西亚试剂：Boosting Brain Uptake of a Therapeutic Antibody by Reducing

Boosting Brain Uptake of a Therapeutic Antibody by Reducing Its Affinity for a Transcytosis Target

Yu, Y. Joy; Zhang, Yin; Kenrick, Margaret; Hoyte, Kwame; Luk, Wilman; Lu, Yanmei; Atwal, Jasvinder; Elliott, J. Michael; Prabhu, Saileta; Watts, Ryan J.; Dennis, Mark S.

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