Brain delivery and efficacy of a BBB shuttle-enhanced aducanumab biosimilar in a mouse model of Alzheimer’s disease

Aβ-directed antibodies with enhanced CNS access have the potential to improve therapeuticoutcomes in Alzheimer's disease (AD). The present study aimed to simultaneously 3D map whole-braindistribution and Aβ plaque clearing efficiency of a blood-brain barrier (BBB) shuttle-enhanced Aβantibody in a transgenic mouse model of AD. 5–9-month-old APP/PS1 transgenic ARTE10 mice (n=8-10 per group) were treated with an aducanumab biosimilar (AduBS, 10 or 50 nmol/kg), aducanumabbiosimilar fused with a mouse transferrin receptor (mTfR) binder as BBB-shuttle (AduBS-BBB, 10nmol/kg) or control hIgG (50 nmol/kg) for 12 weeks. Intact brain hemispheres were co-stained withantibodies against hIgG (drug labelling) and hAβ (plaque labelling), cleared and scanned on a lightsheet fluorescence microscope. Deep-learning image analysis was applied for automated 3Dvisualization, segmentation, anatomical mapping and quantification of drug distribution and Aβplaque load using a custom mouse brain atlas. Both therapeutic Aβ antibody accumulated in brainareas with significant plaque load. Compared to AduBS, similar brain distribution pattern and plaquelowering efficacy was achieved using a five times lower dose of AduBS-BBB. Both compounds elicitedplaque clearing effects in a discrete set of brain regions, including brain regions with less prominentcompound accumulation. TfR binding BBB-shuttle enhances brain delivery of a therapeutic Aβantibody, facilitating plaque clearing efficiency at significantly lower doses in transgenic AD mice.