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

• 成果类型: Article
• 署名作者: 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, Rene; 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
• 署名单位: Biogen; University of Minnesota System; University of Minnesota Twin Cities
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9508
• DOI: 10.1126/science.ads3204
• 发表日期: 2025-08-07
• 关键词: perivascular drainage pathways; central-nervous-system; alzheimers-disease; in-vivo; imaging abnormalities; beta; blood; angiopathy; fluid; diffusion

摘要

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-beta protein (anti-A beta) using asymmetrical Fc mutations (ATVcisLALA) that mitigates TfR-related liabilities and retains effector function when bound to A beta. Administration of ATVcisLALA:A beta in mice exhibited broad brain distribution and enhanced parenchymal plaque target engagement. This biodistribution reduced ARIA-like lesions and vascular inflammation. Taken together, ATVcisLALA has the potential to improve the next generation of A beta immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.