Modified orthopoxvirus vectors
Inventors
Bell, John C. • Le Boeuf, Fabrice • HUH, Michael S. • TANG, Matthew Y. • PELIN, Adrian • KELLER, Brian Andrew • BREITBACH, Caroline J. • BURGESS, Michael F. • BERNSTEIN, Steven H.
Assignees
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Publication Number
US-11802292-B2
Publication Date
2023-10-31
Expiration Date
Abstract
The disclosure relates to modified orthopoxvirus vectors, as well as methods of using the same for the treatment of various cancers. The disclosure provides modified orthopoxvirus vectors that exhibit various beneficial therapeutic activities, including enhanced oncolytic activity, spread of infection, immune evasion, tumor persistence, capacity for incorporation of exogenous DNA sequences and safety. The viruses we have discovered are also amenable to large scale manufacturing protocols.
Core Innovation
The invention relates to a nucleic acid comprising a recombinant orthopoxvirus genome engineered with extensive deletions across specified genes, comprising deletions in each of 23 named genes and deletions in each of 9 additional named genes. The genome is further defined by inclusion of transgenes selected from a transgene encoding a tumor-associated antigen, a transgene encoding an immune checkpoint inhibitor, and transgenes encoding immune-stimulatory molecules including an interleukin, an interferon, a TNF superfamily member protein, and a cytokine.
The nucleic acid comprises one or more of these transgenes and allows any combination thereof. The gene deletion strategy can include deletion of B8R for enhanced safety by preventing neutralization of human IFN-gamma, and transgenes may be inserted into the B8R locus.
The described treatment concepts use these engineered recombinant orthopoxvirus nucleic acids as oncolytic vectors for cancers in mammalian patients, including human patients, and encompass administration for cancer treatment. The partial content further indicates combinations with immune checkpoint inhibitors and other cytokine or immune agents through the use of the above transgene categories.
Claims Coverage
The independent claims provided cover a nucleic acid encoding a recombinant orthopoxvirus genome with a defined multi-gene deletion architecture and containing one or more immune-related transgenes. The main inventive features are the specified deletion sets and the selectable combination of immune/transgene payloads.
23 specified gene deletions plus 9 specified gene deletions in a recombinant orthopoxvirus genome
A nucleic acid comprising a recombinant orthopoxvirus genome comprising deletions in each of 23 genes and further comprises deletions in each of 9 genes.
Selectable combination of transgenes encoding tumor and immune modulators
The nucleic acid further comprises a transgene encoding a tumor-associated antigen, a transgene encoding an immune checkpoint inhibitor, a transgene encoding an interleukin, a transgene encoding an interferon, a transgene encoding a TNF superfamily member protein, a transgene encoding a cytokine, or any combination thereof.
Across the independent claim, the core coverage is the combination of a recombinant orthopoxvirus genome with the specified deletion set and an immune/transgene payload selected from tumor-associated antigen, immune checkpoint inhibitor, interleukin, interferon, TNF superfamily member protein, and cytokine in any combination.
Stated Advantages
Enhanced safety by preventing neutralization of human IFN-gamma when including deletion of B8R.
Documented Applications
Oncolytic treatment and administration of cancers in mammalian patients, including human patients, using the engineered recombinant orthopoxvirus vectors.
Combination concepts with immune checkpoint inhibitors and other cytokine or immune agents.
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