Taking immunogenicity assessment of therapeutic proteins to the next level
Introduction
For nearly 30 years, therapeutic proteins have revolutionised the treatment of numerous diseases. Different classes of biotherapeutics have become available, such as antibodies, hormones, enzymes, growth and blood factors allowing major progress in treatment. However, it became obvious that many of these products bear the risk of an unwanted immune response (which will be referred to as “immunogenicity” throughout this report). The immunogenic profile of therapeutic proteins and the ensuing risk to patients is determined by a multiplicity of product-, process- and patient-related factors that have to be systematically evaluated during the clinical development of the therapeutic agent to ensure a proper benefit/risk assessment. Clinical consequences of immunogenicity range from no effect, a reduction or loss of efficacy to severe complications due to neutralisation of the natural counterpart or general immune system reactions. Often these “common rare” events have an incidence of less than 1% of treated patients and become only obvious at the late stage of phase III trials or after approval.
Research has added considerable knowledge about the pathogenesis of immunogenicity, comprising ‘classical’ immune reactions to neo-antigens as well as the breakdown of immune tolerance to self-antigens. At the same time, manufacturing and analytical characterisation technologies have changed and are constantly evolving. Thus, regulatory agencies are facing a highly dynamic process.
Regulations and guidelines have been developed to support drug developers and regulators to ensure the safety of therapeutic proteins. Such guidance is expected to be sufficiently specific but needs to be flexible enough to take into account ongoing technical and scientific progress. To provide a forum for discussion and taking the next steps to handle unwanted immunogenicity from a regulatory perspective, the International Association for Biologicals (IABS), the Paul-Ehrlich-Institute (PEI) (Federal Institute for Vaccines and Biologicals, Germany), and the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) organised an international conference on ‘Taking immunogenicity assessment of therapeutic proteins to the next level’ that was held in Langen, Germany, on the 10.–11. June 2010. Experts in the field of unwanted immunogenicity from industry, academia and regulatory agencies worldwide discussed the phenomenon of undesired immunogenicity from different angles.
The conference aimed at taking the regulatory assessment of immunogenicity risk to the next level: first, to enhance the dialogue on the application of regulatory guidance on identifying and controlling risks associated with undesirable immunogenicity and second, to discuss how unwanted immunogenicity is practically handled to achieve an appropriate overall benefit-risk estimation. Available guidance documents and the progress on new guidelines that are currently under development were presented as well as case studies with regard to immunogenicity assessment and the pathogenesis of an unwanted immune response.
After an opening keynote lecture by the PEI president Klaus Cichutek, the first two sessions, chaired by Christian K. Schneider and Isabel C. Büttel (PEI, Germany), Harald Kropshofer (Hoffmann-La Roche, Switzerland) and Paul Chamberlain (NDA Advisory Board, France), respectively, provided a wide overview of existing and upcoming guidelines. The third session, chaired by Huub Schellekens (Utrecht University, The Netherlands) and Falk Ehmann (European Medicines Agency [EMA], United Kingdom [UK]), asked what we learned from case studies and how new insights could be incorporated into advanced testing strategies. The following sessions, chaired by Anthony Mire-Sluis (Amgen, United States of America [USA]), Jean-Hugues Trouvin, (Agence française de sécurité sanitaire des produits de Santé [AFSSAPS], France), Martina Weise (Federal Institute for Drugs and Medical Devices [BfArM], Germany), and Philippe Stas (Algonomics [Lonza], Belgium) reflected on the pathogenesis of immunogenicity. The panel discussion, chaired by Johannes Löwer (BfArM, Germany), focussed on immunogenicity data that are required during product development and in the post-marketing phase. Christian K. Schneider then summarised the conclusions and recommendations of the meeting.
Section snippets
General guidelines
Therapeutic proteins are highly complex molecules because of the diversity of characteristics that are inherent to both the drug substance or product itself and its manufacturing process. In addition to these product-related factors, several patient- and regimen-related factors may contribute to immunogenicity. It became obvious that the heterogeneity of testing strategies, analytical methods, and sampling schedules impede the systematic assessment of immunogenicity between the different
The risk-based approach
Risk is defined as the product of probability and consequences. Therefore, risk-based strategies for immunogenicity assessment involve various factors influencing the probability of an unwanted immune response and the severity of any clinical consequences due to unwanted immunogenicity. More specifically, (i) the identification of the risk factors; (ii) an impact assessment that balances probability vs. severity vs. detectability; and (iii) the risk management strategy. The probability depends
Aggregation
One of the major issues throughout the whole conference was the intrinsic tendency of therapeutic proteins to form aggregates. It was suggested that protein aggregates contribute to the immunogenicity of therapeutic protein preparations, either by revealing new epitopes or by forming highly repetitive motifs. Although there have been some reports [35], [36] that suggest a causal link between levels of aggregates and the immunogenic potential of biopharmaceutical products, open questions remain
Conclusions and recommendations
Assessment of the benefit-risk balance of therapeutic proteins is the key element of the scientific evaluation of a marketing authorisation application, which encompasses also immunogenic potential in the context of clinical considerations. In his closing remarks, Christian K. Schneider summarised the different approaches for the assessment of unwanted immunogenicity that were proposed during the meeting. Furthermore, he integrated these approaches into a framework of risk estimation, risk
Disclaimer
The views expressed in this article are the personal views of the authors and are not to be understood or quoted as being made on behalf of the EMA, one of its committees, or of the FDA, nor reflecting the position of the EMA, one of its committees, one of its Working Parties, or the FDA.
Acknowledgements
We thank Dr Stefan Lang (Osdorf, Germany) who provided scientific writing services and editorial assistance. The authors also wish to thank the present President of the PEI, Prof Klaus Cichutek, for the possibility to hold the conference at the PEI and for hosting the event, and the former President of the PEI, Prof Johannes Löwer, for excellent chairmanship of the panel discussion. The authors thank Daniel Gaudry (IABS), Anthony Lubiniecki (IABS), Uta Hornischer (IABS) and Ryoko Krause (IABS,
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- 1
Jean-Hugues Trouvin is the Chair of the Biologics Working Party of the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA), London, UK.
- 2
Martina Weise is the German Alternate of the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA) and Vice-Chair of the Biosimilar Working Party of the CHMP.
- 3
Christian K. Schneider is a member of the CHMP at the European Medicines Agency (EMA), and Rapporteur for the CHMP Guideline on Immunogenicity Assessment of Biotechnology-derived Therapeutic Proteins.