Preclinical evaluation of the mono-PEGylated recombinant human interleukin-11 in cynomolgus monkeys

Kuo Ming Yu, Johnson Yiu Nam Lau, Manson Fok, Yuk Keung Yeung, Siu Ping Fok, Suxing Zhang, Peizhen Ye, Kezhi Zhang, Xiaobo Li, Juan Li, Qin Xu, Wing Tak Wong, Qui Lim Choo

Research output: Journal article publicationJournal articleAcademic researchpeer-review

6 Citations (Scopus)

Abstract

The mono-PEGylated recombinant human interleukin-11 (rhIL-11) was evaluated for its pharmacology and toxicology profile in non-human primates. This PEGylated IL-11 (PEG-IL11) showed a much prolonged circulating half-life of 67 h in cynomolgus monkeys as compared to its un-PEGylated counterpart (~ 3 h) through subcutaneous administration, implicating that a single injection of the recommended dose will effectively enhance thrombopoiesis in humans for a much longer period of time compared to rhIL-11 in humans (t1/2 = 6.9 h). The toxicokinetics study of single dose and multiple doses showed that systemic exposure was positively correlated with the dosing level, implying that efficacy and toxicity were mechanism-based. A single high dose at 6.25 mg/kg through subcutaneous route revealed tolerable and transient toxicity. Multiple-dose in monkeys receiving 0.3 mg/kg weekly of the drug developed only mild to moderate toxicity. Major adverse events and immunogenicity in monkeys were only observed in the overdose groups. Bones were positively impacted; while reversible toxicities in heart, liver, kidney and lung observed were likely to be consequences of fluid retention. In summary, the PEG moiety on rhIL-11 did not elicit additional toxicities, and the drug under investigation was found to be well tolerated in monkeys after receiving a single effective dose of 0.1–0.3 mg/kg through subcutaneous delivery, which may be allometrically scaled to a future clinical dose at 30–100 μg/kg, creating a potential long acting, safer, and more convenient treatment approach based on rhIL-11.

Original languageEnglish
Pages (from-to)39-49
Number of pages11
JournalToxicology and Applied Pharmacology
Volume342
DOIs
Publication statusPublished - 1 Mar 2018

Keywords

  • IL-11
  • Interleukin
  • Monkeys
  • PEGylated
  • Preclinical
  • Toxicology

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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