(151c) Role of FcRn-Mediated Recycling in IgG Transport across an in Vitro Blood-Brain Barrier

Immunoglobulin G (IgG)-based therapies for numerous neurodegenerative indications are being evaluated in clinical trials as first-in-class disease-modifying agents. Although promising, poor brain delivery of IgG (~0.01% of the administered dose) – attributed to the restrictive phenotype of brain endothelial cells (BECs) that form the blood-brain barrier – necessitates dosing regimens that raise concern regarding treatment cost and accessibility. Successful strategies to improve IgG brain delivery, such as antibody engineering, must first identify the processes influencing IgG transport across BECs. To overcome the experimental complications of in vivo models/methods that have contributed to conflicting hypotheses, mainly concerning the neonatal Fc receptor (FcRn) that regulates IgG recycling and transport in peripheral endothelial cells, IgG transport and trafficking was systematically evaluated using an in vitro model of brain endothelium derived from human pluripotent stem cells. Complementary super-resolution and live-cell fluorescence microscopy were used to correlate intracellular distributions and transport rates for IgGs exhibiting disparate FcRn engagement. Relationships between processing and transport were further explored using modified IgG and other macromolecules, which revealed the impact of endocytoic pathways on transport rates. Collectively, our findings shed light on the factors influencing the rate of brain entry for conventional therapeutic IgG and also provide possible routes to engineer improved variants with enhanced brain delivery.