title: 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.
authors: Neurodegeneration Labs, Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Y Joy
authors: YJ
authors: Yu
authors: Yin
authors: Y
authors: Zhang
authors: Margaret
authors: M
authors: Kenrick
authors: Kwame
authors: K
authors: Hoyte
authors: Wilman
authors: W
authors: Luk
authors: Yanmei
authors: Y
authors: Lu
authors: Jasvinder
authors: J
authors: Atwal
authors: J Michael
authors: JM
authors: Elliott
authors: Saileta
authors: S
authors: Prabhu
authors: Ryan J
authors: RJ
authors: Watts
authors: Mark S
authors: MS
authors: Dennis