen from c-Met-activation-related cancers that are HGF-dependent, HGF-independent, or both. 
     
     
         25 . A method for inhibiting the growth and/or the proliferation of tumor cells, the method comprising administering to a subject in need thereof a composition comprising a pharmaceutically acceptable vehicle and a monoclonal antibody comprising: a heavy chain comprising complementarity determining regions (CDR) CDR-H1, CDR-H2, and CDR-H3 comprising amino acid sequences SEQ ID Nos. 1, 2, and 3, respectively; a light chain comprising CDR-L1, CDR-L2, and CDR-L3, comprising amino acid sequences SEQ ID Nos. 5, 6, and 7; and a modified hinge region comprising the amino acid sequence SEQ ID No. 26. 
     
     
         26 . The method of  claim 25 , wherein the antibody is a chimeric antibody. 
     
     
         27 . The method of  claim 25 , wherein the antibody is a human antibody. 
     
     
         28 . The method of  claim 25 , wherein the antibody is a humanized antibody. 
     
     
         29 . The method of  claim 25 , wherein the antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID No. 4; and a light chain variable domain comprising amino acid sequence SEQ ID No. 10. 
     
     
         30 . The method of  claim 29 , wherein the antibody comprises a human light chain constant region and a human heavy chain constant region. 
     
     
         31 . The method of  claim 30 , wherein the human light chain constant region is of the IgG1 kappa isotype. 
     
     
         32 . The method of  claim 25 , wherein the antibody comprises a human light chain constant region and a human heavy chain constant region. 
     
     
         33 . The method of  claim 32 , wherein the human light chain constant region is of the IgG1 kappa isotype. 
     
     
         34 . The method of  claim 30 , wherein the antibody is chemically coupled to a mitotic inhibitor. 
     
     
         35 . The method of  claim 32 , wherein the antibody is chemically coupled to a mitotic inhibitor. 
     
     
         36 . A method for treating cancer, the method comprising administering to a subject in need thereof a composition comprising a pharmaceutically acceptable vehicle and a monoclonal antibody comprising: a heavy chain comprising complementarity determining regions (CDR) CDR-H1, CDR-H2, and CDR-H3 comprising amino acid sequences SEQ ID Nos. 1, 2, and 3, respectively; a light chain comprising CDR-L1, CDR-L2, and CDR-L3, comprising amino acid sequences SEQ ID Nos. 5, 6, and 7; and a modified hinge region comprising the amino acid sequence SEQ ID No. 26. 
     
     
         37 . The method of  claim 36 , wherein the antibody is a chimeric antibody. 
     
     
         38 . The method of  claim 36 , wherein the antibody is a human antibody. 
     
     
         39 . The method of  claim 36 , wherein the antibody is a humanized antibody. 
     
     
         40 . The method of  claim 36 , wherein the antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID No. 4; and a light chain variable domain comprising amino acid sequence SEQ ID No. 10. 
     
     
         41 . The method of  claim 40 , wherein the antibody comprises a human light chain constant region and a human heavy chain constant region. 
     
     
         42 . The method of  claim 41 , wherein the human light chain constant region is of the IgG1 kappa isotype. 
     
     
         43 . The method of  claim 36 , wherein the antibody comprises a human light chain constant region and a human heavy chain constant region. 
     
     
         44 . The method of  claim 43 , wherein the human light chain constant region is of the IgG1 kappa isotype. 
     
     
         45 . The method of  claim 41 , wherein the antibody is chemically coupled to a mitotic inhibitor. 
     
     
         46 . The method of  claim 43 , wherein the antibody is chemically coupled to a mitotic inhibitor. 
     
     
         47 . The method according to  claim 25 , wherein the cancer is chosen from prostate cancer, osteosarcoma, lung cancer, breast cancer, endometrial cancer, glyoblastoma, and colon cancer. 
     
     
         48 . The method according to  claim 25 , wherein the cancer is a c-Met-activation-related cancer chosen from c-Met-activation-related cancers that are HGF-dependent, HGF-independent, or both. 
     
     
         49 . The method according to  claim 12 , further comprising administering an anti-tumoral antibody in a simultaneous, separate, or sequential fashion. 
     
     
         50 . The method according to  claim 12 , further comprising administering cytotoxic/cytostatic agent in a simultaneous, separate, or sequential fashion. 
     
     
         51 . The method according to claim  2546 , further comprising administering an anti-tumoral antibody in a simultaneous, separate, or sequential fashion. 
     
     
         52 . The method according to  claim 25 , further comprising administering cytotoxic/cytostatic agent in a simultaneous, separate, or sequential fashion. 
     
     
         53 . The method according to  claim 49 , wherein at least one of said antibodies is conjugated with a cell toxin and/or a radioelement. 
     
     
         54 . The method according to  claim 50 , wherein said cytotoxic/cytostatic agent is coupled chemically to the antibody. 
     
     
         55 . The method according to  claim 51 , wherein at least one of said antibodies is conjugated with a cell toxin and/or a radioelement. 
     
     
         56 . The method according to  claim 52 , wherein at least one of said antibodies is conjugated with a cell toxin and/or a radioelement.