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Antibody transport vehicle improves amyloid targeting in Alzheimer's models, suggesting safety benefits by reducing 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.
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Pizzo et al. (2025) studied this question.
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