Immunointeractive molecules

Abstract

The present invention relates generally to immunointeractive molecules and more particularly antibodies which bind to vascular endothelial 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 antibody or antigen-binding fragment thereof which binds to mammalian VEGF-B or an antibody-binding portion thereof, wherein the binding of the antibody to VEGF-B antagonizes binding between VEGF-B and VEGF-R1.  
     
     
         2 . The antibody of  claim 1  wherein the antibody Is a monoclonal antibody.  
     
     
         3 . The antibody of  claim 2  wherein the VEGF-B is of human origin.  
     
     
         4 . The antibody of  claim 3  wherein the antibody is a human antibody.  
     
     
         5 . The antibody of  claim 3  wherein the antibody is a deimmunized antibody.  
     
     
         6 . The antibody of  claim 3  wherein the antibody is a humanized antibody.  
     
     
         7 . The antibody of any one of  claims 1  to  6  wherein the antibody is a fragment of a whole antibody.  
     
     
         8 . The antibody of  claim 7  wherein the antibody fragment is an Fv, Fab, Fab′ or F(ab′) 2  fragment or a single chain form thereof.  
     
     
         9 . A deimmunized, humanized or human monoclonal antibody or an antigen-binding fragment thereof which binds to human VEGF-B or an antibody-binding portion thereof and which inhibits or otherwise reduces VEGF-B binding to VEGF-R1.  
     
     
         10 . A method for producing an antibody having specificity for human VEGF-B, said method comprising immunizing a non-human animal with a VEGF-B polypeptide, or 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.  
     
     
         11 . A method for producing a hybridoma cell line comprising immunizing a non-human animal with human VEGF-B or 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 VEGF-B or a fragment thereof.  
     
     
         12 . The method of  claim 10  or  11  wherein the non-human animal is a mouse.  
     
     
         13 . The method of  claim 12  wherein the mouse is a transgenic mouse which produces human antibodies.  
     
     
         14 . A composition comprising an antibody of any one of  claims 1  to  9 .  
     
     
         15 . A method of treating a disease condition in a mammal comprising administering to said mammal an effective amount of an antibody of any one of  claims 1  to  9  or a composition of  claim 14 .  
     
     
         16 . The method of  claim 15  wherein the mammal is a human.  
     
     
         17 . The method of  claim 16  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.  
     
     
         18 . 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 a deimmunized, humanized or human antibody specific for VEGF-B for a time and under conditions sufficient to inhibit or otherwise reduce VEGF-B signaling via VEGF-R1.  
     
     
         19 . The method of  claim 18  wherein the mammal is a human.  
     
     
         20 . Use of deimmunized, humanized or human monoclonal antibody specific for human VEGF-B or its equivalent in the manufacture of a medicament in the treatment or prophylaxis of a vascular condition in a subject.  
     
     
         21 . The use of  claim 20  wherein the subject is a human.