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

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. In this study, we investigated brain delivery and effects on plaque burden of Aducanumab (Adu), a clinically validated anti-amyloid beta (Aβ) antibody, when fused to a mouse TfR1-binding Fab fragment as BBB shuttle (TfR1-Adu). Whole-organ clearing and immunolabeling coupled with light sheet fluorescence microscopy of whole brain hemispheres was applied for quantitative 3D assessment of brain distribution of therapeutic antibodies and plaque burden in a transgenic APP/PS1 mouse model of Alzheimer's disease (AD). Compared to unmodified Adu, TfR1-Adu demonstrated enhanced brain delivery and a more homogeneous brain distribution following both acute and chronic systemic administration. Additionally, the addition of the TfR1 shuttle mitigated the periarterial drug distribution observed with unmodified Adu. While high-dose chronic Adu was able to reduce Aβ plaque burden across multiple brain regions, a comparable reduction in plaque burden was achieved with a five-fold lower dose of TfR1-Adu. Collectively, these findings provide strong support for the use of TfR1-mediated BBB shuttle strategies to enhance brain delivery of anti-Aβ antibodies and thereby reduce amyloid plaque burden, while highlighting the value of advanced whole-brain imaging platforms to guide the rational development of next-generation drugs for AD and other CNS disorders.