Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target.

Abstract

Monoclonal antibodies have therapeutic potential for treating diseases of the central nervous system, but their accumulation in the brain is limited by the blood-brain barrier (BBB). Here, we show that reducing the affinity of an antibody for the transferrin receptor (TfR) enhances receptor-mediated transcytosis of the anti-TfR antibody across the BBB into the mouse brain where it reaches therapeutically relevant concentrations. Anti-TfR antibodies that bind with high affinity to TfR remain associated with the BBB, whereas lower-affinity anti-TfR antibody variants are released from the BBB into the brain and show a broad distribution 24 hours after dosing. We designed a bispecific antibody that binds with low affinity to TfR and with high affinity to the enzyme β-secretase (BACE1), which processes amyloid precursor protein into amyloid-β (Aβ) peptides including those associated with Alzheimer's disease. Compared to monospecific anti-BACE1 antibody, the bispecific antibody accumulated in the mouse brain and led to a greater reduction in brain Aβ after a single systemic dose. TfR-facilitated transcytosis of this bispecific antibody across the BBB may enhance its potency as an anti-BACE1 therapy for treating Alzheimer's disease.

DOI: 10.1126/scitranslmed.3002230

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@article{Yu2011BoostingBU, title={Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target.}, author={Y Joy Yu and Yin Zhang and Margaret Kenrick and Kwame Hoyte and Wilman Luk and Yanmei Lu and Jasvinder Atwal and J Michael Elliott and Saileta Prabhu and Ryan J Watts and Mark S Dennis}, journal={Science translational medicine}, year={2011}, volume={3 84}, pages={84ra44} }