Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 363, Issue 2, Pages 275-283Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.117.243014
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Funding
- Ministry of Health, Labour and Welfare of Japan
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology of Japan [24390042]
- Target-driven RD Agency
- Platform for Drug Discovery, Informatics, and Structural Life Science of the Ministry of Education, Culture, Sports, Science and Technology of Japan
- Takeda Science Foundation
- Japan Society for the Promotion of Science [15J10065]
- Grants-in-Aid for Scientific Research [17K19487, 17J03990, 16K08370, 15J10065, 16H04729, 16H06579] Funding Source: KAKEN
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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.
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