Creighton University School of Medicine, Phoenix, Arizona.
Laboratory on Neurodegeneration and Translational Research, Roseman University of Health Sciences College of Medicine, Las Vegas, Nevada.
Expert Opin Investig Drugs. 2023 Feb;32(2):89-94. doi: 10.1080/13543784.2023.2178414. Epub 2023 Feb 28.
Nearly a dozen monoclonal antibodies (mAbs) directed against beta-amyloid (Aβ) have been developed for the treatment of Alzheimer disease (AD), and most of these mAbs are undergoing clinical trials. Newer mAbs have targeted more specific Aβ types. Lecanemab Eisai has a high affinity for large and soluble Aβ protofibrils. Data from phase 2 clinical trials have suggested the possibility of a robust efficacy signal and manageable risk of amyloid-related imaging abnormalities (ARIAs). Lecanemab is currently being studied in phase 3 trials.
This article briefly reviews mAbs that target Aβ in AD and discusses the biology, mechanism of action, and targets of lecanemab.
mAbs that target Aβ are an important focus of therapeutic development for AD, with several soon to be considered for US Food and Drug Administration approval. The experience of aducanumab informs the development of other mAbs, such as lecanemab. One consideration is the conformation of Aβ targets. Targeting monomeric species has not resulted in robust clinical efficacy, whereas targeting Aβ in the form of oligomers, protofibrils, and plaques has shown evidence of slowing clinical decline. Another consideration is that mAbs will require safety monitoring for ARIAs.
已有十几种针对β-淀粉样蛋白(Aβ)的单克隆抗体(mAbs)被开发用于治疗阿尔茨海默病(AD),其中大多数 mAbs 正在进行临床试验。更新的 mAbs 针对更特定的 Aβ 类型。Eisai 的 lecanemab 对大而可溶性的 Aβ原纤维具有高亲和力。来自 2 期临床试验的数据表明,其可能具有强大的疗效信号和可管理的淀粉样蛋白相关成像异常(ARIA)风险。lecanemab 目前正在 3 期临床试验中进行研究。
本文简要回顾了 AD 中靶向 Aβ 的 mAbs,并讨论了 lecanemab 的生物学、作用机制和靶点。
靶向 Aβ 的 mAbs 是 AD 治疗开发的一个重要重点,其中几种很快将被考虑获得美国食品和药物管理局(FDA)的批准。aducanumab 的经验为其他 mAbs 的开发提供了信息,如 lecanemab。一个考虑因素是 Aβ 靶点的构象。针对单体物种并未产生强大的临床疗效,而针对寡聚体、原纤维和斑块形式的 Aβ 已显示出减缓临床衰退的证据。另一个考虑因素是,mAbs 将需要对 ARIA 进行安全监测。