Oncolytic viruses targeting stat3

Abstract

This disclosure relates to modified viruses, e.g., oncolytic vaccinia viruses, which have been modified to contain an exogenous nucleic acid that expresses a protein that modulates STAT3 activity. It is based, at least in part, on the discovery that vaccinia viruses modified to contain nucleic acid encoding PIAS3 and that express PIAS3 or a fragment thereof can inhibit STAT3 activity and enhance the anti-cancer activity of the vaccinia virus. Accordingly, this disclosure provides for oncolytic vaccinia viruses and methods of using them in the treatment of cancers.

1 . A virus comprising an exogenous nucleic acid encoding a suppressor of cytokine signaling 3 (SOCS3) protein or a functional fragment thereof. 
     
     
         2 . The virus of  claim 1 , wherein the SOCS3 protein or functional fragment thereof comprises a human SOCS3 protein or a functional fragment thereof, or a conservative substitution thereof. 
     
     
         3 . The virus of  claim 1 , wherein the SOCS3 protein or functional fragment thereof comprises an amino acid sequence that is at least about 85% identical to the amino acid sequence set forth in SEQ ID NO: 28, or a conservative substitution thereof. 
     
     
         4 . The virus of  claim 1 , wherein the SOCS3 protein or functional fragment thereof comprises an amino acid sequence that is at least about 85% identical to the amino acid sequence set forth in SEQ ID NO: 30, or a conservative substitution thereof. 
     
     
         5 . The virus of  claim 1 , wherein the SOCS3 protein or functional fragment thereof comprises the amino acid sequence set forth in SEQ ID NO: 28. 
     
     
         6 . The virus of  claim 1 , wherein the SOCS3 protein or functional fragment thereof comprises the amino acid sequence set forth in SEQ ID NO: 30. 
     
     
         7 . The virus of  claim 1 , wherein the exogenous nucleic acid comprises a nucleotide sequence that is at least about 85% identical to the nucleotide sequence set forth in SEQ ID NO: 29. 
     
     
         8 . The virus of  claim 1 , wherein the exogenous nucleic acid comprises a nucleotide sequence that is at least about 85% identical to the nucleotide sequence set forth in SEQ ID NO: 31. 
     
     
         9 . The virus of  claim 1 , wherein the exogenous nucleic acid comprises the nucleotide sequence set forth in SEQ ID NO: 29. 
     
     
         10 . The virus of  claim 1 , wherein the exogenous nucleic acid comprises the nucleotide sequence set forth in SEQ ID NO: 31. 
     
     
         11 . The virus of  claim 1 , wherein the exogenous nucleic acid further encodes a cell-penetrating protein. 
     
     
         12 . The virus of  claim 11 , wherein the cell-penetrating protein comprises a TAT protein of HIV-1 or a functional fragment thereof, a YopM protein or a functional fragment thereof, a transportan protein or a functional fragment thereof, a penetratin or a functional fragment thereof, a poly-arginine, or a combination thereof. 
     
     
         13 . The virus of  claim 11 , wherein the cell-penetrating protein is encoded by a nucleotide sequence selected from the group consisting of SEQ ID NOs: 12-14, 17, 19, 21 and 23. 
     
     
         14 . The virus of  claim 11 , wherein the cell penetrating protein comprises a TAT protein or a functional fragment thereof, wherein the TAT protein or functional fragment thereof comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 15, 16, 18, 20 and 22, and conservative substitutions thereof. 
     
     
         15 . The virus of  claim 1 , wherein the virus comprises an oncolytic vaccinia virus. 
     
     
         16 . The virus of  claim 15 , wherein the oncolytic vaccinia virus comprises a Western Reserve strain. 
     
     
         17 . A pharmaceutical composition comprising the virus of  claim 1 , and an excipient. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the excipient comprises a buffering agent, a stabilizer, an antioxidant, a binder, a diluent, a dispersing agent, a rate controlling agent, a lubricant, a glidant, a disintegrant, a plasticizer, a preservative, or a combination thereof. 
     
     
         19 . The pharmaceutical composition of  claim 17 , wherein the pharmaceutical composition further comprises a preservative, a diluent, a carrier, or a combination thereof. 
     
     
         20 . The pharmaceutical composition of  claim 17 , comprising an additional oncolytic vaccinia virus.