Laboratory for Medicinal Chemistry Research, Shionogi Pharmaceutical Research Center.
Laboratory for Drug Discovery & Disease Research, Shionogi Pharmaceutical Research Center.
Chem Pharm Bull (Tokyo). 2024;72(7):602-609. doi: 10.1248/cpb.c24-00069.
Amyloid-β (Aβ) plaques and neurofibrillary tangles containing phosphorylated tau protein are major hallmarks of Alzheimer's disease (AD). Drug discovery efforts to target Aβ and tau have been the primary focus for several decades. Recently, substantial breakthroughs have been achieved in the clinical development of Aβ antibodies; aducanumab was approved under conditional accelerated pathway by Food and Drug Administration (FDA) in the U.S. as the first disease-modifying agent for treating AD, and lecanemab has been granted traditional full approved in the U.S. and Japan. In addition, donanemab met the primary endpoint in a phase 3 study. On the other hand, tau-targeting therapies have failed to show clinical benefit although that increased tau levels show a strong correlation with cognitive impairment relative to Aβ depositions. Currently, tau immunotherapies, such as anti-tau antibodies and tau vaccines, have shown functional benefits in clinical trials. Also, clinical trials for combination therapy of Aβ and tau antibodies to see their potential are being investigated. In this review, we provide updates on the results of clinical trials of anti-Aβ antibodies and anti-tau therapeutics and suggest future directions for these therapeutics.
淀粉样蛋白-β（Aβ）斑块和含有磷酸化 tau 蛋白的神经原纤维缠结是阿尔茨海默病（AD）的主要标志。几十年来，靶向 Aβ 和 tau 的药物发现一直是主要焦点。最近，Aβ 抗体的临床开发取得了重大突破；aducanumab 在美国获得了食品和药物管理局（FDA）有条件加速途径的批准，成为治疗 AD 的首个疾病修饰药物，lecanemab 在美国和日本获得了传统的完全批准。此外，donanemab 在一项 3 期研究中达到了主要终点。另一方面，尽管 tau 水平的升高与 Aβ 沉积相比与认知障碍有很强的相关性，但靶向 tau 的治疗方法未能显示出临床益处。目前，tau 免疫疗法，如抗 tau 抗体和 tau 疫苗，在临床试验中显示出了功能益处。此外，正在研究 Aβ 和 tau 抗体联合治疗的临床试验，以观察它们的潜力。在这篇综述中，我们提供了抗 Aβ 抗体和抗 tau 治疗的临床试验结果的最新情况，并为这些治疗方法提出了未来的方向。
