Preclinical safety of recombinant human interleukin-18.
Recombinant human interleukin-18 (rHuIL-18) is currently in clinical trials for treatment of cancer. This report presents results of preclinical toxicity studies with rHuIL-18 in cynomolgus monkeys and recombinant murine IL-18 (rMuIL-18) in mice. The rHuIL-18 was administered intravenously in 1 or 2 different 5-day cycles at doses 0.3 to 75 mg/kg/day in monkeys. Decreases in red cell mass, neutrophil, and platelet counts, increases in monocyte and large unstained cell counts, and lymphoid hyperplasia in spleen and lymph nodes were mild, reversible, and likely related to the pharmacologic activity of IL-18. The only toxic effect was protein cast nephropathy, secondary to coprecipitation of administered IL-18 and Tamm-Horsfall protein in the distal nephron, that only occurred at 75 mg/kg/day. Other adverse effects of rHuIL-18 were related to strong immunogenicity in monkeys and were manifest only during a second dosing cycle. The rMuIL-18, at similar dosing levels and cycles in mice, resulted in reduced red cell mass, increased white blood cell counts, spleen and lymph node hyperplasia, and mild, reversible changes in intestine, liver, and lungs. Protein cast nephropathy occurred in mice at doses > or = 30 mg/kg/day. In conclusion, preclinical safety studies showed that rIL-18 was well tolerated at pharmacologically active doses in both monkeys and mice.
Herzyk
Danuta J
DJ
Department of Safety Assessment, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. danuta.j.herzyk@gsk.com
Bugelski
Peter J
PJ
Hart
Timothy K
TK
Wier
Patrick J
PJ
D000818:Animals; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D020382:Interleukin-18 / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009088:Mucoproteins / Q000187:drug effects; D009402:Nephrosis, Lipoid / Q000209:etiology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000633:toxicity; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013997:Time Factors; D058949:Uromodulin
D020382:Interleukin-18; D009088:Mucoproteins; D011994:Recombinant Proteins; C548612:UMOD protein, human; C548613:Umod protein, mouse; D058949:Uromodulin