Bi-specific antibodies for enhanced tumor selectivity and inhibition and uses thereof

Abstract

A heterodimeric bispecific immunoglobulin molecule includes a first Fab or scFv fragment which specifically binds to EGFR, and a second Fab or scFv fragment which specifically binds to c-MET, and an antibody hinge region, an antibody CH2 domain and an antibody CH3 domain including a hybrid protein-protein interaction interface domain. Each of the interaction interface domains is formed by an amino acid segment of the CH3 domain of a first member and an amino acid segment of the CH3 domain of a second member. The hybrid protein-protein interface domain of the first chain is interacting with the protein-protein-interface of the second chain by homodimerization of a corresponding amino acid segment of the same member of the immunoglobulin superfamily within interaction domains.

1 - 34 . (canceled) 
     
     
         35 . An antibody or antigen-binding fragment thereof that binds to c-MET, comprising:
 a)
 a light chain variable region, VL, selected from the group consisting of SEQ ID NO: 31, SEQ ID NO: 47, and SEQ ID NO: 51, and 
 a heavy chain variable region, VH, selected from the group consisting of SEQ ID NO: 32 and SEQ ID NO: 48; 
   b)
 a VL of SEQ ID NO: 33, and 
 a VH selected from the group consisting of SEQ ID NO: 34 and SEQ ID NO: 52; or 
   c) a humanized version of the antibody or antigen-binding fragment thereof of a) or b).   
     
     
         36 . The antibody or antigen-binding fragment thereof according to  claim 35 , wherein said antibody or antigen-binding fragment thereof is an immunoglobulin molecule comprising a Fab or scFv fragment that binds to c-MET. 
     
     
         37 . The antibody or antigen-binding fragment thereof according to  claim 35 , wherein said antibody or antigen-binding fragment thereof binds c-MET with a K D  of at least 5×10 −8  M. 
     
     
         38 . The antibody or antigen-binding fragment thereof according to  claim 35 , wherein said antibody or antigen-binding fragment thereof is a one-armed monovalent antibody. 
     
     
         39 . The antibody or antigen-binding fragment thereof according to  claim 35 , comprising:
 the antibody or antigen-binding fragment of a) or the humanized version of the antibody or antigen-binding fragment thereof of a).   
     
     
         40 . The antibody or antigen-binding fragment thereof according to  claim 35 , comprising:
 the VL of SEQ ID NO: 31 and the VH of SEQ ID NO: 32; or   a humanized version of the antibody or antigen-binding fragment thereof comprising the VL of SEQ ID NO: 31 and the VH of SEQ ID NO: 32.   
     
     
         41 . The antibody or antigen-binding fragment thereof according to  claim 35 , comprising:
 the VL of SEQ ID NO: 51 and the of SEQ ID NO: 32; or   a humanized version of the antibody or antigen-binding fragment thereof comprising the VL of SEQ ID NO: 51 and the VH of SEQ ID NO: 32.   
     
     
         42 . The antibody or antigen-binding fragment thereof according to  claim 35 , comprising:
 the VL of SEQ ID NO: 47 and the VH of SEQ ID NO: 48; or   a humanized version of the antibody or antigen-binding fragment thereof comprising the VL of SEQ ID NO: 47 and the VH of SEQ ID NO: 48.   
     
     
         43 . The antibody or antigen-binding fragment thereof according to  claim 35 , comprising:
 the VL of SEQ ID NO: 33 and the VH selected from the group consisting of SEQ ID NO: 34 and SEQ ID NO: 52; or   a humanized version of the antibody or antigen-binding fragment thereof comprising the VL of SEQ ID NO: 33 and the VH of SEQ ID NO: 34 or 52.   
     
     
         44 . The antibody or antigen-binding fragment thereof according to  claim 35 , comprising:
 the VL of SEQ ID NO: 33 and the VH of SEQ ID NO: 34; or   a humanized version of the antibody or antigen-binding fragment comprising the VL of SEQ ID NO: 33 and the VH of SEQ ID NO: 34.   
     
     
         45 . The antibody or antigen-binding fragment thereof according to  claim 35 , comprising:
 the VL of SEQ ID NO: 33 and the of SEQ ID NO: 52; or   a humanized version of the antibody or antigen-binding fragment thereof comprising the VL of SEQ ID NO: 33 and the VH of SEQ ID NO: 52.