Abstract
The regulatory success rate for central nervous system (CNS) drugs is less than half that of non‐CNS drugs. A current bottleneck in the development of CNS drugs is the lack of drug delivery systems to the brain. The blood‐brain barrier (BBB) is a membrane barrier formed by brain capillary endothelial cells and protects the brain from harmful materials circulating in the blood. Most small and all large drugs do not readily cross the BBB. The intercellular space between endothelial cells of the 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. Here, to investigate whether CLDN‐5 can be a target for CNS delivery of drugs, we generated monoclonal antibodies (mAbs) specific to the extracellular domain of CLDN‐5 using DNA immunization. Treatment of MDCKII/CLDN‐5 cells with anti‐CLDN‐5 mAbs time‐ and dose‐dependently decreased the integrity of TJs. The integrity was restored by removal of the anti‐CLDN‐5 mAbs. In an in vitro model of the BBB, anti‐CLDN‐5 mAbs also attenuated the integrity of TJs and enhanced permeability of small (Mw 376 Da) and large (4 kDa) solutes. The anti‐CLDN‐5 mAbs did not decrease TJ integrity in human intestinal epithelium models. In conclusion, CLDN‐5 is a potential target for the development of drug delivery systems to the brain. The anti‐CLDN‐5 mAb is a potential lead compound for development of novel drug delivery systems targeting the CNS.Support or Funding InformationThis study was partly supported by Grant‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (18K19400, 18H03190, 16K13044).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
