The AAPS Journal

, Volume 19, Issue 2, pp 377–385 | Cite as

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

  • Laura I. Salazar-FontanaEmail author
  • Dharmesh D. Desai
  • Tarik A. Khan
  • Renuka C. Pillutla
  • Sandra Prior
  • Radha Ramakrishnan
  • Jennifer Schneider
  • Alexandra Joseph
Review Article Theme: Controlling Unwanted Immunogenicity to Biotherapeutics
Part of the following topical collections:
  1. Theme: Controlling Unwanted Immunogenicity to Biotherapeutics


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.


anti-drug antibodies immune mitigation immune prediction therapeutic proteins tolerance 



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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Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Laura I. Salazar-Fontana
    • 1
    Email author
  • Dharmesh D. Desai
    • 2
  • Tarik A. Khan
    • 3
  • Renuka C. Pillutla
    • 2
  • Sandra Prior
    • 4
  • Radha Ramakrishnan
    • 5
    • 6
  • Jennifer Schneider
    • 6
  • Alexandra Joseph
    • 1
  1. 1.Translational Medicine and Early DevelopmentSanofi Genzyme R&DFraminghamUSA
  2. 2.Bioanalytical Sciences-BiologicsBristol-Myers SquibbPrincetonUSA
  3. 3.Pharmaceutical Development & Supplies, PTD Biologics EuropeF. Hoffmann-La Roche Ltd.BaselSwitzerland
  4. 4.Division of BiotherapeuticsNational Institute for Biological Standards and Control (NIBSC)HertfordshireUK
  5. 5.Department of Metabolism and PharmacokineticsBristol-Myers SquibbPenningtonUSA
  6. 6.Department of Pharmaceutical SciencesUniversity at Buffalo, the State University of New YorkBuffaloUSA

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