Oncolytic adenovirus compositions with enhanced replication properties
AssigneeThe Salk Institute for Biological Studies
InventorsClodagh O'Shea, Michael Lyman, William Partlo, Shigeki Miyake-Stoner
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Abstract
Tumor-selective recombinant adenoviruses that possess deletions or modifications in the E3 region are described. Recombinant adenoviruses that express adenovirus death protein (ADP) but have a deletion of at least three of the remaining six E3 genes exhibit enhanced virus replication. The recombinant adenoviruses further include additional modifications to allow selective replication in tumor cells and to detarget viruses from the liver. Use of the recombinant adenoviruses for cancer treatment is described.
Claims40
1-40. (canceled)
A method of inhibiting tumor cell viability, comprising contacting the tumor cell with a recombinant adenovirus comprising a genome comprising:
- an E1A region encoding a modified E1a protein;
- an E3 region encoding an adenovirus death protein (ADP) and comprising a modification or deletion of the coding sequences of each of E3 genes 12.5 k, 6.7 k, 19 k, RIDα, RIDβ and 14.7 k, wherein the modification prevents expression of each of the encoded proteins;
- and
- an E4 region comprising a modification or deletion of the E4orf6/7 coding sequence that prevents expression of the encoded protein, abolishes or impairs its E2F binding site, and/or deletes or impairs the nuclear localization signal.
A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a recombinant adenovirus comprising a genome comprising:
- an E1A region encoding a modified E1a protein;
- an E3 region encoding an adenovirus death protein (ADP) and comprising a modification or deletion of the coding sequences of each of E3 genes 12.5 k, 6.7 k, 19 k, RIDα, RIDβ and 14.7 k, wherein the modification prevents expression of each of the encoded proteins;
- and
- an E4 region comprising a modification or deletion of the E4orf6/7 coding sequence that prevents expression of the encoded protein, abolishes or impairs its E2F binding site, and/or deletes or impairs the nuclear localization signal,
- thereby treating cancer in the subject.
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Dependencies are inferred from the claim text.