期刊
MOLECULES
卷 26, 期 24, 页码 -出版社
MDPI
DOI: 10.3390/molecules26247461
关键词
cytokines; innate immunity; immunogenicity; peptides; teriparatide
资金
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research/Office of Generic Drugs, under an Inter-Agency Agreement
- NCL/NCI/NIH [224-19-3008S]
The study evaluates the applicability of several in vitro assays for the screening of innate immune responses induced by IIRMIs and a model biotherapeutic, identifying cytokine secretion as a sensitive method. Signature cytokines, broad and narrow multiplex cytokine panels, and assay logistics are discussed in the context of performance of this in vitro assay.
Understanding, predicting, and minimizing the immunogenicity of peptide-based therapeutics are of paramount importance for ensuring the safety and efficacy of these products. The so-called anti-drug antibodies (ADA) may have various clinical consequences, including but not limited to the alteration in the product's distribution, biological activity, and clearance profiles. The immunogenicity of biotherapeutics can be influenced by immunostimulation triggered by the presence of innate immune response modulating impurities (IIRMIs) inadvertently introduced during the manufacturing process. Herein, we evaluate the applicability of several in vitro assays (i.e., complement activation, leukocyte proliferation, and cytokine secretion) for the screening of innate immune responses induced by ten common IIRMIs (Bacillus subtilis flagellin, FSL-1, zymosan, ODN2006, poly(I:C) HMW, poly(I:C) LMW, CLO75, MDP, ODN2216, and Escherichia coli O111:B4 LPS), and a model biotherapeutic Forteo (TM) (teriparatide). Our study identifies cytokine secretion from healthy human donor peripheral blood mononuclear cells (PBMC) as a sensitive method for the in vitro monitoring of innate immune responses to individual IIRMIs and teriparatide (TP). We identify signature cytokines, evaluate both broad and narrow multiplex cytokine panels, and discuss how the assay logistics influence the performance of this in vitro assay.
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