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 (ATVcisLALA) that mitigates TfR-related liabilities and retains effector function when bound to Aβ. Administration of ATVcisLALA:Aβ 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 Aβ immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.