Bispecific, bivalent anti-vegf/anti-ang2 antibodies

Abstract

The present invention relates to bispecific, bivalent antibodies against human vascular endothelial growth factor (VEGF/VEGF-A) and against human angiopoietin-2 (ANG-2), methods for their production, pharmaceutical compositions containing said antibodies, and uses thereof.

1 . A bispecific, bivalent antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein
 i) said first antigen-binding site comprises as heavy chain variable domain (VH) the amino acid sequence of SEQ ID NO: 1, and as light chain variable domain (VL) the amino acid sequence of SEQ ID NO: 2; and wherein   ii) said second antigen-binding site comprises as heavy chain variable domain (VH) the amino acid sequence of SEQ ID NO: 3, and as light chain variable domain (VL) the amino acid sequence of SEQ ID NO: 4.   
     
     
         2 . The bispecific antibody according to  claim 1  comprising
 a) a heavy chain and a light chain of a first full length antibody that specifically binds to VEGF; and 
 b) a modified heavy chain and a modified light chain of a full length antibody that specifically binds to ANG-2, wherein the constant domains CL and CH1 are replaced by each other. 
 
     
     
         3 . The bispecific antibody according to  claim 2  wherein
 a) the heavy chain of the first full length antibody comprises the amino acid sequence of SEQ ID NO: 7, and the light chain of the first full length antibody comprises the amino acid sequence of SEQ ID NO: 5, and wherein 
 b) the modified heavy chain of the second full length antibody comprises the amino acid sequence of SEQ ID NO: 8, and the modified light chain of the second full length antibody comprises the amino acid sequence of SEQ ID NO: 6. 
 
     
     
         4 . The bispecific antibody according to  claim 2  wherein
 a) the heavy chain of the first full length antibody comprises the amino acid sequence of SEQ ID NO: 11, and the light chain of the first full length antibody comprises the amino acid sequence of SEQ ID NO: 9, and wherein 
 b) the modified heavy chain of the second full length antibody comprises the amino acid sequence of SEQ ID NO: 12, and the modified light chain of the second full length antibody comprises the amino acid sequence of SEQ ID NO: 10. 
 
     
     
         5 . The bispecific antibody according to  claim 2 , wherein
 a) the heavy chain of the first full length antibody comprises the amino acid sequence of SEQ ID NO: 15, and the light chain of the first full length antibody comprises the amino acid sequence of SEQ ID NO: 13, and wherein   b) the modified heavy chain of the second full length antibody comprises the amino acid sequence of SEQ ID NO: 16, and the modified light chain of the second full length antibody comprises the amino acid sequence of SEQ ID NO: 14.   
     
     
         6 . A pharmaceutical composition comprising the antibody according to any one of  claims 1  to  5 . 
     
     
         7 . A method of treating a patient suffering from cancer, comprising administering to the patient an effective amount of the antibody according to any one of  claims 1  to  5 . 
     
     
         8 . The method of  claim 7 , wherein the cancer is colorectal cancer, lung cancer, breast cancer, renal cancer, ovarian cancer or glioblastoma. 
     
     
         9 . A method of treating a patient suffering from vascular diseases, comprising administering to the patient an effective amount of the antibody according to any one of  claims 1  to  5 . 
     
     
         10 . A method of inhibiting angiogenesis in a patient having a pathological condition associated with angiogenesis, comprising administering to the patient an effective amount of the antibody according to any one of  claims 1  to  5 . 
     
     
         11 . An isolated nucleic acid encoding the bispecific antibody according to any one of  claims 1  to  5 . 
     
     
         12 . An expression vector comprising the nucleic acid according  claim 11 . 
     
     
         13 . A prokaryotic or eukaryotic host cell comprising the nucleic acid according to  claim 11 . 
     
     
         14 . A method for producing the bispecific antibody according to any one of  claims 1  to  5 , comprising culturing the host cell of  claim 13  so that the antibody is produced. 
     
     
         15 . The method of  claim 14 , further comprising recovering said antibody from the host cell. 
     
     
         16 . A bispecific antibody obtained by the method of  claim 14 . 
     
     
         17 . A bispecific, bivalent antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein the antibody comprises the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8. 
     
     
         18 . A bispecific, bivalent antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein the antibody comprises the amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12. 
     
     
         19 . A bispecific, bivalent antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein the antibody comprises the amino acid sequences of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.