Immunogenicity assessment during the development of protein therapeutics

Objective Here we provide a critical review of the state of the art with respect to non‐clinical assessments of immunogenicity for therapeutic proteins. Key findings The number of studies on immunogenicity published annually has more than doubled in the last 5 years. The science and technology, which have reached a critical mass, provide multiple of non‐clinical approaches (computational, in vitro, ex vivo and animal models) to first predict and then to modify or eliminate T‐cell or B‐cell epitopes via de‐immunization strategies. We discuss how these may be used in the context of drug development in assigning the immunogenicity risk of new and marketed therapeutic proteins. Summary Protein therapeutics represents a large share of the pharma market and provide medical interventions for some of the most complex and intractable diseases. Immunogenicity (the development of antibodies to therapeutic proteins) is an important concern for both the safety and efficacy of protein therapeutics as immune responses may neutralize the activity of life‐saving and highly effective protein therapeutics and induce hypersensitivity responses including anaphylaxis. The non‐clinical computational tools and experimental technologies that offer a comprehensive and increasingly accurate estimation of immunogenic potential are surveyed here. This critical review also discusses technologies which are promising but are not as yet ready for routine use.