Adenoviruses and methods for using adenoviruses

Abstract

This invention relates to methods and materials for nucleic acid delivery, vaccination, and/or treating cancer. More specifically, methods and materials for nucleic acid delivery, vaccination, and/or treating cancer using one or more recombinant adenoviruses (Ads) as an oncolytic agent are provided.

1 . A recombinant adenovirus (Ad) strain 6, comprising one or more modified fiber proteins. 
     
     
         2 . The recombinant adenovirus (Ad) of  claim 1 , wherein the modified fiber protein comprises an Ad strain 35 fiber protein. 
     
     
         3 . The recombinant adenovirus (Ad) of  claim 2 , comprising the amino acid sequence of SEQ ID NO:61. 
     
     
         4 . The recombinant adenovirus (Ad) of  claim 1 , wherein the modified fiber protein comprises an extension of seven lysines (K7) on the Ad strain 6 fiber protein. 
     
     
         5 . The recombinant adenovirus (Ad) of  claim 4 , comprising the amino acid sequence of SEQ ID NO:62. 
     
     
         6 . The recombinant adenovirus (Ad) of  claim 1 , wherein the modified fiber protein comprises a chimpanzee adenovirus C68 fiber protein. 
     
     
         7 . The recombinant adenovirus (Ad) of  claim 6 , comprising the amino acid sequence of SEQ ID NO:63. 
     
     
         8 . The recombinant adenovirus (Ad) of  claim 6 , further comprising an extension of 7 lysines (K7) on the fiber protein, wherein the fiber protein comprises the amino acid sequence of SEQ ID NO:64 or SEQ ID NO:65. 
     
     
         9 . The recombinant Ad of  claim 1 , further comprising a modification in the E3 region of the Ad strain 6. 
     
     
         10 . The recombinant Ad of  claim 9 , wherein the modification in the E3 region of the Ad strain 6 comprises a deletion in part of E3 12.5K and full deletion of E3 6.7K, 19K and 11.6K (ADP). 
     
     
         11 . The recombinant adenovirus (Ad) of  claim 1 , comprising nucleic acids which encode a heterologous antigen. 
     
     
         12 . The recombinant adenovirus (Ad) of  claim 11 , wherein the heterologous antigen is selected from a human folate receptor alpha polypeptide, an HIV envelope polypeptide, a hepatitis C virus (HCV) antigen or hepatitis B virus (HBV) antigen, and a Human Papilloma Virus (HPV) antigen. 
     
     
         13 . The recombinant adenovirus (Ad) of  claim 1 , comprising nucleic acids which encode one or more proteins selected from 4-1BBL, human granulocyte macrophage stimulating factor (hGMCSF), CD40L and IL-21. 
     
     
         14 . The recombinant adenovirus (Ad) of  claim 1 , further comprising cysteine amino acid substitutions, and wherein N-Hydroxysuccinimide (NHS) or maleimide polyethylene glycol (PEGylation) or biotin acceptor peptide (BAPylation) modification bind to cysteine substituted Ad capsid hexon hypervariable region (HVR) polypeptides. 
     
     
         15 . A method of targeting a cancerous tumor with an Adenovirus (Ad) and lowering infection of the liver by the Ad comprising, administering an Ad strain to a subject in need thereof, and subsequently administering to the subject in one or more rounds of treatment, an alternate Ad strain having a modified fiber protein. 
     
     
         16 . The method of  claim 15 , wherein the Ad comprises a covalent polymer conjugation. 
     
     
         17 . The method of  claim 15 , wherein the alternate Ad strain is the Ad of  claim 1 . 
     
     
         18 . A conditionally-replicating Adenovirus (CRAd) comprising, a recombinant Adenovirus (Ad) strain 6 which has been modified in an E1A gene encoding an E1A polypeptide, wherein the CRAd exhibits amino acid substitutions in the E1A polypeptide relative to wild-type E1A polypeptide of an Ad strain. 
     
     
         19 . The CRAd of  claim 11 , wherein the N-terminal portion of the E1A polypeptide comprises an amino acid sequence set forth in SEQ ID NO:43, SEQ ID NO:44 or SEQ ID NO:45.