Abstract

Brain delivery of therapeutic antibodies and biologics is restricted due to the presence of the blood-brain barrier (BBB). However, their delivery can be improved with the use of “carrier” antibodies that target receptors on the luminal surface of the BBB which initiate a process termed receptor-mediated transcytosis (RMT). This review describes key steps and transcellular pathways various BBB-crossing antibodies undertake to deliver therapeutic cargos into the brain via RMT. The pathway is initiated with the receptor-mediated endocytosis through clathrin- and/or caveolin-dependent or independent pathways. Once internalized the antibodies are routed to various endosomal compartments where decisions are made regarding their fate during endosomal protein sorting process. During this process antibodies with specific attributes will be either discarded and degraded in lysosomes or rerouted into compartments destined for release on the abluminal surface of the brain endothelial cells. Different RMT receptors may engage different shuttling pathways between the luminal and abluminal sides of the BBB. Based on this knowledge, antibodies can be engineered to add attributes that facilitate preferential routing through pathways that result in enhanced BBB crossing.

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