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Strategies to Determine Assay Format for the Assessment of Neutralizing Antibody Responses to Biotherapeutics

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Abstract

Most biotherapeutics can elicit immune responses in dosed recipients generating anti-drug antibodies (ADAs). Neutralizing antibodies (NAbs) are a subpopulation of ADAs that can potentially impact patient safety and directly mediate loss of drug efficacy by blocking the biological activity of a therapeutic product. Therefore, NAb detection is an important aspect of immunogenicity assessment, requiring sensitive and reliable methods reflective of the therapeutic mechanism of action (MoA). Both cell-based and non cell-based assays are viable options for NAb assessment. However, the scientific approach for the selection of a suitable assay format (cell-based or non cell-based) for NAb assessment is not currently well defined. In this manuscript, the authors summarize the design and utility of cell-based and non cell-based NAb assays and recommend a NAb assay format selection approach that relies on a combination of three factors. These include (i) the therapeutic MoA, (ii) the evidence of desirable assay performance characteristics, and (iii) risk of immunogenicity. The utility of correlating NAb response with pharmacodynamic data is also discussed. The aim of this paper is to provide a consistent strategy that will guide the selection of scientifically justified assay formats capable of detecting clinically relevant NAbs for biotherapeutics with varying MoAs and diverse complexity.

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Notes

  1. Quotation is from lines 283–285 of 2009 FDA draft guidance “Assay Development for Immunogenicity Testing”. The 2016 FDA draft guidance “Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein Products” is being finalized and consistent with the quotation cited in this manuscript.

  2. Quotation is from lines 606–607 of 2012 FDA draft guidance “Scientific Considerations in Demonstrating Biosimilarity to a Reference product”.

  3. Quotation is from page 8 of 2008 EMA guideline “Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins”.

  4. Quotation is from page 3 of 2012 EMA guideline “Immunogenicity Assessment of Monoclonal Antibodies Intended for in vivo Clinical Use”.

  5. Quotation is from page 6 of 2012 EMA guideline “Immunogenicity Assessment of Monoclonal Antibodies Intended for in vivo Clinical Use”.

  6. Quotation is from page 6 of 2012 EMA guideline “Immunogenicity Assessment of Monoclonal Antibodies Intended for in vivo Clinical Use”.

  7. Quotation is from page 6 of 2012 EMA guideline “Immunogenicity Assessment of Monoclonal Antibodies Intended for in vivo Clinical Use”.

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Acknowledgments

This work was sponsored by the Ligand Binding Assay Bioanalytical Focus Group (LBABFG) of the American Association of Pharmaceutical Scientists (AAPS). The authors would like to thank all the individuals for critical review and helpful discussion of the manuscript and would like to acknowledge Drs. Boris Gorovits (Pfizer), Gopi Shankar (Janssen Research and Development), Fabio Garoforo (Angelini Pharma), An Song (Genentech Inc.), Martin Schaefer (Roche), and Alvydas Mikulskis (Biogen). We particularly appreciate the regulatory input from Susan Kirshner (Food and Drug Administration), Meenu Wadhwa (National Institute for Biological Standards and Control), and Jiang Wang (Health Canada).

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Author notes

  1. Jim McNally & Joleen T. White

    Present address: EMD Serono, 45A Middlesex Turnpike, Billerica, Massachusetts, 01821, USA

Authors and Affiliations

  1. Janssen Research & Development, LLC, Johnson & Johnson, 1400 McKean Road, P.O. Box 776, Spring House, Pennsylvania, 19477, USA

    Bonnie Wu

  2. Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA

    Shan Chung

  3. AstraZeneca, One MedImmune Way, Gaithersburg, Maryland, 20878, USA

    Xu-Rong Jiang

  4. Pfizer, 1 Burtt Road, Andover, Massachusetts, 01810, USA

    Jim McNally

  5. Center for Drug Evaluation and Research, Office of Biotechnology Products, Division of Biotech Review and Reseach III, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993, USA

    Joao Pedras-Vasconcelos

  6. Bristol-Myers Squibb, Route 206 & Provinceline Road, Princeton, New Jersey, 08543, USA

    Renuka Pillutla

  7. Biogen, 250 Binney Street, Cambridge, Massachusetts, 02142, USA

    Joleen T. White

  8. Alnylam Pharmaceuticals, 300 Third Street, Cambridge, Massachusetts, 02142, USA

    Yuanxin Xu

  9. Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California, 91320, USA

    Shalini Gupta

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  1. Bonnie Wu
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Correspondence to Bonnie Wu.

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Wu, B., Chung, S., Jiang, XR. et al. Strategies to Determine Assay Format for the Assessment of Neutralizing Antibody Responses to Biotherapeutics. AAPS J 18, 1335–1350 (2016). https://doi.org/10.1208/s12248-016-9954-6

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