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Approaches to Mitigate the Unwanted Immunogenicity of Therapeutic Proteins during Drug Development

  • Review Article
  • Theme: Controlling Unwanted Immunogenicity to Biotherapeutics
  • Published:
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ABSTRACT

All biotherapeutics have the potential to induce an immune response. This immunological response is complex and, in addition to antibody formation, involves T cell activation and innate immune responses that could contribute to adverse effects. Integrated immunogenicity data analysis is crucial to understanding the possible clinical consequences of anti-drug antibody (ADA) responses. Because patient- and product-related factors can influence the immunogenicity of a therapeutic protein, a risk-based approach is recommended and followed by most drug developers to provide insight over the potential harm of unwanted ADA responses. This paper examines mitigation strategies currently implemented and novel under investigation approaches used by drug developers. The review describes immunomodulatory regimens used in the clinic to mitigate deleterious ADA responses to replacement therapies for deficiency syndromes, such as hemophilia A and B, and high risk classical infantile Pompe patients (e.g., cyclophosphamide, methotrexate, rituximab); novel in silico and in vitro prediction tools used to select candidates based on their immunogenicity potential (e.g., anti-CD52 antibody primary sequence and IFN beta-1a formulation); in vitro generation of tolerogenic antigen-presenting cells (APCs) to reduce ADA responses to factor VIII and IX in murine models of hemophilia; and selection of novel delivery systems to reduce in vivo ADA responses to highly immunogenic biotherapeutics (e.g., asparaginase). We conclude that mitigation strategies should be considered early in development for biotherapeutics based on our knowledge of existing clinical data for biotherapeutics and the immune response involved in the generation of these ADAs.

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Acknowledgements

This work was sponsored by the Therapeutic Product Immunogenicity Focus Group (TPIFG) of the BIOTEC Section, American Association of Pharmaceutical Scientists. Special thanks to Gopi Shankar and the TPIFG steering committee for their valuable feedback on the content of the manuscript and their support on the publication of this review.

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Authors and Affiliations

  1. Translational Medicine and Early Development, Sanofi Genzyme R&D, Framingham, Massachusetts, USA

    Laura I. Salazar-Fontana & Alexandra Joseph

  2. Bioanalytical Sciences-Biologics, Bristol-Myers Squibb, Princeton, New Jersey, USA

    Dharmesh D. Desai & Renuka C. Pillutla

  3. Pharmaceutical Development & Supplies, PTD Biologics Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland

    Tarik A. Khan

  4. Division of Biotherapeutics, National Institute for Biological Standards and Control (NIBSC), Hertfordshire, UK

    Sandra Prior

  5. Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Pennington, New Jersey, USA

    Radha Ramakrishnan

  6. Department of Pharmaceutical Sciences, University at Buffalo, the State University of New York, Buffalo, New York, USA

    Radha Ramakrishnan & Jennifer Schneider

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  1. Laura I. Salazar-Fontana
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  2. Dharmesh D. Desai
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  8. Alexandra Joseph
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Correspondence to Laura I. Salazar-Fontana.

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Guest Editors: Alexandra Joseph, Vibha Jawa, and Shibani Mitra-Kaushik

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Salazar-Fontana, L.I., Desai, D.D., Khan, T.A. et al. Approaches to Mitigate the Unwanted Immunogenicity of Therapeutic Proteins during Drug Development. AAPS J 19, 377–385 (2017). https://doi.org/10.1208/s12248-016-0030-z

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