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manoj rajadhyaksha Manoj Rajadhyaksha, Ph.D., is a Director of Bioanalytical Sciences at Regeneron Pharmaceuticals. Rajadhyaksha currently serves as a sponsor of the Immunogenicity Prediction Action Program Area (IPAPA) on the Steering Committee of the Therapeutic Protein Immunogenicity Focus Group within the BIOTECnology section of the American Association of Pharmaceutical Scientists (AAPS).

In the context of drug development, “immunogenicity” refers to the ability of a biotherapeutic to elicit an unwanted immune response. It is difficult to predict immunogenicity risk in humans based on preclinical study results. Therefore the immunogenic potential of a biotherapeutic needs to be assessed in clinical trials. The mechanistic aspects of immune response induction are not completely understood. However, some known drivers of adaptive immune responses to biotherapeutics have been identified and can be generally categorized as product-related (intrinsic) factors or patient-related (extrinsic) factors. Most of the AAPS National Biotechnology Conference (NBC) programming has focused on these drivers, shedding light on how immunogenicity impacts biotherapeutic development. This summer, AAPS is also launching an ecourse dedicated to this topic.

Despite many years of drug development experience with various therapeutic modalities, immunogenicity remains a significant scientific and intellectual challenge. With the advent of newer structural platforms (peptides, nanobodies, bi-specific antibodies, protein conjugates, and oligonucleotides), the unknowns multiply and the challenge grows exponentially.

However, there is a perception of a sort of “immunogenicity fatigue” at NBC due to several programming sessions focused on issues related to immunogenicity. Upon closer observation, it can be seen that these sessions address critical aspects of immunogenicity that are not limited to bioanalytical assessments, but rather these sessions discuss immunogenicity and its impact in several key areas of drug development. What is important to note here is that the successful development of a biotherapeutic drug requires significant contributions from various disciplines that must communicate and work in concert to provide both substantive and subtle contributions.

The general perception is that immunogenicity impacts only safety and that it is a concern only during development. However, immunogenicity impacts multiple disciplines of biotherapeutic drug development. Therefore, understanding and communicating advances in the field of immunogenicity is critical not only to bioanalysts but also to other stakeholders in formulations, clinical, safety, pharmacometrics, and translational medicine. Some of the scientific areas immunogenicity impacts include drug safety, pharmacokinetics/pharmacometrics, translational biology, and formulation.

Immunogenicity and other areas of drug development can benefit from more productive and value-added collaborations. Therefore, in the May issue of the AAPS Newsmagazine, we provide a high-level summary of the impact and significance of immunogenicity in different aspects of drug development and the association of immunogenicity with these key disciplines. Read Immunogenicity: Beyond Bioanalysis, from the Biotechnology section (BIOTEC) of AAPS, and then participate in the discussion point below.

What challenges do you see during assessments of immunogenicity and in the interpretation of results? What impact do these challenges have on the drug development process?