Vegf-related protein

Abstract

A human VEGF-related protein (VRP) has been identified and isolated that binds to, and stimulates the phosphorylation of, the receptor tyrosine kinase Flt4. The VRP is postulated to be a third member of the VEGF protein family. Also provided are antibodies that bind to VRP and neutralize a biological activity of VRP, compositions containing the VRP or antibody, methods of use, chimeric polypeptides, and a signal polypeptide for VRP.

1 . A monoclonal antibody that specifically binds to amino acid residues 1 to 157 or 21 to 157 of SEQ ID NO:3. 
     
     
         2 . The monoclonal antibody of  claim 1 , wherein the antibody neutralizes a biological activity of VRP. 
     
     
         3 . The monoclonal antibody of  claim 2 , wherein the biological activity of VRP is promoting neovascularization, vascular permeability, or vascular endothelial cell growth in a mammal. 
     
     
         4 . The monoclonal antibody of  claim 2 , comprising a humanized antibody. 
     
     
         5 . The monoclonal antibody of  claim 2 , comprising a chimeric antibody. 
     
     
         6 . A composition comprising a monoclonal antibody of  claim 2  with a pharmaceutically acceptable carrier. 
     
     
         7 . A method for treating disease or disorders characterized by neovascularization or vascular permeability in a mammal, the method comprising administering to the mammal an effective amount of a monoclonal antibody of  claim 2 . 
     
     
         8 . A method for treating a dysfunctional state characterized by excessive activation or inhibition of a receptor for VRP in a mammal comprising administering to the mammal an effective amount of a monoclonal antibody of  claim 2 . 
     
     
         9 . A method for detecting VRP expression in a cell, tissue, or serum comprising contacting the cell, tissue, or serum with a monoclonal antibody of  claim 2  and assaying for bound monoclonal antibody to detect the presence of VRP. 
     
     
         10 . A VRP antagonist comprising a VRP receptor fusion protein capable of binding VRP. 
     
     
         11 . The VRP antagonist of  claim 10 , the VRP receptor fusion protein comprising an extracellular domain of a Flt-4 receptor fused to an immunoglobulin. 
     
     
         12 . The VRP antagonist of  claim 11 , wherein the extracellular domain of the Flt-4 receptor is fused to a Fc region of a human IgG heavy chain. 
     
     
         13 . The VRP antagonist of  claim 11 , comprising peptides of 70, 80, and 150 kDa. 
     
     
         14 . The VRP antagonist of  claim 13 , the 70 and 150 kDa peptides comprising independently amino acid sequence of SEQ ID NO:9. 
     
     
         15 . The VRP antagonist of  claim 13 , the 80 kDa peptide comprising amino acid sequence SEQ ID NO:10. 
     
     
         16 . A method for stimulating tyrosine phosphorylation of a Flt-4 receptor, comprising contacting the receptor with antiserum to a VRP antagonist of  claim 10 . 
     
     
         17 . A method for treating a dysfunctional state characterized by excessive activation or inhibition of a receptor for VRP in a mammal comprising administering to the mammal an effective amount of a VRP antagonist of  claim 11 . 
     
     
         18 . A method for detecting VRP expression in a cell, tissue, or serum comprising contacting the cell, tissue, or serum with a VRP antagonist of  claim 10  and assaying for VRP by detecting VRP antagonist bound to the cell, tissue, or serum. 
     
     
         19 . A composition comprising a VRP antagonist of  claim 10  with a pharmaceutically acceptable carrier. 
     
     
         20 . A method for inhibiting endothelial cell growth mediated by VRP in a mammal, the method comprising administering to the mammal a VRP antagonist of  claim 10  in an amount effective to inhibit the growth of endothelial cells. 
     
     
         21 . A method for inhibiting neovascularization or vascular permeability in a mammal, the method comprising administering to the mammal an effective amount of a VRP antagonist of  claim 10 . 
     
     
         22 . A method for purifying VRP comprising amino acid residues 1 to 157 or 21 to 157 of SEQ ID NO:3 from a mixture, the method comprising immobilizing a VRP antagonist of  claim 11  on a suitable support, contacting the immobilized antagonist with the mixture, and removing the VRP bound to the immobilized antagonist with a solvent.