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An In Vitro Assessment of Immunostimulatory Responses to Ten Model Innate Immune Response Modulating Impurities (IIRMIs) and Peptide Drug Product, Teriparatide

  1. Author:
    Holley,Claire
    Cedrone,Edward
    Donohue,Duncan
    Neun,Barry
    Verthelyi, Daniela
    Pang, Eric S.
    Dobrovolskaia, Marina A.

  2. Author Address

    NCI, Nanotechnol Characterizat Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res Sponsored, Ft Detrick, MD 21702 USA.Data Management Serv Inc, Stat Dept, Frederick Natl Lab Canc Res, NCI, Ft Detrick, MD 21702 USA.US FDA, Lab Innate Immun, Div Biotechnol Review & Res 3, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA.US FDA, Div Therapeut Performance, Off Res & Stand, Off Gener Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA.
    1. Year: 2021
    2. Date: Dec
  2. Journal: Molecules
  3. MDPI,
    1. 26
    2. 24
  5. Type of Article: Article
  6. Article Number: 7461
  7. ISSN: 1420-3049
  1. Abstract:

    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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External Sources

  1. View Full Text
  2. DOI: 10.3390/molecules26247461
  3. View record in Web of Science®
  4. WOS: 000736760500001

Library Notes

  1. Fiscal Year: FY2021-2022
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