Claudin-5-Binders Enhance Permeation of Solutes across the Blood-Brain Barrier in a Mammalian Model

A current bottleneck in the development of central nervous system (CNS) drugs is the lack of drug delivery systems targeting the CNS. The intercellular space between endothelial cells of the blood-brain barrier (BBB) is sealed by complex protein-based structures called tight junctions (TJs). Claudin...

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Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2017-11, Vol.363 (2), p.275-283
Main Authors: Hashimoto, Yosuke, Shirakura, Keisuke, Okada, Yoshiaki, Takeda, Hiroyuki, Endo, Kohki, Tamura, Maki, Watari, Akihiro, Sadamura, Yoshifusa, Sawasaki, Tatsuya, Doi, Takefumi, Yagi, Kiyohito, Kondoh, Masuo
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - immunology
Blood-Brain Barrier - metabolism
Cell Line, Tumor
Claudin-5 - chemistry
Claudin-5 - immunology
Claudin-5 - metabolism
Extracellular Space - metabolism
Female
Humans
Male
Mice
Permeability
Protein Domains
Tight Junctions - metabolism
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Summary:A current bottleneck in the development of central nervous system (CNS) drugs is the lack of drug delivery systems targeting the CNS. The intercellular space between endothelial cells of the blood-brain barrier (BBB) is sealed by complex protein-based structures called tight junctions (TJs). Claudin-5 (CLDN-5), a tetra-transmembrane protein is a key component of the TJ seal that prevents the paracellular diffusion of drugs into the CNS. In the present study, to investigate whether CLDN-5 binders can be used for delivery of drugs to the CNS, we generated monoclonal antibodies (mAbs) specific to the extracellular domains of CLDN-5. In an in vitro model of the BBB, the anti-CLDN-5 mAbs attenuated trans-epithelial/endothelial electrical resistance and enhanced solute permeation. These anti-CLDN-5 mAbs are potential leads for the development of novel drug delivery systems targeting the CNS.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.117.243014