Vascular endothelial growth factor 2

Abstract

Disclosed are human VEGF2 polypeptides, biologically active, diagnostically or therapeutically useful fragments, analogs, or derivatives thereof, and DNA (RNA) encoding such VEGF2 polypeptides. Also provided are procedures for producing such polypeptides by recombinant techniques and antibodies and antagonists against such polypeptides. Such polypeptides may be used therapeutically for stimulating wound healing and for vascular tissue repair. Also provided are methods of using the antibodies and antagonists to inhibit tumor angiogenesis and thus tumor growth, inflammation, diabetic retinopathy, rheumatoid arthritis, and psoriasis.

1 . A method of treating a mammal having breast cancer characterized by endothelial cells that express Flt4 tyrosine kinase (Flt4), comprising a step of administering to said mammal a composition, said composition comprising an inhibitor of binding between Flt4 ligand protein and Flt4 expressed in cells of said organism, thereby inhibiting Flt4 function, wherein the inhibitor comprises a member selected from the group consisting of: 
 (a) an anti-Flt4 antibody or a polypeptide comprising an antigen binding fragment thereof;    (b) an anti-VEGF-C antibody or a polypeptide comprising an antigen binding fragment thereof;    (c) an anti-VEGF-D antibody or a polypeptide comprising an antigen binding fragment thereof; and    (d) a soluble polypeptide comprising a fragment of Flt4, wherein the polypeptide and the fragment are capable of binding to human VEGF-C (SEQ ID NO: 2).    
     
     
         2 . A method according to  claim 1 , wherein the mammal is human.  
     
     
         3 . A method according to  claim 2 , comprising a screening step preceding the administering step, wherein the screening step comprises screening a human to identify breast cancer characterized by endothelial cells expressing FIt4; and wherein the administering step comprises administering the composition to a human identified by the screening step as having breast cancer characterized by endothelial cells expressing Flt4.  
     
     
         4 . A method according to any one of claims  2 - 3  wherein the inhibitor comprises a member selected from the group consisting of: 
 (a) an anti-Flt4 antibody or a polypeptide comprising an antigen binding fragment thereof; and    (b) a soluble polypeptide comprising a fragment of Flt4, wherein the polypeptide and the fragment are capable of binding to human VEGF-C (SEQ ID NO: 2).    
     
     
         5 . A method according to  claim 1 , wherein the inhibitor further comprises an anti-neoplastic agent conjugated to the antibody or polypeptide.  
     
     
         6 . A method according to  claim 1 , wherein the composition further comprises a pharmaceutically acceptable diluent, adjuvant, or carrier.  
     
     
         7 . A method of treating a human having breast cancer characterized by endothehlial cells that express Flt4 tyrosine kinase (Flt4), comprising a step of administering to said human a composition, said composition comprising an inhibitor of binding between FIt4 ligand protein and FIt4 expressed in cells of said human, thereby inhibiting Flt4 function, wherein the inhibitor comprises a polypeptide comprising an FIt4 binding fragment of human prepro-VEGF-C (SEQ ID NO: 2) or human prepro-VEGF-D conjugated to an antineoplastic agent.  
     
     
         8 . A method according to  claim 7 , comprising a screening step preceding the administering step, wherein the screening step comprises screening a human to identify breast cancer characterized by endothelial cells expressing Flt4; and wherein the administering step comprises administering the composition to a human identified by the screening step as having breast cancer characterized by endothelial cells expressing Flt4.  
     
     
         9 . A method of treating a mammal having breast cancer characterized by endothelial cells that express a tyrosine kinase receptor capable of binding VEGF-C, comprising a step of administering to said mammal a composition, said composition comprising an inhibitor of binding between VEGF-C and the receptor expressed in cells of said organism, thereby inhibiting receptor function, wherein the inhibitor comprises a member selected from the group consisting of: 
 (a) an anti-VEGF-C antibody or a polypeptide comprising an antigen binding fragment thereof; and    (b) a soluble polypeptide comprising a fragment of the receptor, wherein the polypeptide and the fragment are capable of binding to human VEGF-C (SEQ ID NO: 2).    
     
     
         10 . A method according to  claim 9 , wherein the mammal is human.  
     
     
         11 . A method according to  claim 10 , comprising a screening step preceding the administering step, wherein the screening step comprises screening a human to identify breast cancer characterized by endothelial cells expressing the receptor; and wherein the administering step comprises administering the composition to a human identified by the screening step as having breast cancer characterized by endothelial cells expressing the receptor.  
     
     
         12 . A method according to any one of claims  10 - 11  wherein the inhibitor comprises a soluble polypeptide comprising a fragment of the receptor, wherein the polypeptide and the fragment are capable of binding to human VEGF-C (SEQ ID NO: 2).  
     
     
         13 . A method according to  claim 9 , wherein the inhibitor further comprises an anti-neoplastic agent conjugated to the antibody or polypeptide.  
     
     
         14 . A method according to  claim 9 , wherein the composition further comprises a pharmaceutically acceptable diluent, adjuvant, or carrier.  
     
     
         15 . A method of treating a human having breast cancer characterized by endothelial cells that express a tyrosine kinase receptor capable of binding VEGF-C, comprising a step of administering to said human a composition, said composition comprising an inhibitor of binding between VEGF-C and the receptor expressed in cells of said human, thereby inhibiting receptor function, wherein the inhibitor comprises a polypeptide comprising a receptor binding fragment of human prepro-VEGF-C (SEQ ID NO: 2) conjugated to an antineoplastic agent.  
     
     
         16 . A method according to  claim 15 , comprising a screening step preceding the administering step, wherein the screening step comprises screening a human to identify breast cancer characterized by endothelial cells expressing the receptor; and wherein the administering step comprises administering the composition to a human identified by the screening step as having breast cancer characterized by endothelial cells expressing the receptor.