Aggregates of IVIG or Avastin, but not HSA, modify the response to model innate immune response modulating impurities

Polumuri, Swamy Kumar; Haile, Lydia A.; Ireland, Derek D.  C.; Verthelyi, Daniela

doi:10.1038/s41598-018-29850-4

Aggregates of IVIG or Avastin, but not HSA, modify the response to model innate immune response modulating impurities

Journal Article · Tue Jul 31 00:00:00 UTC 2018 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-018-29850-4· OSTI ID:1624412

Polumuri, Swamy Kumar ^[1]; Haile, Lydia A. ^[2]; Ireland, Derek D. C. ^[2]; Verthelyi, Daniela ^[2]

U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research. Office of Biotechnology Products. Division of Biotechnology Review and Research-III; DOE/OSTI
U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research. Office of Biotechnology Products. Division of Biotechnology Review and Research-III

Therapeutic proteins can induce immune responses that affect their safety and effcacy. Product aggregates and innate immune response modulating impurities (IIRMI) are risk factors of product immunogenicity. In this study, we use Intravenous Immunoglobulin (IVIG), Avastin, and Human Serum Albumin (HSA) to explore whether increased aggregates activate innate immune cells or modify the response to IIRMI. We show that increased aggregates (shaken or stirred) in IVIG and Avastin, but not HSA, induced activation of MAPKs (pp38, pERK and pJNK) and transcription of immune-related genes including IL8, IL6, IL1β, CSF1, CCL2, CCL7, CCL3, CCL24, CXCL2, IRAK1, EGR2, CEBPβ, PPARg and TNFSF15 in human PBMC. The immunomodulatory effect was primarily mediated by FcγR, but not by TLR. Interestingly, increased aggregates in IVIG or Avastin magnified innate immune responses to TLR2/4 agonists, but diminished responses to TLR3/9 agonists. This study shows that IIRMI and aggregates can modify the activity of immune cells potentially modifying the milieu where the products are delivered highlighting the complex interplay of different impurities on product immunogenicity risk. Further, we show that aggregates could modify the sensitivity of PBMC-based assays designed to detect IIRMI. Understanding and managing immunogenicity risk is a critical component of product development and regulation.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: SC0014664

OSTI ID:: 1624412

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 8; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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