转铁蛋白受体靶向抗淀粉样蛋白抗体增强脑传递并减轻ARIA

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-08-07 DOI:10.1126/science.ads3204

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

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引用次数: 0

摘要

淀粉样蛋白相关成像异常（ARIA）是脑磁共振成像中抗淀粉样蛋白药物的副作用，是阿尔茨海默病患者的主要安全问题。我们利用不对称Fc突变（ATV cisLALA）开发了一种靶向转铁蛋白受体（TfR）的抗体运输载体（ATV），用于脑递送抗淀粉样蛋白-β (anti-Aβ)，该载体减轻了TfR相关的负担，并在与Aβ结合时保留了效应功能。给药ATV cisLALA:Aβ小鼠表现出广泛的脑分布和增强的脑实质斑块靶结合。这种生物分布减少了aria样病变和血管炎症。综上所述，ATV cisLALA有潜力通过加强血脑屏障转运介导的生物分布来改善下一代的Aβ免疫治疗。

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

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 cisLALA ) that mitigates TfR-related liabilities and retains effector function when bound to Aβ. Administration of ATV cisLALA :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 cisLALA has the potential to improve the next generation of Aβ immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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