Receptor-mediated transcytosis of macromolecules across the blood-brain barrier

IntroductionThe blood-brain barrier (BBB) restricts brain access of virtually all therapeutic macromolecules. Receptor-mediated transcytosis (RMT) is one strategy to deliver those molecules into the brain. In this strategy, targeting ligands conjugated to a therapeutic payload or decorating particles containing the payload interact with one or several molecules on brain capillary endothelial cells (BCEC), triggering internalization, trafficking through and release from BCEC. Knowledge about this process can improve the design of BBB-crossing constructs.Areas coveredRMT at the BBB has leveraged multiple formats of macromolecules and large particles. Interactions between those and BCEC have been studied primarily using monoclonal antibodies, with findings applicable to the rational design of larger particles decorated with targeting ligands. BBB-penetrant constructs have also been found in screening campaigns and directed evolution, and subsequently found to interact with RMT targets on BCEC. In addition, BCEC targeted by constructs incorporating genomic payload can be made to produce and secrete therapeutic proteins.Expert opinionWhile brain targeting and RMT may not be strictly necessary to reach a therapeutic effect for all macromolecules and in all conditions, they can improve the molecule’s transport across the BBB, giving it access to the entire brain parenchyma and potentially enhancing its therapeutic effect. Constructs with better BCEC transcytosis may be designed rationally, leveraging knowledge about trafficking within BCEC, and found in large screening campaigns, where this knowledge can reduce the search space and improve iterative refinement. Identification of new shuttle targets may also help generate constructs with better transcytosis potential.