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US 2026/0102445 A1Published application
Oncolytic adenoviral vector and methods of use
AssigneeUnleash Immuno Oncolytics, Inc.
InventorImre Kovesdi
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Abstract
Provided herein is a conditionally-replicating serotype 5 adenovirus or adenoviral vector expressing a mutant E1A protein under control of a promoter that is responsive to hypoxia and inflammation and one or more immune modulators under control of a tumor-specific promoter. The adenovirus or adenoviral vector also comprises serotype 3 fiber domain. Also provided is a method of inducing cytotoxicity in tumor cells using a composition containing the adenovirus or adenoviral vector.
Claims21
A serotype 5 adenovirus or adenoviral vector comprising:
- (a) a nucleic acid sequence encoding a mutant E1A protein operatively linked to a first promoter that is responsive to hypoxia and inflammation,
- (b) a deletion of all or part of the E1B-19K region of the adenoviral genome with the E1B-55K region intact,
- (c) an expression cassette located between the left ITR and the E1 region of the adenovirus genome,
- (d) one or more non-native nucleic acid sequences, each of which encodes an immune modulator and is operatively linked to a second promoter that is active in tumor cells,
- (e) one or more non-native nucleic acid sequences, each of which encodes an immune modulator and is operatively linked to the adenovirus native E3 promoter, and
- (f) a fiber protein comprising a serotype 3 adenovirus fiber knob domain.
3 more elements
A serotype 5 adenovirus or adenoviral vector comprising:
- (a) a nucleic acid sequence encoding a mutant E1A protein operatively linked to a secreted protein acidic and rich in cysteine (SPARC) promoter which comprises one or more hypoxia-responsive elements (HREs) and one or more nuclear factor kappa B (NF-κB) inflammation responsive elements (κBRE),
- (b) a deletion of all or part of the E1B-19K region of the adenoviral genome with the E1B-55K region intact,
- (c) a first exogenous nucleic acid sequence encoding CD40 ligand (CD40L) and a second exogenous nucleic acid sequence encoding 4-1BB ligand (4-1BBL), wherein the first and second exogenous nucleic acid sequences are (i) separated by an internal ribosome entry site (IRES) and (ii) operatively linked to a composite human telomerase reverse transcriptase (hTERT) promoter operatively linked to a minimal human CMV promoter and (iii) transcribed from an expression cassette located between the left ITR and the E1 region of the adenovirus genome,
- (d) a third exogenous nucleic acid sequence encoding IL-21 operatively linked to the adenovirus native E3 promoter, and
- (e) a fiber protein comprising a serotype 3 adenovirus fiber knob domain.
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Dependencies are inferred from the claim text.