Transferrin receptor-binding blood-brain barrier shuttle enhances brain delivery and efficacy of a therapeutic anti-Abeta antibody

Vega, M. R.; Hansen, H. H.; Jensen, C. S.; Alexiou, E.; Madsen, M. R.; Wichern, F.; Skytte, J. L.; Salinas, C. G.; Sotty, F.; Jensen, A.; Vergo, S.; Hecksher-Soerensen, J.

doi:10.1101/2025.02.14.638216

bioRxiv · 10.1101/2025.02.14.638216

Transferrin receptor-binding blood-brain barrier shuttle enhances brain delivery and efficacy of a therapeutic anti-Abeta antibody

Vega, M. R.·Hansen, H. H.·Jensen, C. S.·Alexiou, E.·Madsen, M. R.·Wichern, F.·Skytte, J. L.·Salinas, C. G.·Sotty, F.·Jensen, A.·Vergo, S.·Hecksher-Soerensen, J.

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Abstract

Transferrin receptor-1 (TfR1) transcytosis-mediated delivery of therapeutic monoclonal antibodies across the blood-brain barrier (BBB) is a promising concept in drug development for CNS disorders. We sought to investigate brain delivery and efficacy of Aducanumab (Adu), an anti-A{beta} antibody, when fused to a mouse TfR1-binding Fab fragment as BBB shuttle (TfR1-Adu). Automated 3D light sheet fluorescence imaging coupled with computational analysis was applied to evaluate drug IgG distribution and plaque counts throughout the intact brain of transgenic APP/PS1 mice. TfR1-Adu demonstrated enhanced brain delivery and more homogeneous distribution after both acute and chronic dosing in transgenic APP/PS1 mice compared with unmodified Adu. Also, importantly, only unmodified Adu showed perivascular labelling. While high-dose Adu promoted A{beta} plaque depletion in multiple brain regions, similar plaque-clearing efficacy was achieved with a five-fold lower dose of TfR1-Adu. Furthermore, low-dose TfR1-Adu demonstrated greater capacity to reduce congophilic plaque burden. Collectively, these observations strongly support the applicability of TfR1-enabled BBB shuttle strategies to improve brain delivery and plaque-clearing efficacy while mitigating the risk of vascular-associated amyloid-related imaging abnormalities (ARIA) adverse effects associated with current A{beta} immunotherapeutics.

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Vega, M. R., Hansen, H. H., Jensen, C. S., Alexiou, E., Madsen, M. R., Wichern, F., Skytte, J. L., Salinas, C. G., Sotty, F., Jensen, A., Vergo, S., Hecksher-Soerensen, J.. 2025-02-16. Transferrin receptor-binding blood-brain barrier shuttle enhances brain delivery and efficacy of a therapeutic anti-Abeta antibody. https://doi.org/10.1101/2025.02.14.638216

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