George S. Wise Faculty of Life Sciences, School of Molecular Cell Biology and Biotechnology, Tel Aviv University, Tel Aviv, Israel.
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, United States.
Front Immunol. 2020 Aug 18;11:1951. doi: 10.3389/fimmu.2020.01951. eCollection 2020.
Monoclonal antibodies (mAbs) are a crucial asset for human health and modern medicine, however, the repeated administration of mAbs can be highly immunogenic. Drug immunogenicity manifests in the generation of anti-drug antibodies (ADAs), and some mAbs show immunogenicity in up to 70% of patients. ADAs can alter a drug's pharmacokinetic and pharmacodynamic properties, reducing drug efficacy. In more severe cases, ADAs can neutralize the drug's therapeutic effects or cause severe adverse events to the patient. While some contributing factors to ADA formation are known, the molecular mechanisms of how therapeutic mAbs elicit ADAs are not completely clear. Accurate ADA detection is necessary to provide clinicians with sufficient information for patient monitoring and clinical intervention. However, ADA assays present unique challenges because both the analyte and antigen are antibodies, so most assays are cumbersome, costly, time consuming, and lack standardization. This review will discuss aspects related to ADA formation following mAb drug administration. First, we will provide an overview of the prevalence of ADA formation and the available diagnostic tools for their detection. Next, we will review studies that support possible molecular mechanisms causing the formation of ADA. Finally, we will summarize recent approaches used to decrease the propensity of mAbs to induce ADAs.
单克隆抗体 (mAbs) 是人类健康和现代医学的重要资产，然而，mAbs 的重复给药可能具有高度免疫原性。药物免疫原性表现为产生抗药物抗体 (ADA)，一些 mAbs 在高达 70%的患者中表现出免疫原性。ADA 可以改变药物的药代动力学和药效学特性，降低药物疗效。在更严重的情况下，ADA 可以中和药物的治疗效果或导致患者出现严重的不良反应。虽然已知 ADA 形成的一些促成因素，但治疗性 mAbs 如何引发 ADA 的分子机制尚不完全清楚。准确检测 ADA 对于为临床医生提供足够的信息以进行患者监测和临床干预是必要的。然而，ADA 检测方法存在独特的挑战，因为分析物和抗原都是抗体，因此大多数检测方法繁琐、昂贵、耗时且缺乏标准化。这篇综述将讨论 mAb 药物给药后 ADA 形成的相关方面。首先，我们将概述 ADA 形成的流行率和用于检测它们的现有诊断工具。接下来，我们将回顾支持导致 ADA 形成的可能分子机制的研究。最后，我们将总结最近用于降低 mAbs 诱导 ADA 倾向的方法。
