Cell-Based Assays to Detect Innate Immune Response Modulating Impurities: Application to Biosimilar Insulin

Characterizing and mitigating factors that impact product immunogenicity can aid in risk assessment and/or managing risk following manufacturing changes. For follow-on products that have the same indication, patient population, and active product ingredient, the residual immunogenicity risk resides...

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Bibliographic Details
Published in:The AAPS journal 2024-12, Vol.27 (1), p.20, Article 20
Main Authors: Her, Cheng, Thacker, Seth, Balsamo, Joseph, Kelley Baker, Logan, Ireland, Derek DC, Pang, Eric, Verthelyi, Daniela
Format: Article
Language:English
Subjects:
Biochemistry
Biomedical and Life Sciences
Biomedicine
Biosimilar Pharmaceuticals
Biotechnology
Drug Contamination - prevention & control
Humans
Hypoglycemic agents
Immunity, Innate - drug effects
Immunity, Innate - immunology
Insulin Glargine - immunology
Pharmacology/Toxicology
Pharmacy
Recombinant proteins
Research Article
Risk assessment
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Summary:Characterizing and mitigating factors that impact product immunogenicity can aid in risk assessment and/or managing risk following manufacturing changes. For follow-on products that have the same indication, patient population, and active product ingredient, the residual immunogenicity risk resides predominantly on differences in product and process related impurities. Characterizing differences in innate immune modulating impurities (IIRMI), which could act as adjuvants by activating local antigen presenting cells (APCs), can inform the immunogenicity risk assessment potentially reducing the need for clinical trials. To date, assays to detect trace levels of IIRMI are being used to support regulatory decisions by FDA for selected synthetic peptide drug products that refer to reference listed drugs of rDNA origin but not recombinant protein or peptide products where more complex mixtures of trace impurities including host cell proteins are expected. Here we describe an exercise to explore whether or not there are differences in the innate immune response elicited by an insulin glargine (produced in E. coli ) and its interchangeable biosimilar insulin (produced in P. pastoris ) that could indicate differences in IIRMI. Our results suggest the two products elicit comparable innate immune responses as determined by the expression of 90 immune-related genes, including IL-1α, IL-1β, IL-6, CCL3, CCL2, and CXCL8. The data suggest that these assays can provide useful information when assessing recombinant proteins for the presence of IIRMI. Graphical Abstract
ISSN:1550-7416
1550-7416
DOI:10.1208/s12248-024-00983-x