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 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
2025-08-07
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.