Immunogenicity and toxicokinetics assessment of the mono-PEGylated recombinant human interleukin-11 in cynomolgus monkeys.

Autor: Li X; Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Sci-tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou 510445, China., Pang PS; Nansha Biologics (Hong Kong) Limited, Avalon BioMedical (Management) Limited, Unit 1511-1513 & 1515, Level 15, Tower II, Grand Central Plaza, 138 Shatin Rural Committee Road, Shatin, NT, Hong Kong., Zhang S; KG Pharma Limited, Foshan 528000, China., Ru L; Sci-tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou 510445, China., Yuan Z; Sci-tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou 510445, China., Liu R; Sci-tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou 510445, China., Choo QL; Nansha Biologics (Hong Kong) Limited, Avalon BioMedical (Management) Limited, Unit 1511-1513 & 1515, Level 15, Tower II, Grand Central Plaza, 138 Shatin Rural Committee Road, Shatin, NT, Hong Kong., Wang Q; Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Sci-tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou 510445, China., Song J; Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China., Xu Q; Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China., Zhang K; KG Pharma Limited, Foshan 528000, China., Yu KM; Nansha Biologics (Hong Kong) Limited, Avalon BioMedical (Management) Limited, Unit 1511-1513 & 1515, Level 15, Tower II, Grand Central Plaza, 138 Shatin Rural Committee Road, Shatin, NT, Hong Kong. Electronic address: kyu@nansha-biologics.com., Xu Z; Sci-tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou 510445, China. Electronic address: xzy080@163.com.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2020 Oct 15; Vol. 259, pp. 118244. Date of Electronic Publication: 2020 Aug 11.
DOI: 10.1016/j.lfs.2020.118244
Abstrakt: Aim: Protein therapeutics have potential to elicit immune responses resulting in undesirable anti-drug antibodies (ADA) that might affect product efficacy and patient safety, and should be assessed in animals before applying the treatment to humans. In this paper, we aim to assess the immunogenicity and toxicokinetics of the mono-PEGylated recombinant human interleukin-11 (rhIL-11), a novel protein therapeutic for the treatment of chemotherapy-induced thrombocytopenia, in repeated administration to cynomolgus monkeys.
Main Methods: Enzyme-linked immunosorbent assay (ELISA) methods were developed to measure ADA responses and plasma PEGylated IL-11 (PEG-IL11) concentration in monkeys. Assay parameters of immunogenicity and toxicokinetics methods were evaluated during validation in accordance with regulatory guidelines. We also employed cell-based assays to test the neutralizing activity of ADA provoked in monkeys.
Key Findings: The results showed that weak immunogenicity occurred in some monkeys after receiving repeated dose of 0.1-0.3 mg/kg by subcutaneous administration and disappeared after the recovery period. More pronounced immunogenicity occurred at high dose of 0.9 mg/kg, with a higher positive rate and titer, and some ADAs had neutralizing activity, but it can be greatly reduced after recovery. Such ADAs generated in monkeys may be accounted for the plasma toxicokinetics changes of PEG-IL11 and a minor reduction in systemic exposure.
Significance: These methods have been successfully applied to immunogenicity and toxicokinetic studies of PEG-IL11 in repeated dose toxicity following subcutaneous administration to monkeys, and could be successfully used in clinical trials after some modifications.
Competing Interests: Declaration of competing interest K.Y and P.P. are ex-employees of Nansha Biologics (Hong Kong) Limited. Q.C. is the employee of Nansha Biologics (Hong Kong) Limited. S.Z.and K.Z. are the employees of KG Pharma Ltd. X.L., L.R., Z.Y., R.L., S.Z, Q.W. and Z.X. are the employees of Sci-tech Industrial Park, Guangzhou University of Chinese Medicine. J.S. and Q.X. are the professors of the Guangzhou University of Chinese Medicine.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: