Evaluation of Long-Term Toxicity of Ad/hIFN- γ,an Adenoviral Vector Encoding the Human Interferon- γ Gene,in Nonhuman Primates

Abstract

Interferon-γ(IFN-γ) plays an important role in the immunomodulation and growth inhibition of many tumor cells, but its clinical application is limited by its systemic toxicity. Ad/hIFN-γ, a nonreplicating adenoviral vector encoding human IFN-γ, has been reported to inhibit tumor growth in vitro and in a xenograft model. In this study, the long-term toxicity of Ad/hIFN-γ was assessed in cynomolgus macaques (Macaca fascicularis). Thirty animals were enrolled into 5 groups, and administered intramuscularly, respectively, Ad/hIFN-γ (3.3 × 10¹⁰, 3.3 × 10¹¹, or 3.3 × 10¹² VP/kg), Ad/LacZ (vector control, 3.3 × 10¹¹ VP/kg), or excipient 3 times per week for 8 weeks, followed by a 4-week recovery period. At 12 weeks all experimental animals appeared generally healthy, and there were no statistically significant differences in body weight, urinalysis, hemogram, blood biochemistry, and electrocardiogram results between the treatment and control groups. No significant toxic effects were noted on macroscopic and microscopic examinations of organs and tissues. Preliminary investigation of the immunotoxicity of Ad/IFN-γ indicated that anti-adenoviral and anti-hIFN-γ antibodies were generated. These data demonstrate that long-term, high-dose intramuscular administration of Ad/IFN-γ was not notably toxic and might be safe for clinical therapeutic use.