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Pharmacogenetics and the immunogenicity of protein therapeutics

Nature Biotechnology volume 29, pages 870–873 (2011)Cite this article

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To the Editor:

The development of anti-drug antibodies (ADAs) to therapeutic proteins can lead to adverse events and also make a biologic less effective for its intended use. Immunogenicity assessments are now critical for the development, regulatory licensure and use of biologics and it has been argued that it is highly unlikely that regulatory approval would be granted for a biologic without an assessment of its immunogenicity1. The development of ADAs does not necessarily affect the safety and/or efficacy of a protein therapeutic and thus risk-based approaches are generally advocated to evaluate the clinical consequences2. For example, although therapies that involve replacement of proteins that are lacking or nonfunctional in patients have had spectacular results in the clinical management of many chronic diseases, such therapies are particularly prone to have adverse consequences as a result of so-called neutralizing ADAs3. Several reviews have previously catalogued the product and patient-related risk factors for immunogenicity (refs. 4,5 and references therein and Supplementary Fig. 1).

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Figure 1: Schematic of a proposed decision tree for the evaluation of immunogenicity in individual patients or populations.
Figure 2: Estimating potential ADA responses to factor VIII in individual patients.

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Acknowledgements

We thank C.K. Sarfaty and B. Golding for helpful comments during discussions and G.S. Pandey for editorial assistance. This work was supported by funds from the Center for Biologics Evaluation and Research, Food and Drug Administration's Modernization of Science program (ZES). The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy.

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Authors and Affiliations

  1. Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Chen Yanover

  2. Division of Hematology, Clinical Review Branch, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA

    Nisha Jain

  3. Biogen Idec Hemophilia, Waltham, Massachusetts, USA

    Glenn Pierce

  4. Department of Pathology and Laboratory Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA

    Tom E Howard

  5. Division of Hematology, Laboratory of Hemostasis, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA

    Zuben E Sauna

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Corresponding author

Correspondence to Zuben E Sauna.

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Competing interests

G.P. is an employee of BiogenIDEC.

Additional information

C.Y. analyzed the data, generated Figure 2 and contributed to the writing of the manuscript. G.P. wrote the section on the clinical development and regulatory requirements for developing a personalized approach to protein replacement therapy. T.E.H. and N.J. provided the discussion of the clinical and regulatory issues, respectively. Z.E.S. was responsible for conceptualizing this project and overall writing of the manuscript.

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Yanover, C., Jain, N., Pierce, G. et al. Pharmacogenetics and the immunogenicity of protein therapeutics. Nat Biotechnol 29, 870–873 (2011). https://doi.org/10.1038/nbt.2002

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