Efficient brain delivery and sustained retention of antibodies via dual targeting of blood-brain barrier and intra-brain proteins.

摘要

Efficient delivery of therapeutic antibodies to the brain has been increasingly achieved using receptor-mediated transcytosis (RMT) approaches such as transferrin receptor (TfR)-mediated shuttle systems. Moreover, a strategy for enhancing brain retention has recently emerged as a focus of attention to overcome the rapid clearance of TfR shuttles from the brain. Here, we propose a novel approach that combines binding to intra-brain proteins, such as myelin oligodendrocyte glycoprotein (MOG), cell adhesion molecule 3, and chondroitin sulfate proteoglycan 5, for sustained retention in the brain with binding to blood-brain barrier (BBB) proteins, such as TfR and insulin-like growth factor 1 receptor, for enhanced BBB permeability. A mouse pharmacokinetic study demonstrated that the anti-MOG/TfR antibody reached a higher maximum concentration and maintained higher concentrations in the brain for 4 months than anti-MOG and anti-TfR antibodies. In immunohistochemistry and brain 3D-imaging study, the anti-MOG/TfR antibody distributed throughout the whole brain, suggesting it penetrates the BBB across the whole brain parenchyma and is retained there. Finally, this antibody technology was applied to brain delivery of neprilysin, an enzyme that degrades amyloid beta, demonstrating that it can enhance both the brain exposure and the pharmacodynamic effect of the potential therapeutic molecule. In conclusion, the concept of achieving sustained high brain exposure by combining BBB transport with enhanced brain retention was shown to be broadly applicable. This novel antibody technology platform is expected to deliver and retain various therapeutic molecules efficiently within the brain, addressing critical challenges in drug development for the central nervous system.