Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA, USA.
Department of BioAnalytical Sciences, Genentech, Inc., South San Francisco, CA, USA.
Nat Rev Drug Discov. 2024 Dec;23(12):898-913. doi: 10.1038/s41573-024-01051-x. Epub 2024 Oct 18.
Remarkable progress has been made in recent decades in engineering antibodies and other protein therapeutics, including enhancements to existing functions as well as the advent of novel molecules that confer biological activities previously unknown in nature. These protein therapeutics have brought major benefits to patients across multiple areas of medicine. One major ongoing challenge is that protein therapeutics can elicit unwanted immune responses (immunogenicity) in treated patients, including the generation of anti-drug antibodies. In rare and unpredictable cases, anti-drug antibodies can seriously compromise therapeutic safety and/or efficacy. Systematic deconvolution of this immunogenicity problem is confounded by the complexity of its many contributing factors and the inherent limitations of available experimental and computational methods. Nevertheless, continued progress with the assessment and mitigation of immunogenicity risk at the preclinical stage has the potential to reduce the incidence and severity of clinical immunogenicity events. This Review focuses on identifying key unsolved anti-drug antibody-related challenges and offers some pragmatic approaches towards addressing them. Examples are drawn mainly from antibodies, given that the majority of available clinical data are from this class of protein therapeutics. Plausible and seemingly tractable solutions are in sight for some immunogenicity problems, whereas other challenges will likely require completely new approaches.
近几十年来，在工程抗体和其他蛋白质治疗药物方面取得了显著进展，包括增强现有功能以及出现了以前自然界中未知的具有生物活性的新型分子。这些蛋白质治疗药物为医学多个领域的患者带来了重大益处。一个主要的持续挑战是，蛋白质治疗药物会在接受治疗的患者中引起不必要的免疫反应（免疫原性），包括产生抗药物抗体。在罕见且不可预测的情况下，抗药物抗体可能会严重影响治疗的安全性和/或疗效。由于其许多促成因素的复杂性以及现有实验和计算方法的固有局限性，系统地剖析这种免疫原性问题变得复杂。尽管如此，在临床前阶段继续评估和减轻免疫原性风险仍有可能降低临床免疫原性事件的发生率和严重程度。这篇综述重点介绍了确定与抗药物抗体相关的关键未解决挑战，并提供了一些解决这些问题的实用方法。这些例子主要来自抗体，因为大多数现有的临床数据都来自这一类蛋白质治疗药物。一些免疫原性问题似乎有合理且可行的解决方案，而其他挑战可能需要全新的方法。
