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 asso...