Mechanisms and Methods for Evaluating Drug Delivery via Transcytosis to the Brain

The CNS exists in a privileged space that is protected by the existence of the blood–brain barrier (BBB). The BBB prevents detrimental blood constituents from accessing the brain and is an obstacle to the delivery of peripherally administered therapeutics. Herein we discuss antibody-based methods for delivering bio-therapeutics across the BBB via receptor-mediated transcytosis (RMT). We examine mechanistic aspects of transcytosis and antibody attributes that affect their ability to undergo RMT. Moreover, we provide a discussion of evidence supporting the various RMT-capable receptors identified to date in brain endothelial cells. We also describe various preclinical and clinical methods used to assess RMT-mediated therapeutic delivery to the brain. The state of the art for the rational design of BBB-penetrant antibodies and the methods used for their validation have evolved significantly since RMT was first discovered, leading to the emergence of clinical success stories involving bio-therapeutic delivery to the CNS.