IMMUNOPHARMACOLOGY OF RECOMBINANT HUMAN INTERLEUKIN-18 IN NON-HUMAN PRIMATES

Abstract

Recombinant human interleukin (IL)-18 (rHuIL-18) has a potential as a therapeutic agent in cancer and is currently in drug development. Since human IL-18 displays 96% and 100% amino acid sequence homology with cynomolgus monkey and chimpanzee IL-18, respectively, the biological responses to rHuIL-18 were evaluated in these species. A single intravenous dose of rHuIL-18 at 1 or 10 mg/kg in cymonolgus monkeys caused a transient reduction in lymphocyte counts, induction of IL-1α and tumour necrosis factor alpha (TNF-α) mRNA in whole blood cells and a marked increase in plasma neopterin. rHuIL-18 administered to cynomolgus monkeys at doses of 0.3 or 3 mg/kg for two 5-day cycles (Days 1–5 and 15–19) resulted in increased monocyte counts, induction of NK cells and concomitant increases in plasma IL-12 and neopterin. Administration of repeat doses of rHuIL-18 at 10 mg/kg to chimpanzees was associated with increased monocyte counts, upregulation of FcγRI surface expression on monocytes, and increased IL-8, IL-12 and neopterin in plasma. These studies demonstrate, for the first time, the immunostimulatory activity of rHuIL-18 in vivo. The described pharmacological profile of rHuIL-18 in both cynomolgus monkeys and chimpanzees is indicative of the immunotherapeutic potential of rHuIL-18 in the treatment of cancer.