NOVEL 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 both in a ligand-dependent and in a ligand-independent manner, 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 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 being further characterized in that it also comprises a hinge region comprising the amino acid sequence SEQ ID No. 56. 
     
     
         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. 72 to 86. 
     
     
         5 . The antibody of  claim 1 , or a divalent functional fragment or derivative thereof characterized in that it consists of a chimeric antibody. 
     
     
         6 . The antibody of  claim 1 , or a divalent functional fragment or derivative thereof, characterized in that it consists of a human antibody. 
     
     
         7 . The antibody of  claim 1 , or a divalent functional fragment or derivative thereof, characterized in that it consists of a humanized antibody. 
     
     
         8 . The antibody of  claim 7 , 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. 
     
     
         9 . The antibody of  claim 8 , 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. 
     
     
         10 . The antibody of  claim 8 , 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. 
     
     
         11 . The antibody of  claim 8 , 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. 
     
     
         12 . The antibody of  claim 8 , 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. 
     
     
         13 . The antibody of  claim 8 , 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 fight 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. 
     
     
         14 . The antibody of  claim 8 , 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 IB No. 28. 
     
     
         15 . An isolated nucleic acid, characterized in that it is chosen from the following nucleic acids:
 a) a nucleic acid, DNA or RNA, coding for an antibody, or a divalent functional fragment or derivative thereof as claimed in one of  claims 1  to  14 ;   b) a nucleic acid comprising a DNA sequence comprising the sequences SEQ ID No. 11, SEQ ID No. 12, SEQ ID No. 13 and the sequences SEQ ID No. 15, SEQ ID No. 16 and SEQ ID No. 17;   c) a nucleic acid comprising a DNA sequence comprising the sequences SEQ ID No. 14 and SEQ ID No. 18, 19 or 20;   d) the corresponding RNA nucleic acids of the nucleic acids as defined in b) or c);   e) the complementary nucleic acids of the nucleic acids as defined in a), b) and c);   f) a nucleic acid of at least 18 nucleotides capable of hybridizing under conditions of high stringency with at least one of the CDRs of sequence SEQ ID Nos. 11 to 13 and 15 to 17.   
     
     
         16 . An isolated nucleic acid, characterized in that it is chosen from the following nucleic acids:
 a nucleic acid, DNA or RNA, coding for an antibody, or one of its functional fragments or derivatives, according to the present invention and wherein the nucleic sequence coding for the hinge region of said antibody comprises or has a sequence selected from the group consisting of the sequences SEQ ID Nos. 29 to 35 and SEQ ID Nos. 73 to 87.   
     
     
         17 . A vector comprising a nucleic acid as claimed in  claim 15  or  16 . 
     
     
         18 . A host cell comprising a vector as claimed in  claim 17 . 
     
     
         19 . A transgenic animal with the exception of man comprising at least one cell transformed by a vector as claimed in  claim 17 . 
     
     
         20 . A process for production of an antibody, or a divalent functional fragment or derivative thereof, as claimed in one of  claims 1  to  14 , characterized in that it comprises the following stages:
 a) culture in a medium and appropriate culture conditions of a cell as claimed in  claim 18 ; and 
 b) the recovery of said antibody, or a divalent functional fragment or derivative thereof, thus produced starting from the culture medium or said cultured cells. 
 
     
     
         21 . An antibody, or a divalent functional fragment or derivative thereof, capable of being obtained by a process as claimed in  claim 20 . 
     
     
         22 . The antibody of  claims 1  to  14  and  21  as a medicament. 
     
     
         23 . A 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  14 ,  21  or  22 . 
     
     
         24 . The composition of  claim 23 , characterized in that it comprises, moreover, as a combination product for simultaneous, separate of sequential use, an anti-tumoral antibody. 
     
     
         25 . The composition of  claim 23 , characterized in that it comprises, moreover, as a combination product for simultaneous, separate or sequential use, a cytotoxic/cytostatic agent. 
     
     
         26 . The composition of  claim 23 , characterized in that one, at least, of said antibodies, of a divalent functional fragment or derivative thereof, is conjugated with a cell toxin and/or a radioelement. 
     
     
         27 . The composition of  claim 25  or  26 , characterized in that said cytotoxic/cytostatic agent or said toxin and/or a radioelement is coupled chemically to at least one of the elements of said composition for simultaneous use. 
     
     
         28 . The composition as claimed in one of  claims 23  to  27  as a medicament. 
     
     
         29 . The use of an antibody, or a divalent functional fragment or derivative thereof, of  claims 1  to  14 ,  21  or  22  or of a composition of  claims 23  to  28  for the preparation of a medicament intended to inhibit the growth and/or the proliferation of tumor cells. 
     
     
         30 . The use of an antibody, or a divalent functional fragment or derivative thereof, of  claims 1  to  14 ,  21  or  22  or of a composition of  claims 23  to  28 , or the use of  claim 29 , for the preparation of a medicament intended for the prevention or for the treatment of cancer. 
     
     
         31 . The use of  claim 30 , characterized in that said cancer is a cancer chosen from prostate cancer, osteosarcomas, lung cancer, breast cancer, endometrial cancer, glyoblastoma or colon cancer. 
     
     
         32 . The use of  claim 30  or  31 , characterized in that said cancer is a HGF dependant and independent Met-activation related cancer. 
     
     
         33 . The use as defined by  claim 30 , for the prevention or the treatment of a patient in need thereof having a cancer characterized by ligand-independent activation of c-Met. 
     
     
         34 . The use as defined by  claim 30 , for the prevention or the treatment of a patient in need thereof having a cancer characterized by overexpression of c-Met. 
     
     
         35 . The use as defined by  claim 30  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. 
     
     
         36 . The use as defined by  claim 35 , 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. 
     
     
         37 . The use of  claim 35 , wherein said cancer is selected from the group consisting of renal cell carcinoma and gastric cancer. 
     
     
         38 . The use of  claim 36 , wherein said cancer is selected from the group consisting of renal cell carcinoma and gastric cancer. 
     
     
         39 . A method of in vitro diagnosis of illnesses induced by an overexpression or an underexpression of the c-Met receptor starting from a biological sample in which the abnormal presence of c-Met receptor is suspected, characterized in that said method comprises a step wherein said biological sample is contacted with an antibody of  claims 1  to  14 ,  21  or  22 , it being possible for said antibody to be, if necessary, labelled.