NOVEL ANTI-cMET ANTIBODY

Abstract

The present invention relates to a novel divalent antibody capable of binding specifically to the human c-Met receptor and/or capable of specifically inhibiting the tyrosine kinase activity of said receptor, preferably both in a ligand-dependent and in a ligand-independent manner as well as the amino acid and nucleic acid sequences coding for said antibody. More preferably said antibody comprises a modified hinge region and exhibits an improved antagonistic activity. More particularly, the antibody according to the invention is capable of inhibiting the c-Met dimerization. The invention likewise comprises the use of said antibody as a medicament for the prophylactic and/or therapeutic treatment of cancers, preferably for cancer characterized by a ligand-independent activation of c-Met, or any pathology connected with the over expression of said receptor as well as in processes or kits for diagnosis of illnesses connected with the over-expression of c-Met. The invention finally comprises products and/or compositions comprising such an antibody in combination with other antibodies and/or chemical compounds directed against other growth factors involved in tumor progression or metastasis and/or compounds and/or anti-cancer agents or agents conjugated with toxins and their use for the prevention and/or the treatment of certain cancers.

1 . A monoclonal antibody, or a divalent functional fragment or derivative thereof, capable to inhibit the c-Met dimerization,
 said antibody comprising a heavy chain comprising CDR-H1, CDR-H2 and CDR-H3 with respectively the amino acid sequences SEQ ID Nos. 1, 2 and 3; and a light chain comprising CDR-L1, CDR-L2 and CDR-L3 with respectively the amino acid sequences SEQ ID Nos. 5, 6 and 7, said antibody further comprising a hinge region comprising the amino acid sequence SEQ ID No. 56;   for use for the prevention or the treatment of a patient in need thereof having a cancer characterized by ligand-independent activation of c-Met.   
     
     
         2 . The antibody of  claim 1 , or a divalent functional fragment or derivative thereof, characterized in that said hinge region comprises the amino acid sequence SEQ ID No. 57. 
     
     
         3 . The antibody of  claim 1 , or a divalent functional fragment or derivative thereof, characterized in that said hinge region comprises the amino acid sequence SEQ ID No. 21. 
     
     
         4 . The antibody of  claim 1 , or a divalent functional fragment or derivative thereof, characterized in that said hinge region comprises an amino acid sequence selected from the group consisting of SEQ ID Nos. 22 to 28 and SEQ ID Nos. 58 to 72. 
     
     
         5 . The antibody of  claim 1 , or a divalent functional fragment or derivative thereof, for use for the prevention or the treatment of a patient in need thereof having a cancer characterized by overexpression of c-Met. 
     
     
         6 . The antibody of  claim 1 , or a divalent functional fragment or derivative thereof, for use for the prevention or the treatment of a patient in need thereof having a cancer characterized by overexpression of c-Met resulting from genic amplification of c-Met. 
     
     
         7 . The antibody of  claim 6 , or a divalent functional fragment or derivative thereof, for use for the prevention or the treatment of a patient in need thereof having a cancer characterized by overexpression of c-Met resulting from genic amplification of c-Met and resulting in ligand-independent activation of c-Met. 
     
     
         8 . The antibody of  claim 6 , or a divalent functional fragment or derivative thereof, for use for the prevention or the treatment of a patient in need thereof having a cancer characterized by overexpression of c-Met resulting from genic amplification of c-Met, wherein said cancer is selected from the group consisting of renal cell carcinoma and gastric cancer. 
     
     
         9 . The antibody of  claim 1 , or a divalent functional fragment or derivative thereof, characterized in that it consists of a chimeric antibody. 
     
     
         10 . The antibody of  claim 1 , or a divalent functional fragment or derivative thereof, characterized in that it consists of a human antibody. 
     
     
         11 . The antibody of  claim 1 , or a divalent functional fragment or derivative thereof, characterized in that it consists of a humanized antibody. 
     
     
         12 . The antibody of  claim 11 , or a divalent functional fragment or derivative thereof, characterized in that it comprises a heavy chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 4; and a light chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 8, 9 or 10. 
     
     
         13 . The antibody of  claim 12 , or a divalent functional fragment or derivative thereof, characterized in that it comprises a heavy chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 4; a light chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 8; and a hinge region comprising the amino acid sequence SEQ ID No. 22. 
     
     
         14 . The antibody of  claim 12 , or a divalent functional fragment or derivative thereof, characterized in that it comprises a heavy chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 4; a light chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 9; and a hinge region comprising the amino acid sequence SEQ ID No. 22. 
     
     
         15 . The antibody of  claim 12 , or a divalent functional fragment or derivative thereof, characterized in that it comprises a heavy chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 4; a light chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 10; and a hinge region comprising the amino acid sequence SEQ ID No. 22. 
     
     
         16 . The antibody of  claim 12 , or a divalent functional fragment or derivative thereof, characterized in that it comprises a heavy chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 4; a light chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 8; and a hinge region comprising the amino acid sequence SEQ ID No. 28. 
     
     
         17 . The antibody of  claim 12 , or a divalent functional fragment or derivative thereof, characterized in that it comprises a heavy chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 4; a light chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 9; and a hinge region comprising the amino acid sequence SEQ ID No. 28. 
     
     
         18 . The antibody of  claim 12 , or a divalent functional fragment or derivative thereof, characterized in that it comprises a heavy chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 4; a light chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 10; and a hinge region comprising the amino acid sequence SEQ ID No. 28. 
     
     
         19 . The antibody of  claims 1  to  18  as a medicament. 
     
     
         20 . A composition for the prevention or the treatment of a patient in need thereof having a cancer characterized by ligand-independent activation of c-Met, said composition comprising by way of active principle a compound consisting of an antibody, or a divalent functional fragment or derivative thereof, as claimed in one of  claims 1  to  19 . 
     
     
         21 . The composition of  claim 20  as a medicament. 
     
     
         22 . The use of an antibody, or a divalent functional fragment or derivative thereof, of  claims 1  to  19  or of a composition of  claim 20  or  21  for the preparation of a medicament for the prevention or the treatment of a patient in need thereof having a cancer characterized by ligand-independent activation of c-Met.