Safety toxicity study of plasmid-based IL-12 therapy in Cynomolgus monkeys.

We have investigated the potential toxicity of hlL-12 DNA plasmid formulated with 5% polyvinylpyrrolidone (PVP) administered twice weekly via subcutaneous injections to Cynomolgus monkeys for four weeks, and have evaluated recovery from any effects of the test article over a four-week treatment-free period. Doses of the formulated hlL-12 plasmid were selected based on anti-tumour efficacy studies previously conducted in mice. The duration of the study and the frequency of dosing were designed to support clinical trials. No clinical signs indicative of an adverse effect of administration of formulated hlL-12 plasmid were observed. There were no apparent effects of the formulated hlL-12 plasmid on body weights or on serum chemistry, haematology, coagulation or urinalysis parameters. No treatment-related ocular abnormalities were evident. In addition, examination of the electrocardiograms from all monkeys at the pre-study, week-4, and week-8 time points did not reveal any treatment-related effects. No treatment-related gross lesions were noted at days 28 or 57. Slight histopathological changes associated with high doses of PVP vehicle were observed at both time points. These results suggested that the administration of formulated hlL-12 plasmid at a dose level up to 18 mg kg -1 dose twice per week for four weeks to experimentally naive Cynomolgus monkeys did not result in significant toxicity. These results support further testing of this gene therapy in clinical trials.