title: Approaches to Mitigate the Unwanted Immunogenicity of Therapeutic Proteins during Drug Development.
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.
authors.affiliation: Translational Medicine and Early Development, Sanofi Genzyme R&D, Framingham, Massachusetts, USA. Laura.Salazar-Fontana@sanofi.com.
authors.forename: Laura I
authors.initials: LI
authors.lastname: Salazar-Fontana
authors.affiliation: Bioanalytical Sciences-Biologics, Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Dharmesh D
authors.initials: DD
authors.lastname: Desai
authors.affiliation: Pharmaceutical Development & Supplies, PTD Biologics Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Tarik A
authors.initials: TA
authors.lastname: Khan
authors.affiliation: Bioanalytical Sciences-Biologics, Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Renuka C
authors.initials: RC
authors.lastname: Pillutla
authors.affiliation: Division of Biotherapeutics, National Institute for Biological Standards and Control (NIBSC), Hertfordshire, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Prior
authors.affiliation: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Pennington, New Jersey, USA.|Department of Pharmaceutical Sciences, University at Buffalo, the State University of New York, Buffalo, New York, USA.
authors.forename: Radha
authors.initials: R
authors.lastname: Ramakrishnan
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, the State University of New York, Buffalo, New York, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schneider
authors.affiliation: Translational Medicine and Early Development, Sanofi Genzyme R&D, Framingham, Massachusetts, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Joseph
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D051379:Mice; D011506:Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000906:Antibodies; D007155:Immunologic Factors; D011506:Proteins
keywords: anti-drug antibodies; immune mitigation; immune prediction; therapeutic proteins; tolerance