Brain Shuttle Antibody for Alzheimer's Disease with Attenuated Peripheral Effector Function due to an Inverted Binding Mode.

Receptors show promise for the transport of monoclonal antibodies (mAbs) across the blood-brain barrier. However， safety liabilities associated with peripheral receptor binding and Fc effector function have been reported. We present the Brain Shuttle-mAb (BS-mAb) technology， and we investigate the role of Fc effector function in?vitro and in an Fcγ receptor (FcγR)-humanized mouse model. Strong first infusion reactions (FIRs) were observed for a conventional mAb against transferrin receptor (TfR) with a wild-type immunoglobulin G1 (IgG1) Fc. Fc effector-dead constructs completely eliminated all FIRs. Remarkably， no FIR was observed for the BS-mAb construct with a native IgG1 Fc function. Using various BS-mAb constructs， we show that TfR binding through the C-terminal BS module attenuates Fc-FcγR interactions， primarily because of steric hindrance. Nevertheless， BS-mAbs maintain effector function activity when binding their brain target. Thus， mAbs with full effector function can be transported in a stealth mode in the periphery while fully active when engaged with their brain target.