Compositions and methods for treatment of neovascular diseases

Abstract

The present invention provides compositions and methods of treating neovascular diseases, such as a retinal neovascular diseases and tumors, by administering to a patient suffering from a neovascular disease or tumor a vascular development inhibiting amount of a combination of the angiogenesis suppressing drugs comprising an angiostatic fragment of tryptophanyl-tRNA synthetase (TrpRS) and at least one compound selected from the group consisting of a vascular endothelial growth factor (VEGF) signaling inhibitor and an integrin signaling inhibitor. Compositions for use in the methods include an admixture of an angiostatic fragment of tryptophanyl-tRNA synthetase (TrpRS) and at least one of a vascular endothelial growth factor (VEGF) signaling inhibitor and an integrin signaling inhibitor, together with a pharmaceutically acceptable excipient.

1 . A composition comprising an angiostatic fragment of tryptophanyl-tRNA synthetase (TrpRS) and at least one anti-angiogenic agent selected from the group consisting of a VEGF aptamer and an angiostatic integrin antagonist. 
     
     
         2 . The composition of  claim 1  wherein the angiostatic fragment of TrpRS has the amino acid residue sequence of SEQ ID NO: 1 or SEQ ID NO: 2. 
     
     
         3 . The composition of  claim 2  wherein the at least one anti-angiogenic agent comprises a VEGF- 165 aptamer. 
     
     
         4 . The composition of  claim 3  wherein the VEGF-165 aptamer is a 2′-fluoropyrimidine RNA-based VEGF-165 aptamer. 
     
     
         5 . The composition of  claim 4  wherein the 2′-fluoropyrimidine RNA-based VEGF-165 aptamer is pegaptanib sodium. 
     
     
         6 . The composition of  claim 1  wherein the at least one anti-angiogenic agent comprises an angiostatic antagonist of α v β 3  integrin or α v β 5  integrin. 
     
     
         7 . The composition of  claim 6  wherein the angiostatic antagonist of α v β 3  integrin or α v β 5  integrin has the formula of Compound (1): 
       
         
           
           
               
               
           
         
       
     
     
         8 . The composition of  claim 1  wherein the at least one anti-angiogenic agent comprises pegaptanib sodium and a compound having the formula of Compound (1): 
       
         
           
           
               
               
           
         
       
     
     
         9 . The composition of  claim 1  further comprising at least one therapeutic agent selected from the group consisting of an angiostatic steroid, an anti-neoplastic agent, an anti-bacterial agent, an anti-viral agent, and an anti-inflammatory agent. 
     
     
         10 . The composition of claim  13  wherein the angiostatic fragment of TrpRS is a dimer. 
     
     
         11 . A pharmaceutical composition comprising a composition of  claim 1  and a pharmaceutically acceptable carrier therefor.