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

Autor: Yu KM; Nansha Biologics (Hong Kong) Ltd., Unit 608-613, IC Development Centre, No. 6 Science Park West Avenue, Hong Kong Science Park, Shatin, Hong Kong, China; Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, 11 Yuk Choi Road, Hung Hom, Kowloon, Hong Kong. Electronic address: kyu@nansha-biologics.com., Lau JY; Nansha Biologics (Hong Kong) Ltd., Unit 608-613, IC Development Centre, No. 6 Science Park West Avenue, Hong Kong Science Park, Shatin, Hong Kong, China., Fok M; Nansha Biologics (Hong Kong) Ltd., Unit 608-613, IC Development Centre, No. 6 Science Park West Avenue, Hong Kong Science Park, Shatin, Hong Kong, China., Yeung YK; Nansha Biologics (Hong Kong) Ltd., Unit 608-613, IC Development Centre, No. 6 Science Park West Avenue, Hong Kong Science Park, Shatin, Hong Kong, China., Fok SP; Nansha Biologics (Hong Kong) Ltd., Unit 608-613, IC Development Centre, No. 6 Science Park West Avenue, Hong Kong Science Park, Shatin, Hong Kong, China., Zhang S; KG Pharma Limited, Wuhua Road, Zhangcha Subdistrict, Foshan 528000, China., Ye P; KG Pharma Limited, Wuhua Road, Zhangcha Subdistrict, Foshan 528000, China., Zhang K; KG Pharma Limited, Wuhua Road, Zhangcha Subdistrict, Foshan 528000, China., Li X; New South Center for Safety Evaluation of Drugs, 436, Chentai Road, Baiyun District, Guangzhou, China., Li J; New South Center for Safety Evaluation of Drugs, 436, Chentai Road, Baiyun District, Guangzhou, China., Xu Q; New South Center for Safety Evaluation of Drugs, 436, Chentai Road, Baiyun District, Guangzhou, China; Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, China., Wong WT; Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, 11 Yuk Choi Road, Hung Hom, Kowloon, Hong Kong., Choo QL; Nansha Biologics (Hong Kong) Ltd., Unit 608-613, IC Development Centre, No. 6 Science Park West Avenue, Hong Kong Science Park, Shatin, Hong Kong, China.
Jazyk: angličtina
Zdroj: Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2018 Mar 01; Vol. 342, pp. 39-49. Date of Electronic Publication: 2018 Feb 02.
DOI: 10.1016/j.taap.2018.01.016
Abstrakt: 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 67h in cynomolgus monkeys as compared to its un-PEGylated counterpart (~3h) 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 (t 1/2 =6.9h). 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 6.25mg/kg through subcutaneous route revealed tolerable and transient toxicity. Multiple-dose in monkeys receiving 0.3mg/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 0.1-0.3mg/kg through subcutaneous delivery, which may be allometrically scaled to a future clinical dose at 30-100μg/kg, creating a potential long acting, safer, and more convenient treatment approach based on rhIL-11.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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