Transferrin receptor-targeted anti-amyloid antibody enhances brain delivery and mitigates ARIA.
basic_science · Level V
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- Record sourced from PubMed, PMID 40773560.
- Also identified by DOI 10.1126/science.ads3204.
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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<sup>cisLALA</sup>) that mitigates TfR-related liabilities and retains effector function when bound to Aβ. Administration of ATV<sup>cisLALA</sup>: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<sup>cisLALA</sup> has the potential to improve the next generation of Aβ immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.
Medical subject headings
- Receptors, Transferrin
- Amyloid beta-Peptides
- Brain
- Alzheimer Disease
- Antibodies, Monoclonal