Yang Han-Mo
Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea.
Int J Mol Sci. 2025 Jun 28;26(13):6271. doi: 10.3390/ijms26136271.
Alzheimer's disease (AD) impacts more than half a million people worldwide, with no cure available. The regulatory approval of three anti-amyloid monoclonal antibodies (mAbs), including aducanumab, lecanemab, and donanemab, has established immunotherapy as a therapeutic approach to modify disease progression. Its multifactorial pathology, which involves amyloid-β (Aβ) plaques, tau neurofibrillary tangles, neuroinflammation, and cerebrovascular dysfunction, limits the efficacy of single-target therapies. The restricted blood-brain barrier (BBB) penetration and amyloid-related imaging abnormalities (ARIA), together with small treatment effects, demonstrate the necessity for advanced biologic therapies. Protein engineering advancements have created bispecific antibodies that bind to pathological proteins (e.g., Aβ, tau) and BBB shuttle receptors to boost brain delivery and dual therapeutic effects. This review combines existing information about antibody-based therapy in AD by focusing on bispecific antibody formats and their preclinical and clinical development, as well as biomarker-based patient selection and upcoming combination strategies. The combination of rationally designed bispecific antibodies with fluid and imaging biomarkers could show potential for overcoming existing therapeutic challenges and delivering significant clinical advantages.
阿尔茨海默病（AD）在全球影响着超过50万人，目前尚无治愈方法。三种抗淀粉样蛋白单克隆抗体（mAb），包括阿杜卡努单抗、莱卡奈单抗和多纳奈单抗，已获得监管批准，确立了免疫疗法作为一种改变疾病进展的治疗方法。其多因素病理，涉及淀粉样β（Aβ）斑块、tau神经原纤维缠结、神经炎症和脑血管功能障碍，限制了单靶点疗法的疗效。血脑屏障（BBB）穿透受限和淀粉样蛋白相关成像异常（ARIA），以及较小的治疗效果，表明需要先进的生物疗法。蛋白质工程的进步产生了双特异性抗体，其可与病理蛋白（如Aβ、tau）和BBB穿梭受体结合，以提高脑部递送和双重治疗效果。本综述通过关注双特异性抗体形式及其临床前和临床开发，以及基于生物标志物的患者选择和即将到来的联合策略，综合了AD中基于抗体治疗的现有信息。合理设计的双特异性抗体与体液和成像生物标志物的结合可能显示出克服现有治疗挑战并带来显著临床优势的潜力。
