INTRODUCTION: Immunogenicity of biologic agents for inflammatory bowel disease (IBD) is a critical issue, especially for tumor necrosis factor (TNF) inhibitors, where anti-drug antibodies (ADAs) significantly impact drug clearance, efficacy, and safety. Studies have demonstrated that non-TNF biologics tend to have lower susceptibility to immunogenicity, potentially offering advantages, especially in long-term management. Understanding these differences is important for optimizing IBD treatment outcomes. AREAS COVERED: This review examines immunogenicity associated with different classes and individual biologic agents used in IBD
including TNF inhibitors and biologics targeting integrins and interleukins. We discuss key factors influencing ADAs formation, including drug structure, route of administration, and patient-specific factors. The literature reviewed includes recent clinical studies and long-term trials focusing on strategies to reduce immunogenicity such as therapeutic drug monitoring (TDM) and advanced combination. EXPERT OPINION: While newer biologics demonstrate lower immunogenicity compared to anti-TNF agents, challenges remain in management to overcome existing ADAs responses while advances in genetic profiling, point-of-care TDM, and combination therapies offer promising pathways to reduce immunogenicity and enhance treatment durability. Continued research and innovation in biologic delivery methods, such as oral and subcutaneous formulations, will be critical in the next decade to further mitigate immunogenic risks and improve patient outcomes.