High mobility group box i mutant

Abstract

This disclosure relates to modified viruses, e.g., oncolytic vaccinia viruses, which have been modified to contain an exogenous nucleic acid that codes for a variant HMGB1 protein. It provides, at least in part, that vaccinia viruses modified to contain nucleic acid encoding variant HMGB1 and that express a variant HMGB1 or a fragment thereof can achieve a synergistic effect in combination with chemotherapy. Further, this disclosure provides for oncolytic vaccinia viruses and methods of using them in the treatment of various cancers.

What is claimed is: 
     
         1 . A composition, wherein the composition comprises:
 an oncolytic virus, wherein the oncolytic virus comprises an exogenous nucleic acid that codes for a variant High Mobility Group Box 1 (HMGB1) protein, wherein the variant HMGB1 protein comprises at least one variant nuclear localization signal (NLS), thereby allowing for increased cytoplasmic location of the variant HMGB1 compared to a wild type HMGB1.   
     
     
         2 . The composition of  claim 1 , wherein at least one variant NLS sequence comprises a variant in residue 35, 42, or 181, and wherein residue numbering is based on SEQ ID NO: 16. 
     
     
         3 . The composition of  claim 2 , wherein the at least one variant NLS sequence comprises two variant NLS sequences. 
     
     
         4 . The composition of  claim 3 , wherein the two variant NLS sequences comprises a variant in two of residues 35, 42, or 181, and wherein residue numbering is based on SEQ ID NO: 16. 
     
     
         5 . The composition of  claim 1 , wherein the at least one variant NLS sequence comprises a variation in an NLS1 region. 
     
     
         6 . The composition of  claim 1 , wherein the at least one variant NLS sequence comprises a variation in an NLS2 region. 
     
     
         7 . The composition of  claim 1 , wherein the exogenous nucleic acid further comprises a sequence coding for a protein that stabilizes the variant HMGB1 protein. 
     
     
         8 . The composition of  claim 7 , wherein the sequence coding for the protein that stabilizes the variant HMGB1 protein is located 3′ of the variant HMGB1 sequence. 
     
     
         9 . The composition of  claim 7 , wherein the protein that stabilizes the variant HMGB1 protein comprises an immunoglobulin or a domain thereof. 
     
     
         10 . The composition of  claim 9 , wherein the immunoglobulin is IgE. 
     
     
         11 . The composition of  claim 10 , wherein the IgE comprises residues coded by SEQ ID NO: 18. 
     
     
         12 . The composition of  claim 7 , wherein the protein that stabilizes the variant HMGB1 protein comprises an IgE Fc domain. 
     
     
         13 . The composition of  claim 1 , wherein the variant HMGB1 further comprises a cysteine residue at positions 23 and 45, and wherein residue numbering is based on SEQ ID NO: 16 (wild-type HMGB1) 
     
     
         14 . The composition of  claim 1 , wherein the exogenous nucleic acid that codes for the variant High Mobility Group Box 1 (HMGB1) protein is inserted into the oncolytic virus. 
     
     
         15 . The composition of  claim 14 , wherein the exogenous nucleic acid that codes for the variant High Mobility Group Box 1 (HMGB1) protein is inserted into a thymidine kinase gene locus of the oncolytic virus. 
     
     
         16 . The composition of  claim 1 , wherein the oncolytic virus is Herpes Simplex Virus, Adenovirus, Polio virus, Vesicular Stomatitis Virus, Coxsackievirus, reovirus, lentivirus, adeno-associated virus, Measles virus, Maraba virus, Newcastle disease, Seneca valley virus, Reovirus, Mengovirus, and Myxomavir. 
     
     
         17 . The composition of  claim 1 , wherein the oncolytic virus is a vaccinia virus. 
     
     
         18 . The composition of  claim 17 , wherein the vaccinia virus comprises a loss of function of a thymidine kinase gene. 
     
     
         19 . The composition of  claim 1 , wherein the oncolytic virus further comprises an exogenous nucleic acid that codes for a hyaluronidase. 
     
     
         20 . The composition of  claim 19 , wherein the hyaluronidase is PH-20.