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 epithelia...

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Bibliographic Details
Published in:	Fluids and barriers of the CNS Vol. 20; no. 1; pp. 1 - 82
Main Authors:	Holst, Mikkel Roland, de Wit, Nienke Marije, Ozgür, Burak, Brachner, Andreas, Hyldig, Kathrine, Appelt-Menzel, Antje, Sleven, Hannah, Cader, Zameel, de Vries, Helga Eveline, Neuhaus, Winfried, Jensen, Allan, Brodin, Birger, Nielsen, Morten Schallburg
Format:	Journal Article
Language:	English
Published:	London BioMed Central Ltd 06-11-2023 BioMed Central BMC
Subjects:	Antibodies Benchmarks Blood-brain barrier CD133 Cell surface Cell surface receptors Chromatography Comparative analysis Endothelium Health aspects Medical research Microvasculature Pluripotency Podocalyxin Proteins Receptor-mediated transcytosis Sortilin Stem cells Transferrin Transferrin receptor Transferrins Viral antibodies
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Summary:	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. Graphical Keywords: Blood-brain barrier, Receptor-mediated transcytosis, Transferrin receptor, Sortilin, CD133, Podocalyxin, Brain endothelial cells, Caco-2, Therapeutic antibodies, Transcytosis, Cargo receptor
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-8118 2045-8118
DOI:	10.1186/s12987-023-00480-x