Pfizer, San Diego, CA, USA.
University of Leuven, Leuven, Belgium.
J Immunother Cancer. 2019 Apr 15;7(1):105. doi: 10.1186/s40425-019-0586-0.
The increasing use of multiple immunomodulatory (IMD) agents for cancer therapies (e.g. antibodies targeting immune checkpoints, bispecific antibodies, and chimeric antigen receptor [CAR]-T cells), is raising questions on their potential immunogenicity and effects on treatment. In this review, we outline the mechanisms of action (MOA) of approved, antibody-based IMD agents, potentially related to their immunogenicity, and discuss the reported incidence of anti-drug antibodies (ADA) as well as their clinical relevance in patients with cancer. In addition, we discuss the impact of the administration route and potential strategies to reduce the incidence of ADA and manage treated patients. Analysis of published reports indicated that the risk of immunogenicity did not appear to correlate with the MOA of anti-programmed death 1 (PD-1)/PD-ligand 1 monoclonal antibodies nor to substantially affect treatment with most of these agents in the majority of patients evaluated to date. Treatment with B-cell depleting agents appears associated with a low risk of immunogenicity. No significant difference in ADA incidence was found between the intravenous and subcutaneous administration routes for a panel of non-oncology IMD antibodies. Additionally, while the data suggest a higher likelihood of immunogenicity for antibodies with T-cell or antigen-presenting cell (APC) targets versus B-cell targets, it is possible to have targets expressed on APCs or T cells and still have a low incidence of immunogenicity.
多种免疫调节（IMD）药物（例如针对免疫检查点的抗体、双特异性抗体和嵌合抗原受体 [CAR]-T 细胞）越来越多地用于癌症治疗，这引发了对其潜在免疫原性和对治疗影响的疑问。在这篇综述中，我们概述了已批准的基于抗体的 IMD 药物的作用机制（MOA），这些机制可能与其免疫原性有关，并讨论了报告的抗药物抗体（ADA）的发生率及其在癌症患者中的临床相关性。此外，我们还讨论了给药途径的影响以及潜在的策略，以降低 ADA 的发生率并管理接受治疗的患者。对已发表报告的分析表明，免疫原性风险似乎与抗程序性死亡 1（PD-1）/PD-配体 1 单克隆抗体的 MOA 无关，也不会实质性影响迄今为止评估的大多数患者中这些药物的大多数治疗效果。B 细胞耗竭剂的治疗似乎与免疫原性风险低相关。在一组非肿瘤学 IMD 抗体中，静脉内和皮下给药途径的 ADA 发生率没有显著差异。此外，虽然数据表明，针对 T 细胞或抗原呈递细胞（APC）靶点的抗体比针对 B 细胞靶点的抗体更有可能具有免疫原性，但仍有可能针对 APC 或 T 细胞表达的靶点，并且 ADA 的发生率仍然很低。
