Assessing the Immunogenicity of Biopharmaceuticals

Abstract

Biopharmaceuticals have the potential to raise an immunogenic response in treated individuals, which may impact the efficacy and safety profile of these drugs. As a result, it is essential to evaluate immunogenicity throughout the different phases of the clinical development of a biopharmaceutical, including post-marketing surveillance. Although rigorous evaluation of biopharmaceutical immunogenicity is required by regulatory authorities, there is a lack of uniform standards for the type, quantity, and quality of evidence, and for guidance on experimental design for immunogenicity assays or criteria to compare immunogenicity of biopharmaceuticals. Moreover, substantial technological advances in methods to assess immune responses have yielded higher immunogenicity rates with modern assays, and limit comparison of immunogenicity of biopharmaceuticals outside of head-to-head clinical trials. Accordingly, research programs, regulatory agencies, and clinicians need to keep pace with continuously evolving analyses of immunogenicity. Here, we review factors associated with immunogenicity of biopharmaceuticals, potential clinical ramifications, and current regulatory guidance for evaluating immunogenicity, and discuss methods to assess immunogenicity in non-clinical and clinical studies. We also describe special considerations for evaluating the immunogenicity of biosimilar candidates.

Fig. 1

Stepwise approach to assessing immunogenicity of biopharmaceuticals. ADA anti-drug antibody

Fig. 2

Evolution of immunogenicity assays for biopharmaceuticals and assessment of anti-adalimumab antibodies (reprinted from van Leeuwen et al. [43], © 2015, with permission from Elsevier and adapted from Thermo Fisher Scientific [Carlsbad, CA, USA]). ADA anti-drug antibody, ADL adalimumab, ARIA acid-dissociation radioimmunoassay, ECL electrochemiluminescence, ELISA enzyme-linked immunosorbent assay, PIA pH-shift anti-idiotype antigen-binding test, TRIA temperature-shift radioimmunoassay

Fig. 3

One-assay versus two-assay approach for anti-drug antibody screening of biosimilars. ADAs anti-drug antibodies