Utilization of homologous proteins to evaluate the safety of recombinant human proteins--case study: recombinant human interferon-gamma (rhIFN-gamma).
Interferon-gamma is an immunomodulatory cytokine that has an extremely restricted host range of activities. RhIFN-gamma was one of the first species-specific recombinant proteins to be assessed in conventional safety models typically utilized for xenobiotics. Acute, subchronic and Segment I and II reproductive studies in rats revealed no evidence of toxicity at any of the doses tested; these results were not predictive of clinical toxicity, which is not unexpected since rodents are known to be pharmacologically nonresponsive to rhIFN-gamma. In contrast, 4- and 13-week multidose toxicity studies in cynomolgus monkeys with rhIFN- were predictive of many of the dose-limiting clinical toxicities. RhIFN- is active on non-human primate cells, though not at the same level as on human cells. In addition, qualitative similarities were observed between toxicity studies employing rhIFN-gamma in the cynomolgus monkey and recombinant murine interferon-gamma (rmuIFN-gamma) in the mouse. These results suggest that in situations where 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. This information should be evaluated in conjunction with data from studies conducted with the human protein in pharmacologically responsive animal models when possible.
Green
J D
JD
Department of Safety Evaluation, Genentech, Inc., South San Francisco, CA 94080.
Terrell
T G
TG
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D007371:Interferon-gamma / Q000633:toxicity*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D011994:Recombinant Proteins; D013045:Species Specificity
D011994:Recombinant Proteins; D007371:Interferon-gamma