Toxicology profiles of a novel p53-armed replication-competent oncolytic adenovirus in rodents, felids, and nonhuman primates.

Conditionally replicating adenovirus (CRAd) has demonstrated to be safe in clinical studies. We generated a triple-regulated p53-armed CRAd, SG600-p53, in which the partially deleted E1a and E1b genes are regulated under the human telomerase reverse transcriptase promoter and the hypoxia response element. SG600-p53 was proven to be effective both in vitro and in vivo. In this study, the preclinical safety profiles of SG600-p53 in animal models were investigated. SG600-p53 had no adverse effects on mouse behavioral and nervous systems at 1.0 x 10(11) viral particles (VP)/kg, 2.0 x 10(11) VP/kg and 4.0 x 10(11) VP/kg doses, and on cat cardiovascular and respiratory systems at 2.0 x 10(10) VP/kg, 4.0 x 10(10) VP/kg, and 8.0 x 10(10) VP/kg doses. In acute toxicity test in mice, the maximum tolerated dose (2.5 x 10(13) VP/kg) induced cachexia, decreased activity, and eye closure in 9/20 mice which could be self-resolved within 30 min. Sensitized by five repeated ip injections at 1.0 x 10(10) VP/kg each ip and excitated by one iv injection at 1.0 x 10(11) VP/kg, guinea pigs did not show any sign of systemic anaphylaxis. In repeat-dose toxicological studies, the no-observable-adverse-effect levels of SG600-p53 in rats (1.0 x 10(11) VP/kg) and cynomolgus monkeys (5.0 x 10(11) VP/kg) were 12-fold and 60-fold of the proposed clinical dose, respectively. Intramuscular injections of SG600-p53 in cynomolgus monkeys caused inflammation at injection sites, which was alleviative at the end of observation period. The anti-virus antibody was produced in animal sera and decreased gradually 4 weeks later. No histopathological changes were found by bone marrow examination. Our data in different animal models suggest that SG600-p53 is a safe antitumor therapeutic agent.