Subcellular trafficking and transcytosis efficacy of different receptor types for therapeutic antibody delivery at the blood-brain barrier

Here, we report an experimental setup to benchmark different receptors for targeted therapeutic antibody delivery at the blood-brain barrier. We used brain capillary endothelial-like cells derived from induced pluripotent stem cells (hiPSC-BECs) as a model system and compared them to colon epithelial Caco-2 cells. This approach helped to identify favourable receptors for transport into the cell layer itself or for directing transport for transcytosis across the cell layer. The sorting receptors transferrin receptor and sortilin were shown to be efficient as antibody cargo receptors for intracellular delivery to the cell layer. In contrast, the cell surface receptors CD133 and podocalyxin were identified as static and inefficient receptors for delivering cargo antibodies. Similar to in vivo studies, the hiPSC-BECs maintained detectable transcytotic transport via transferrin receptor, while transcytosis was restricted using sortilin as a cargo receptor. Based on these findings, we propose the application of sortilin as a cargo receptor for delivering therapeutic antibodies into the brain microvascular endothelium. HiPSC-BECs can be used as a model system to study drug delivery via receptor-mediated transcytosis at the human blood-brain barrier in vitro.The sorting receptors TfR and sortilin show significant internalization of cargo antibodies compared to the cell surface receptors CD133 and podocalyxinSortilin is a putative cargo receptor for therapeutic delivery to brain endothelial cells

Automated summary

This study presents an experimental setup to evaluate different receptors for targeted delivery of therapeutic antibodies at the blood-brain barrier. The findings suggest that transferrin receptor and sortilin are effective receptors for intracellular delivery of antibodies, while CD133 and podocalyxin are static and inefficient receptors for antibody delivery. Additionally, sortilin is proposed as a cargo receptor for delivering therapeutic antibodies to brain microvascular endothelium. The hiPSC-BECs can serve as a model system for studying receptor-mediated transcytosis drug delivery at the human blood-brain barrier in vitro.