Understanding immunogenicity responses

Feb 01, 2009
Volume 21, Issue 2

Immunogenicity can either be wanted or unwanted. Since the first biopharmaceuticals were placed on the market more than 20 years ago, unwanted immunological reactions have been observed in man and, thus, postmarket surveillance contributed to coining this expression. In this context, immunogenicity is the 'unwanted' immune response (IR) that can lead to clinically adverse consequences.1 It can analytically be shown by the detection of neutralizing antibodies (NAbs) and non-neutralizing antibodies (NNAbs) to therapeutic proteins. On the other hand, immunogenicity is also the 'wanted' IR directed against proteins intended for the induction of a protective immunity, such as vaccines.

There are multiple causes for unwanted immunogenicity including:

  • sequence variations
  • glycosylation
  • presence of contaminants and impurities
  • aggregation
  • formulation
  • route of application
  • dosing
  • length of treatment
  • assay technologies
  • a patient's characteristics and/or genetic background.

The 'wanted' immunogenicity requires computational analysis of protein sequences giving rise to potential B-cell and T-cell epitopes, which are the prerequisites for the induction of long-lasting protective immunity, the major goal of designing vaccines.

This article briefly describes the basic principles of immunity and the nature of antibodies, the different concepts of biopharmaceuticals, regulatory considerations on immunogenicity issues, the impact of the different in vitro diagnostic methods used for detection of NAbs and NNAbs, and the information obtained through postmarketing surveillance.


Immunogenicity assessment of biopharmaceuticals is a master of disciplines because it requires knowledge of protein/antibody structures and developmental design, as well as knowledge of the immune system paired with understanding of technological and analytical procedures, methods and techniques and their implementation in monitoring clinical and preclinical studies.

Testing for immunogenicity requires the analysis of NAbs and NNAbs to therapeutic proteins and potential cross-reactivity to endogenous protein (when applicable). Major factors causing immunogenicity are: treatment with proteins of nonhuman origin, the presence of impurities, the formation of aggregates, the immune status of the individual patients in addition to protein/antibody formats, post-translational modifications, degradation of products, storage conditions and dose, route, frequency, and duration of therapeutic protein administration.2–4

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