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US 12,758,601 B2Granted
Oncolytic adenovirus with replication selectivity based on status of P53 transcriptional activity
AssigneeThe Salk Institute for Biological Studies
InventorsWilliam Partlo, Clodagh O'Shea
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Abstract
Oncolytic adenoviruses capable of selectively replicating in tumor cells deficient in p53 transcriptional activity are described. Recombinant adenovirus genomes that encode the p53-selective adenoviruses are also described. The recombinant adenoviruses and adenovirus genomes, or compositions thereof, can be used, for example, to reduce or inhibit tumor progression, or reduce tumor volume in a subject with a tumor having dysregulated p53 activity.
Claims23
A recombinant adenovirus genome, comprising:
- an E1B region encoding a modified 55k protein, wherein p53 degradation activity of the modified 55k protein is reduced compared to a wild-type 55k protein;
- an E2A region comprising a deletion of the DNA binding protein (DBP) open reading frame (ORF);
- an E3 region comprising an adenovirus death protein (ADP) ORF and comprising a deletion of the 12.5k, 6.7k, 19k, RIDα, RIDβ and 14.7k ORFs;
- an E4 region;
- L1, L2, L3, L4 and L5 regions;
- a first exogenous nucleic acid sequence comprising a CMV-Tet-O promoter operably linked to an adenovirus DBP ORF;
- and
- a second exogenous nucleic acid sequence comprising a p53-responsive promoter operably linked to a tetracycline repressor (TetR) protein ORF.
5 more elements
Dependencies are inferred from the claim text.