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.

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

“…133 The therapeutic protein itself can also be a source of immune response, in particular when treating genetic diseases. 134 Despite these challenges, mRNA formulations offer significant potential as vehicles for in vivo gene editing. To date, the most widely used and well-characterized gene-editing technology is the CRISPR-Cas9 system, with an effector domain originating from Streptococcus pyogenes (SpCas9).…”

T-Cell Dependent Immunogenicity of Protein Therapeutics Pre-clinical Assessment and Mitigation–Updated Consensus and Review 2020

“…ADA development to monoclonal antibody-drugs can also lead to loss of response and drug switching, even in the case of fully humanized molecules. In this context, various approaches to inducing immune tolerance to biotherapeutics have been envisaged and reviewed elsewhere (160). ADA responses to other lifesaving therapeutic proteins, such as enzyme replacement therapies, have compromised treatment efficacy and even caused death.…”

Toward Drug-Like Multispecific Antibodies by Design

“…Therefore, immunogenicity is a primary concern for the development of safe and effective biologics. To this end, a number of strategies have been developed for reducing unwanted immunogenic activity of biologics [ 236 , 237 ], and the FDA has recently released guidance for developing and validating assays to assess immunogenicity of therapeutic proteins [ 234 ].…”