Preclinical safety, pharmacokinetics, and pharmacodynamics of recombinant human interleukin-21 in cynomolgus macaques (Macaca fascicularis).
Interleukin-21 (IL-21), a pleiotropic immunostimulatory type I cytokine, has anticancer effects in animal models. Preclinical studies designed to assess the safety of recombinant human IL-21 (rIL-21) for use in phase I oncology studies are described. The rIL-21 (≤3.0 mg/kg per dose) was given intravenously to cynomolgus monkeys (Macaca fascicularis) once daily for 5 days, followed by 9 nondosing days (1 cycle) for ≤4 cycles. The rIL-21 pharmacokinetics was dose-dependent. Accumulation was not observed after repeated dosing, consistent with the short elimination half-life (t                 (1/2,λz); 0.4-0.8 hours). Safety findings included cyclical anemia and thrombocytopenia, clinical pathology changes consistent with acute-phase response, leukocyte infiltrates in hepatic sinusoids, and sporadic serum transaminase elevations (typically <3 times upper-limit of normal); all were reversible upon cessation of treatment. Decreased pharmacodynamic responses with time corresponded to the development of anti-rIL-21 antibodies; effects varied among individuals and were dose-dependent. These studies demonstrated rIL-21 to be generally well-tolerated when administered to cynomolgus monkeys, and all adverse effects were reversible upon treatment cessation. However, development of anti-rIL-21 antibodies may limit the use of this species in long-term studies.
ZymoGenetics, a Bristol-Myers Squibb Company, Preclinical Development, Seattle, WA 98102, USA. kim.waggie@bms.com
Kimberly S
KS
Waggie
Matthew S
MS
Holdren
Kelly
K
Byrnes-Blake
Susan
S
Pedersen
Rafael
R
Ponce
Steven
S
Hughes
Dennis M
DM
Miller
D000210:Acute-Phase Reaction / Q000188:drug therapy; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005260:Female; D006207:Half-Life; D006801:Humans; D007378:Interleukins / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000098546:Interleukin-21
D007378:Interleukins; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D000098546:Interleukin-21