Transport of Transferrin Receptor-Targeted Antibodies Through the Blood-Brain Barrier for Drug Delivery to the Brain

Entering a new era of using biologics for the treatment of diseases within the CNS, a major adjoining advance is the recent conquering of the years-long obstacle that has prevented large molecules from passing the blood-brain barrier (BBB). The BBB, consisting of brain capillary endothelial cells (BCECs) with their intermingling tight junctions, is now passable taking approaches where antibodies specifically target nutrient transporters to enter the brain. Among the nutrient transporters, the receptor for iron-carrying transferrin of the blood plasma is of particular interest, as this receptor is selectively expressed by BCECs and not by endothelial cells elsewhere in the body. Injecting antibodies targeted to the transferrin receptor of BCECs into the circulation leads to a preferential high uptake by BCECs, but the antibodies will only pass through the BBB and enter the brain when experimentally engineered to differ from the conventional binding characteristics of being monovalent with capability of high-binding affinity. Accordingly, antibodies either made bispecific or weakened in their affinity for the transferrin receptor appear able to pass the BBB, allowing such antibodies to achieve therapeutic activity within the brain either by direct antibody-mediated binding to specific targets or by delivering conjugate therapeutics. These new approaches for targeted delivery to the BBB and beyond open up new possibilities for the treatment of diseases within the CNS, and the potential for such treatments, particularly as applied to neurodegenerative diseases where the BBB is not compromised, probably never has been more optimal.