转铁蛋白受体靶向抗淀粉样蛋白抗体增强脑内递送并减轻淀粉样蛋白相关影像学异常（ARIA）

Transferrin receptor-targeted anti-amyloid antibody enhances brain delivery and mitigates ARIA.

作者信息

Pizzo Michelle E, Plowey Edward D, Khoury Nathalie, Kwan Wanda, Abettan Jordan, DeVos Sarah L, Discenza Claire B, Earr Timothy, Joy David, Lye-Barthel Ming, Roche Elysia, Chan Darren, Dugas Jason C, Gadkar Kapil, Hamann Stefan, Meisner René, Sebalusky Jennifer, Silva Amaral Ana Claudia, Becerra Isabel, Chau Roni, Chow Johann, Clemens Allisa J, Dennis Mark S, Duque Joseph, Fusaro Laura, Getz Jennifer A, Kariolis Mihalis S, Kim Do Jin, Lechtenberg Kendra J, Leung Amy Wing-Sze, Moshkforoush Arash, Nguyen Hoang N, Ojo Emmanuel S, Thomsen Elliot R, Torres Vanessa O, Sanchez Pascal E, Shan Lu, Silverman Adam P, Sweeney Zachary K, Solanoy Hilda, Tong Raymond, Calvert Meredith E, Watts Ryan J, Thorne Robert G, Weinreb Paul H, Walsh Dominic M, Lewcock Joseph W, Bussiere Thierry, Zuchero Y Joy Yu

机构信息

Denali Therapeutics, Inc., South San Francisco, CA, USA.

Biogen, Cambridge, MA, USA.

出版信息

Science. 2025 Aug 7;389(6760):eads3204. doi: 10.1126/science.ads3204.

DOI:10.1126/science.ads3204

PMID:40773560

Abstract

Amyloid-related imaging abnormalities (ARIA), side effects of anti-amyloid drugs seen in magnetic resonance imaging of the brain, are a major safety concern in patients with Alzheimer's disease. We developed an antibody transport vehicle (ATV) targeting transferrin receptor (TfR) for brain delivery of anti-amyloid-β protein (anti-Aβ) using asymmetrical Fc mutations (ATV) that mitigates TfR-related liabilities and retains effector function when bound to Aβ. Administration of ATV:Aβ in mice exhibited broad brain distribution and enhanced parenchymal plaque target engagement. This biodistribution reduced ARIA-like lesions and vascular inflammation. Taken together, ATV has the potential to improve the next generation of Aβ immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.

摘要

淀粉样蛋白相关成像异常（ARIA）是在大脑磁共振成像中观察到的抗淀粉样蛋白药物的副作用，是阿尔茨海默病患者的一个主要安全问题。我们开发了一种靶向转铁蛋白受体（TfR）的抗体转运载体（ATV），用于将抗淀粉样β蛋白（抗Aβ）递送至大脑，该载体使用不对称Fc突变（ATV），可减轻与TfR相关的不良反应，并在与Aβ结合时保留效应功能。在小鼠中给予ATV:Aβ显示出广泛的脑部分布，并增强了实质斑块靶向结合。这种生物分布减少了ARIA样病变和血管炎症。综上所述，ATV有可能通过增强血脑屏障转运介导的生物分布来改善下一代Aβ免疫疗法。