Factors involved in the immunogenicity of biopharmaceutical products and mitigation strategies.

This article reviews the immunogenicity of protein-based biopharmaceutical products, focusing on the immune mechanisms involved, factors influencing immunogenicity, and strategies to mitigate immune responses. It highlights that both product-related factors—such as protein structure, aggregation, chemical modifications, contaminants, glycosylation patterns, and formulation—and host-related factors—including genetic background, immune status, and route of administration—contribute to the development of anti-drug antibodies that can reduce therapeutic efficacy and safety. The review also discusses preclinical screening methods and various engineering approaches, such as sequence humanization, PEGylation, removal of T-cell epitopes (agretopes), and improving protein solubility, aimed at reducing immunogenicity. Understanding these factors and mitigation strategies is essential for developing safer and more effective protein therapeutics.