Immunointeractive molecules

Abstract

The present invention relates generally to immunointeractive molecules and more particularly antibodies which bind to vascular endothielial growth factor-B (VEGF-B) or its functional or structural equivalent and inhibit the biological activity of VEGF-B. In particular the present invention relates to deimmunized such as humanized or human antibodies that bind to VEGF-B and inhibit the biological activity of VEGF-B. These antibodies have uses in the treatment or prevention of diseases associated with perturbations in normal vasculogenesis or angiogenesis or vascular remodelling. The present invention further contemplates a method of modulating diseases associated with perturbations in normal vasculogenesis or angiogenesis or vascular remodelling by the administration of the subject antibodies. The present invention further provides an assay system useful for identifying antibodies which bind to VEGF-B and block the biological activity of VEGF-B. Accordingly, a method of screening for inhibitors of the biological activity of VEGF-B is also provided.

1 . An isolated antibody or an antigen-binding fragment thereof which binds to human VEGF-B, wherein the binding of the antibody or the fragment thereof to VEGF-B antagonizes binding between VEGF-B and VEGF-R1. 
     
     
         2 . The antibody or antigen-binding fragment of  claim 1 , wherein said antibody competes with monoclonal antibody 2H10 in binding to human VEGF-B. 
     
     
         3 . The antibody or antigen-binding fragment of  claim 1 , wherein said antibody binds to the same epitope in human VEGF-B as monoclonal antibody 2H10. 
     
     
         4 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         5 . The antibody or antigen-binding fragment of  claim 1 , wherein said antibody is a chimeric antibody comprising a constant region of a human antibody. 
     
     
         6 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody is a human antibody. 
     
     
         7 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody is a humanized antibody. 
     
     
         8 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody fragment is an Fv, Fab, Fab′ or F(ab′) 2  fragment. 
     
     
         9 . The antibody or antigen-binding fragment of  claim 1 , wherein said antibody is in a single chain form. 
     
     
         10 . A composition comprising the antibody or antigen-binding fragment of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         11 . A method of treating a disease condition in a mammal comprising administering to said mammal an effective amount of the antibody or antigen-binding fragment of  claim 1 . 
     
     
         12 . The method of  claim 1  wherein the mammal is a human. 
     
     
         13 . The method of  claim 12  wherein the disease condition is pulmonary hypertension, the growth of angiogenic tumors and the spread or metastases of cancer cells, chronic inflammatory diseases such as rheumatoid arthritis and any other VEGF-B-mediated diseases or conditions where there is known to be a significant angiogenic component. 
     
     
         14 . A method for the treatment or prophylaxis of a condition mediated by VEGF-B, said method comprising administering to a subject an effective amount of the antibody or antigen-binding fragment according to any one of  claims 5 - 7 , for a time and under conditions sufficient to inhibit or otherwise reduce VEGF-B signaling via VEGF-R1. 
     
     
         15 . The method of  claim 14  wherein the mammal is a human. 
     
     
         16 . A method for producing an antibody having specificity for human VEGF-B, said method comprising immunizing a non-human animal with a human VEGF-B polypeptide or an immunogenic part thereof, for a time and under conditions sufficient for antibodies directed against the VEGF-B polypeptide to be generated in said animal and then subjecting said antibody to deimmunized or humanization means. 
     
     
         17 . A method for producing a hybridoma cell line comprising immunizing a non-human animal with human VEGF-B or an immunogenic part thereof harvesting spleen cells from the immunized animal, fusing the harvested spleen cells to a myeloma cell line to generate hybridoma cells and identifying a hybridoma cell line that produces a monoclonal antibody that binds said VEGF-B or a fragment thereof. 
     
     
         18 . The method of  claim 16  or  17  wherein the non-human animal is a mouse. 
     
     
         19 . The method of  claim 16  or  17  wherein the non-human animal is a transgenic animal which produces human antibodies.