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Assessment and Reporting of the Clinical Immunogenicity of Therapeutic Proteins and Peptides—Harmonized Terminology and Tactical Recommendations

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Abstract

Immunogenicity is a significant concern for biologic drugs as it can affect both safety and efficacy. To date, the descriptions of product immunogenicity have varied not only due to different degrees of understanding of product immunogenicity at the time of licensing but also due to an evolving lexicon that has generated some confusion in the field. In recent years, there has been growing consensus regarding the data needed to assess product immunogenicity. Harmonization of the strategy for the elucidation of product immunogenicity by drug developers, as well as the use of defined common terminology, can benefit medical practitioners, health regulatory agencies, and ultimately the patients. Clearly, understanding the incidence, kinetics and magnitude of anti-drug antibody (ADA), its neutralizing ability, cross-reactivity with endogenous molecules or other marketed biologic drugs, and related clinical impact may enhance clinical management of patients treated with biologic drugs. To that end, the authors present terms and definitions for describing and analyzing clinical immunogenicity data and suggest approaches to data presentation, emphasizing associations of ADA development with pharmacokinetics, efficacy, and safety that are necessary to assess the clinical relevance of immunogenicity.

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Acknowledgments

This work was sponsored by The Therapeutic Protein Immunogenicity Focus Group (TPIFG) of the BIOTEC Section, American Association of Pharmaceutical Scientists (AAPS). A global physician survey was conducted by TPIFG in 2010 and 2011 to assess the viewpoints and needs of medical practitioners relative to immunogenicity. Survey results and a call for the harmonization of terminology and the analysis and reporting of clinical immunogenicity were presented at the European Immunogenicity Platform (EIP) Symposium in December 2010 (Gent, Belgium) and at an Open Forum of the AAPS National Biotechnology Conference (NBC) in May 2011 (San Francisco, USA). Draft definitions and work-in-progress data presentation tactics were presented at the EIP symposia in February 2012 (Copenhagen, Denmark) and February 2013 (Munich, Germany) and at AAPS-NBC conventions in May 2012 and May 2013 (San Diego, USA). Finally, a draft manuscript was posted on the AAPS website for public feedback. The authors thank all those who provided feedback, which was considered during the finalization of this manuscript. During the preparation of this manuscript, our recommended terminology, definitions, and approaches for ADA characterization were shared with the ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) consortium, which agreed to adopt them. ABIRISK is a project of the Innovative Medicines Initiative (IMI), a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA), and aims to conduct immunogenicity studies of several biologic drugs, which will be used to develop a database comprising their evaluations of factors underlying immunogenicity and to generate tools for determining how individual patients are likely to respond.

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The contents of this article reflect the personal opinions of the authors and may not represent the official positions or perspectives of their affiliated organizations.

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Authors and Affiliations

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

    G. Shankar

  2. Pfizer Worldwide Research & Development, Cambridge, Massachusetts, USA

    S. Arkin

  3. CERB/Clinical Evaluation Division, Health Canada, Ottawa, Ontario, Canada

    L. Cocea

  4. AbbVie, Inc., Chicago, Illinois, USA

    V. Devanarayan

  5. CDER/Office of Therapeutic Proteins, US Food and Drug Administration, Rockville, Maryland, USA

    S. Kirshner & D. Verthelyi

  6. IPM Biotech GmbH, Hamburg, Germany

    A. Kromminga

  7. Genentech, South San Francisco, California, USA

    V. Quarmby

  8. Sanofi, Framingham, Massachusetts, USA

    S. Richards

  9. Danish National Health and Medicines Authority, Copenhagen, Denmark

    C. K. Schneider

  10. Twincore Center for Infection Research, Hanover, Germany

    C. K. Schneider

  11. Biogen Idec, Inc., Cambridge, Massachusetts, USA

    M. Subramanyam

  12. Amgen, Inc., Thousand Oaks, California, USA

    S. Swanson

  13. Division of Pulmonary, Allergy and Rheumatology Products, US Food and Drug Administration, Rockville, Maryland, USA

    S. Yim

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  1. G. Shankar
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Correspondence to G. Shankar.

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The contents of this article reflect the consensus perspective of the authors and may not represent the official positions or expectations of their affiliated organizations. This article is not a substitute or equivalent of a guidance document from a health regulatory agency.

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Shankar, G., Arkin, S., Cocea, L. et al. Assessment and Reporting of the Clinical Immunogenicity of Therapeutic Proteins and Peptides—Harmonized Terminology and Tactical Recommendations. AAPS J 16, 658–673 (2014). https://doi.org/10.1208/s12248-014-9599-2

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