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 is 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 .- 14 . (canceled) 
     
     
         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  claim 1 ;   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 . (canceled) 
     
     
         17 . A vector comprising a nucleic acid as claimed in  claim 15 . 
     
     
         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  claim 1 , 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 . (canceled) 
     
     
         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  claim 1 . 
     
     
         24 . The composition of  claim 23 , characterized in that it comprises, moreover, as a combination product for simultaneous, separate or sequential use, an anti-tumoral antibody. 
     
     
         25 .- 28 . (canceled) 
     
     
         29 . A method for inhibiting the growth or proliferation of a MET amplified or c-Met overexpressing tumor comprising administering an effective dose of an anti-cMET monoclonal antibody, or a cMET-binding fragment thereof, 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, and a hinge region comprising the amino acid sequence SEQ ID No. 56. 
     
     
         30 . The method of  claim 29 , wherein said hinge region comprises the amino acid sequence SEQ ID No. 57. 
     
     
         31 . The method of  claim 29 , wherein said hinge region comprises the amino acid sequence SEQ ID No.  21 . 
     
     
         32 . The method of  claim 29 , wherein said hinge region comprises the amino acid sequence SEQ ID No. 28. 
     
     
         33 . The method of  claim 29 , wherein said antibody or binding fragment comprises:
 a heavy chain variable domain comprising the amino acid sequence SEQ ID NO. 4;   a light chain variable domain comprising the amino acid sequence SEQ ID NO. 10: and wherein said hinge region comprises the amino acid sequence SEQ ID NO. 28.   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 .- 35 . (canceled) 
     
     
         36 . The method according to  claim 29 , wherein said antibody or binding fragment is a chimeric antibody. 
     
     
         37 . The method according to  claim 29 , wherein said antibody or binding fragment is a human antibody. 
     
     
         38 . The method according to  claim 29 , wherein said antibody or binding fragment is a humanized antibody. 
     
     
         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  claim 1 , it being possible for said antibody to be, if necessary, labelled.