Abstract Although the first generation of immunotherapies for Alzheimer’s disease (AD) are now clinically approved, amyloid-related imaging abnormalities (ARIA) remain a major safety problem for this class of drugs. Here, we report an antibody transport vehicle (ATV) targeting the transferrin receptor (TfR) for brain delivery of amyloid beta (Aý) antibodies that significantly reduced ARIA-like lesions and improved plaque target engagement in a mouse model of amyloid deposition. Asymmetrical Fc mutations (ATV cisLALA ) allowed the molecule to selectively retain effector function only when bound to Aý while mitigating TfR-related hematology liabilities. Mice treated with ATV cisLALA :Aý exhibited broad brain parenchymal antibody distribution; in contrast, anti-Aý IgG was highly enriched at arterial perivascular spaces where vascular Aý localizes and likely plays a role in induction of ARIA. Importantly, ATV cisLALA : Aý almost completely eliminated ARIA-like lesions and vascular inflammation associated with anti-Aý treatment. Taken together, ATV cisLALA has the potential to significantly improve both safety and efficacy of Aý immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.

Engineering anti-amyloid antibodies with transferrin receptor targeting improves brain biodistribution and mitigates ARIA