Nielsen Ole Haagen, Hammerhøj Alexander, Ainsworth Mark Andrew, Gubatan John, D'Haens Geert
Department of Gastroenterology D112, Herlev Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 1, 2730 Herlev, Copenhagen, Denmark.
Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
Drugs. 2025 Jan;85(1):67-85. doi: 10.1007/s40265-024-02115-3. Epub 2024 Nov 13.
The introduction of tumor necrosis factor inhibitors has led to a paradigm shift in the management of inflammatory bowel disease (IBD). The subsequent introduction of both anti-integrins and cytokine blockers has since expanded the biologic armamentarium. However, immunogenicity, defined as the production of anti-drug antibodies (ADAs) to the prescribed biopharmaceutical, means a significant fraction of patients exposed to biologic agents will experience a secondary loss of response to one or more of the drugs. In clinical settings, immunogenicity may be caused by several factors, both patient related (e.g., underlying chronic disease, systemic immune burden, including previous biologic therapy failure, and [epi]genetic background) and treatment related (e.g., dose and administration regimens, drug physical structure, photostability, temperature, and agitation). Here, we outline these elements in detail to enhance biopharmaceutical delivery and therapy for patients with IBD. Moreover, concurrent immunomodulator medication may reduce the risks of ADA generation, especially when using the chimeric drug infliximab. Summarizing the latest developments and knowledge in the field, this review aims to provide strategies to prevent ADA production and information on managing non-responsiveness or loss of response to biologics. Better understanding of the molecular mechanisms underlying the formation of ADAs and the critical factors influencing the immunogenicity of biopharmaceuticals may lead to improved health outcomes in the IBD community that may benefit both the individual patient and society through lower healthcare expenses.
肿瘤坏死因子抑制剂的引入导致了炎症性肠病（IBD）治疗模式的转变。随后抗整合素和细胞因子阻滞剂的引入进一步扩大了生物制剂的种类。然而，免疫原性，即针对所使用的生物制药产生抗药物抗体（ADA），意味着很大一部分接受生物制剂治疗的患者会对一种或多种药物出现继发性反应丧失。在临床环境中，免疫原性可能由多种因素引起，包括与患者相关的因素（如潜在的慢性疾病、全身免疫负担，包括既往生物治疗失败以及[表观]遗传背景）和与治疗相关的因素（如剂量和给药方案、药物物理结构、光稳定性、温度和搅拌）。在此，我们详细阐述这些因素，以加强对IBD患者的生物制药递送和治疗。此外，同时使用免疫调节剂可能会降低ADA产生的风险，尤其是在使用嵌合药物英夫利昔单抗时。本综述总结了该领域的最新进展和知识，旨在提供预防ADA产生的策略以及处理对生物制剂无反应或反应丧失的相关信息。更好地理解ADA形成的分子机制以及影响生物制药免疫原性的关键因素，可能会改善IBD群体的健康结局，通过降低医疗费用使个体患者和社会均受益。
