Replication of an E1B 55-Kilodalton Protein-Deficient Adenovirus (ONYX-015) Is Restored by Gain-of-Function Rather than Loss-of-Function p53 Mutants

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Abstract
ONYX-015 ( dl 1520) is an E1B 55-kilodalton protein-deficient replicating adenovirus that is currently in clinical trials as an antitumor agent. On the basis of the observation that the E1B 55kD gene product is able to bind to and inactivate p53, ONYX-015's mechanism of action is proposed to involve selective replication in and killing of p53-deficient cells. While its efficacy as a therapeutic agent appears evident, the virus's mechanism of cellular selectivity, including a possible role of p53 in this regard, is less clear. Indeed, there have been a number of recent reports suggesting that the p53 status of target cells does not reliably predict ONYX-015 replication or cell killing. To address the role of p53 in ONYX-015 selectivity, we have undertaken a rigorous analysis of the behavior of this virus in small airway-derived primary human epithelial cells expressing either dominant-negative or gain-of-function mutant p53 genes. Examination of small airway epithelial cells expressing a variety of p53 mutant alleles revealed that while all were able to inhibit endogenous p53 activity, only one allele examined, 248W, demonstrated a markedly increased ability to facilitate ONYX-015 replication. This allele is a member of a group of p53 mutants (know as class I mutants) characterized by retention of global structural conformation but loss of DNA-binding activity. These observations indicate that the nature of the p53 mutation affects ONYX-015 replication, help reconcile disparate published findings, and may provide criteria by which to direct clinical application of ONYX-015.