A perfused in vitro human iPSC-derived blood–brain barrier faithfully mimics transferrin receptor-mediated transcytosis of therapeutic antibodies
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2023
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01A - Journal article
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Cellular and Molecular Neurobiology
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43
Issue / Number
8
Pages / Duration
4173-4187
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Springer
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Abstract
Delivering biologics to elicit a therapeutic response in the central nervous system (CNS) remains challenging due to the presence of the blood brain barrier (BBB). Receptor-mediated transcytosis is a strategy to improve brain exposure after systemic drug administration. The availability of a clinically relevant in vitro BBB model is crucial to investigate transcytosis pathways and to predict the penetration of biologics into the CNS. We created a perfused human in vitro BBB model made of induced pluripotent stem cells (iPSC)-derived brain microvascular endothelial cells (BMEC) for studying transferrin receptor-mediated transcytosis. iPSC-derived BMEC were seeded in the top channel of a three-lane microfluidic device (OrganoPlate®). After 2 days in culture, the established cell model exhibited relevant BBB features, including physiological transendothelial electrical resistance in a transwell setting (1500 Ω*cm), reduced apparent permeability (Papp) to the fluorescence tracer Lucifer yellow (20-fold less than cell-free chips), expression of key BBB markers such as tight junctions proteins, transporters, receptors and functional P-gp efflux pump. Moreover, the model exhibited functional transferrin receptor-mediated uptake and transcytosis. To assess selective transferrin receptor-mediated transcytosis, a mixture of anti-human transferrin receptor (MEM-189) and control (sheep IgG anti-bovine serum albumin) antibodies was perfused in the top channel for 2 h. The Papp of MEM-189 was 11-fold higher than that of the control antibody, demonstrating facilitated receptor-mediated transcytosis. Compared to published work reporting a 2-fold ratio, this result is remarkable and establishes the suitability of our model for exploring receptor-mediated transcytosis and screening of antibodies for putative brain shuttle application.
A perfused in vitro human model made of iPSC-derived BMEC with the chief characteristics (barrier tightness, functionality) of the human BBB can be applied to study transferrin receptor (TfR)-mediated transcytosis of therapeutic antibodies. This may bring critical advances in drug shuttle technology. Graphical abstract generated with biorender.com.
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0272-4340
1573-6830
1573-6830
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English
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Yes
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Published
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Gold
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Citation
Burgio, F., Gaiser, C., Brady, K., Gatta, V., Class, R., Schrage, R., & Suter-Dick, L. (2023). A perfused in vitro human iPSC-derived blood–brain barrier faithfully mimics transferrin receptor-mediated transcytosis of therapeutic antibodies. Cellular and Molecular Neurobiology, 43(8), 4173–4187. https://doi.org/10.1007/s10571-023-01404-x