Abstract
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.
Footnotes
- Received May 20, 2017.
- Accepted August 7, 2017.
This work was supported by a Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare of Japan; a research grant from the Japan Agency for Medical Research and Development; a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan [Grant number 24390042]; and funds from the Adaptable and Seamless Technology Transfer Program through Target-driven R&D Agency; Platform for Drug Discovery, Informatics, and Structural Life Science of the Ministry of Education, Culture, Sports, Science and Technology of Japan; and the Takeda Science Foundation. Y.H. was supported by a Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science [Grant number 15J10065].
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|