Transferrin receptor–targeted anti-amyloid antibody enhances brain delivery and mitigates ARIA
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 C. Amaral, Isabel Becerra, Roni Chau, Johann Chow, Allisa Clemens, Mark S. Dennis, Joseph Duque, Laura Fusaro, Jennifer A. Getz, Mihalis S. Kariolis, Do Jin Kim, Kendra J. Lechtenberg, 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 K. Tong, Meredith Calvert, Ryan J. Watts, Robert G. Thorne, Paul H. Weinreb, Dominic M. Walsh, Joseph W. Lewcock, Thierry Bussiere, Y. Joy Yu Zuchero
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 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.