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) a T-cell protein tyrosine phosphatase (TCPTP) protein or a functional fragment thereof, or (b) a dominant-negative mutant signal transducer and activator of transcription 3 (STAT3) protein or a functional fragment thereof. 
     
     
         2 . The virus of  claim 1 , wherein the exogenous nucleic acid encodes the TCPTP protein or functional fragment thereof, wherein the TCPTP protein or functional fragment thereof comprises a human TCPTP protein or a functional fragment thereof, or a conservative substitution thereof. 
     
     
         3 . The virus of  claim 1 , wherein the exogenous nucleic acid encodes the TCPTP protein or functional fragment thereof, wherein the TCPTP 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: 32, SEQ ID NO: 34, or a conservative substitution thereof. 
     
     
         4 . The virus of  claim 1 , wherein the exogenous nucleic acid encodes the TCPTP protein or functional fragment thereof, wherein the TCPTP protein or functional fragment thereof comprises the amino acid sequence set forth in SEQ ID NO: 32 or SEQ ID NO: 34. 
     
     
         5 . The virus of  claim 1 , wherein the exogenous nucleic acid encodes the TCPTP protein or functional fragment thereof, 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: 33 or SEQ ID NO: 35. 
     
     
         6 . The virus of  claim 1 , wherein the exogenous nucleic acid encodes the TCPTP protein or functional fragment thereof, wherein the exogenous nucleic acid comprises the nucleotide sequence set forth in SEQ ID NO: 33 or SEQ ID NO: 35. 
     
     
         7 . The virus of  claim 1 , wherein the exogenous nucleic acid encodes the dominant-negative mutant STAT3 protein or functional fragment thereof, wherein the dominant-negative mutant STAT3 protein or functional fragment thereof comprises a human dominant-negative mutant STAT3 protein or functional fragment thereof, or a conservative substitution thereof. 
     
     
         8 . The virus of  claim 1 , wherein the exogenous nucleic acid encodes the dominant-negative mutant STAT3 protein or functional fragment thereof, wherein the dominant-negative mutant STAT3 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: 36, SEQ ID NO: 38, or a conservative substitution thereof. 
     
     
         9 . The virus of  claim 1 , wherein the exogenous nucleic acid encodes the dominant-negative mutant STAT3 protein or functional fragment thereof, wherein the dominant-negative mutant STAT3 protein or functional fragment thereof comprises the amino acid sequence set forth in SEQ ID NO: 36 or SEQ ID NO: 38. 
     
     
         10 . The virus of  claim 1 , wherein the exogenous nucleic acid encodes the dominant-negative mutant STAT3 protein or functional fragment thereof, wherein the dominant-negative mutant STAT3 protein or functional fragment thereof comprises a nucleotide sequence that is at least about 85% identical to the nucleotide sequence set forth in SEQ ID NO: 37 or SEQ ID NO: 39. 
     
     
         11 . The virus of  claim 1 , wherein the exogenous nucleic acid encodes the dominant-negative mutant STAT3 protein or functional fragment thereof, wherein the dominant-negative mutant STAT3 protein or functional fragment thereof comprises the nucleotide sequence set forth in SEQ ID NO: 37 or SEQ ID NO: 39. 
     
     
         12 . The virus of  claim 1 , wherein the exogenous nucleic acid further encodes a cell-penetrating protein. 
     
     
         13 . The virus of  claim 12 , 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. 
     
     
         14 . The virus of  claim 12 , wherein the cell-penetrating protein (a) is encoded by a nucleotide sequence selected from the group consisting of SEQ ID NOs: 12-14, 17, 19, 21 and 23, or (b) 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.