IMMUNOGENICITY IN PRECLINICAL DRUG DEVELOPMENT: STRATEGIES, RISKS, AND IMPLICATIONS FOR LARGE MOLECULE-BASED BIOLOGICS INCLUDING CAR T-CELL AND GENE THERAPIES

Sagarkumar Patel, Rachna Patel, Ashok H Akabari

Immunogenicity is a critical consideration in developing therapeutic agents, particularly in large molecule-based biologics, CAR T-cell therapies, and gene therapies. This comprehensive review delves into the multifaceted landscape of immunogenicity, elucidating its definition and significance in drug development. Immunogenicity encompasses the complex interplay between therapeutic agents and the immune system, posing opportunities and challenges. It necessitates a nuanced approach to assessment, explored in detail, including the methods and tools employed during preclinical development and the vital role of predictive immunogenicity assays. Factors contributing to immunogenicities, such as protein structure, post-translational modifications, and patient-related variables, are dissected, shedding light on the intricate determinants of immune responses.   Moreover, the review explores how immunogenicity can profoundly impact pharmacokinetics and pharmacodynamics, substantiated by real-world cases. Risk mitigation strategies are a focal point, emphasizing the importance of protein engineering, formulation development, and the judicious use of immunosuppressive therapies. The review further addresses the unique challenges posed by CAR T-cell therapies and gene therapies, highlighting their distinctive immunogenicity considerations. Regulatory guidelines governing immunogenicity assessment and the imperative of addressing this aspect in regulatory submissions are also discussed. Finally, the review provides a series of case studies, offering tangible examples of how immunogenicity has influenced drug development, encompassing successful strategies and encountered challenges. Future directions in immunogenicity research promise to shape the landscape of therapeutic effect, with implications for precision medicine and patient-centric care.