Comparative pathology of recombinant murine interferon-gamma in mice and recombinant human interferon-gamma in cynomolgus monkeys.
Interferon-gamma is a highly species-specific cytokine and has the most restricted host range of activity of the interferons. Recombinant human IFN-gamma was one of the first species-specific recombinant proteins to be thoroughly assessed in conventional safety models used for xenobiotics. Acute single-dose intravenous toxicity studies with rHuIFN-gamma were performed in rats, marmosets, and squirrel monkeys with no indications of toxicity. A complete series of subchronic toxicity studies and segment I and II reproductive studies in the rat revealed no evidence of toxicity at any of the doses tested. These results suggested that studies conducted in pharmacologically nonresponsive species may not be predictive of clinical toxicity. Human IFN-gamma is active on nonhuman primate cells, though not at the same level as on human cells. Multidose studies in cynomolgus monkeys with rHuIFN-gamma for 28 or 90 days were predictive of many of the dose-limiting clinical toxicities. Qualitative similarity was observed between toxicity studies employing rHuIFN-gamma in the cynomolgus monkey and rMuIFN-gamma in the mouse. The adverse effects seen in toxicity studies with cytokines and growth factors are often exaggerated pharmacological effects of the molecules, and therefore can only be studied in a responsive species. In situations in which a high degree of species specificity is encountered, studies employing a recombinant protein in a homologous species may provide a useful test system for preclinical safety assessment.
Terrell
T G
TG
Department of Safety Evaluation Genentech, Inc., South San Francisco, California 94080.
Green
J D
JD
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000818:Animals; D002144:Callithrix; D005260:Female; D005334:Fever / Q000139:chemically induced; D006168:Guinea Pigs; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007371:Interferon-gamma / Q000633:toxicity*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests; D009928:Organ Specificity; D051381:Rats; D011994:Recombinant Proteins; D012098:Reproduction / Q000187:drug effects; D012453:Saimiri; D013045:Species Specificity; D014781:Viscera / Q000187:drug effects / Q000473:pathology
D011994:Recombinant Proteins; D007371:Interferon-gamma