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Immunogenicity and toxicokinetics assessment of the mono-PEGylated recombinant human interleukin-11 in cynomolgus monkeys
- Source :
- Life sciences. 259
- Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Enzyme-Linked Immunosorbent Assay
Pharmacology
030226 pharmacology & pharmacy
General Biochemistry, Genetics and Molecular Biology
law.invention
Polyethylene Glycols
03 medical and health sciences
0302 clinical medicine
Immune system
law
Medicine
Toxicokinetics
Animals
Humans
General Pharmacology, Toxicology and Pharmaceutics
Immunogenetic Phenomena
biology
business.industry
Immunogenicity
Antibodies, Monoclonal
General Medicine
Interleukin-11
Recombinant Proteins
Interleukin 11
Titer
Macaca fascicularis
030104 developmental biology
Pharmaceutical Preparations
Toxicity
biology.protein
Recombinant DNA
Antibody
business
Subjects
Details
- ISSN :
- 18790631
- Volume :
- 259
- Database :
- OpenAIRE
- Journal :
- Life sciences
- Accession number :
- edsair.doi.dedup.....83d358724e9c035e09b57141c803aa8a