Immunopharmacology of recombinant human interleukin-18 in non-human primates.
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 10mg/kg in cymonolgus monkeys caused a transient reduction in lymphocyte counts, induction of IL-1alpha and tumour necrosis factor alpha (TNF-alpha) mRNA in whole blood cells and a marked increase in plasma neopterin. rHuIL-18 administered to cynomolgus monkeys at doses of 0.3 or 3mg/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 10mg/kg to chimpanzees was associated with increased monocyte counts, upregulation of FcgammaRI 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.
Herzyk
Danuta J
DJ
Department of Safety Assessment, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA. danuta.j.herzyk@gsk.com
Soos
Jeanne M
JM
Maier
Curtis C
CC
Gore
Elizabeth R
ER
Narayanan
Padma K
PK
Nadwodny
Kimberly L
KL
Liu
Susan
S
Jonak
Zdenka L
ZL
Bugelski
Peter J
PJ
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D020382:Interleukin-18 / Q000008:administration & dosage / Q000494:pharmacology*; D008252:Macaca fascicularis; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D019798:Neopterin / Q000096:biosynthesis; D002679:Pan troglodytes; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D016176:T-Lymphocyte Subsets; D013618:Tachyphylaxis
D016207:Cytokines; D020382:Interleukin-18; D011994:Recombinant Proteins; D019798:Neopterin