How to systematically evaluate immunogenicity of therapeutic proteins – regulatory considerations

Antibody formation as an immune reaction to a ‘foreign’ protein antigen is an expected physiological reaction that is in many cases intentionally triggered, for example in the case of vaccinations. However, an unwanted immune response to a therapeutic protein may lead to a loss of efficacy and/or to severe side effects. The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) issued a multidisciplinary guideline providing general recommendations from a marketing authorisation perspective on how to assess an unwanted immune response following the administration of a biological drug. In this article, we provide an in-depth regulatory discussion on key principles of systematic evaluation of immunogenicity during development of biotechnological medicinal products, including examples.