Antibody antagonists of ve-cadherin without adverse effects on vascular permeability

Abstract

The murine epitope sequence recognized by antibody E4B9 shares 100% homology with human VE-cadherin, so this antibody was examined to determine if it cross-reacts with human VE-cadherin. Western-blot analysis of several VE-cadherin expressing human and murine cells indicated that E4B9 indeed cross-reacts with human VE-cadherin (FIG. 6 ). This finding facilitates development of a “humanized” E4B9 antibody and its success in the preclinical development since its anti-tumor activity can be tested extensively in several mouse models.

1 - 22 . (canceled) 
     
     
         23 . A method of inhibiting angiogenesis associated with an opthalmological condition in a mammal which comprises:
 administering a pharmaceutical composition to a mammal having an opthalmological condition for a time and in an amount effective to inhibit angiogenesis associated with the opthalmological condition, the pharmaceutical composition comprising:
 an isolated monoclonal antibody or fragment thereof capable of specifically binding to a site on a mouse or human VE-cadherin, said site being within the about first 15 N-terminal amino acids of domain 1 of the VE-cadherin, wherein said antibody or fragment thereof is capable of inhibiting VE-cadherin mediated adherens junction formation in vitro but does not exert any significant or substantial effect on paracellular permeability in vitro, and 
 a pharmaceutically acceptable carrier or diluent. 
   
     
     
         24 . The method of  claim 23 , wherein the antibody or fragment thereof does not exert any significant or substantial effect on vascular permeability in vivo. 
     
     
         25 . The method of  claim 23 , wherein the antibody or fragment thereof inhibits formation of new adherens junctions without disturbing existing adherens junctions. 
     
     
         26 . The method of  claim 23 , wherein the antibody or fragment thereof is a single chain antibody, is humanized, is chimerized or is bispecific. 
     
     
         27 . The method of  claim 23 , wherein the antibody or fragment thereof is fused to a heterologous polypeptide. 
     
     
         28 . The method of  claim 23 , wherein the opthalmological condition is diabetic retinopathy, retrolental fibroplasia or neovascular glaucoma. 
     
     
         29 . The method of  claim 28 , wherein the antibody or fragment thereof does not exert any significant or substantial effect on vascular permeability in vivo. 
     
     
         30 . The method of  claim 28 , wherein the antibody or fragment thereof inhibits formation of new adherens junctions without disturbing existing adherens junctions. 
     
     
         31 . The method of  claim 28 , wherein the antibody or fragment thereof is a single chain antibody, is humanized, is chimerized or is bispecific. 
     
     
         32 . The method of  claim 28 , wherein the antibody or fragment thereof is fused to a heterologous polypeptide.