Abstract
Claudin-5 (CLDN-5) is an essential component of the tight junction seal in the blood-brain barrier. Previously, we showed that CLDN-5 modulation in vitro via an anti-CLDN-5 monoclonal antibody (mAb) may be useful for increasing the permeability of the blood-brain barrier for drug delivery to the brain. Based on these findings, here we examined the safety and efficacy of the anti-CLDN-5 mAb in a non-human primate. Cynomolgus monkeys were intravenously administered the anti-CLDN-5 mAb followed by fluorescein dye (376 Da), and the concentrations of the dye in the cerebrospinal fluid was examined. When the mAb was administered at 3.0 mg/kg, the concentration of dye in the cerebrospinal fluid was increased, and no behavioral changes or changes in plasma biomarkers for inflammation or liver or kidney injury were observed. However, a monkey that received the mAb at 6 mg/kg experienced convulsions, and subsequent histopathological examination of this animal revealed vasodilation in the liver, lung, and kidney; hemorrhage in the lung; and edema in the brain. Together, our data indicate that CLDN-5 might be a potential target for enhancing drug delivery to the brain, but also that the therapeutic window of the anti-CLDN-5 mAb may be narr...Continue Reading
References
Jul 1, 1980·Neurosurgery·E A NeuweltS Hill
Jan 20, 1999·Proceedings of the National Academy of Sciences of the United States of America·K MoritaS Tsukita
Jun 17, 1999·Trends in Cell Biology·S Tsukita, M Furuse
Oct 6, 1999·The Journal of Cell Biology·K MoritaS Tsukita
Jun 16, 2000·Cancer Metastasis Reviews·R O Dillman
May 14, 2003·The Journal of Cell Biology·Takehiro NittaShoichiro Tsukita
Jun 9, 2007·British Journal of Anaesthesia·A HelmyA K Gupta
May 30, 2008·The Journal of Gene Medicine·Matthew CampbellPeter Humphries
Dec 30, 2008·Neurochemistry International·Shinsuke NakagawaMasami Niwa
Feb 1, 2011·FEBS Letters·Katsuhiko MinetaSachiko Tsukita
May 3, 2011·Cellular and Molecular Life Sciences : CMLS·Jörg PiontekIngolf E Blasig
May 24, 2012·Nature Communications·Matthew CampbellPeter Humphries
Jan 23, 2016·Nature Reviews. Drug Discovery·William A Banks
Jun 17, 2016·Science Translational Medicine·Alexandre CarpentierAhmed Idbaih
Jun 30, 2016·Nature Reviews. Molecular Cell Biology·Ceniz ZihniMaria S Balda
May 16, 2017·Annals of the New York Academy of Sciences·Sophie DithmerLars Winkler
Aug 19, 2017·The Journal of Pharmacology and Experimental Therapeutics·Yosuke HashimotoMasuo Kondoh
Oct 11, 2017·Molecular Psychiatry·C GreeneM Campbell
Feb 15, 2018·Nature·Michael VanlandewijckChrister Betsholtz
Jun 1, 2018·Scientific Reports·Yosuke HashimotoHiroyuki Takeda
Jan 20, 2019·Scientific Reports·Mariana Castro DiasBritta Engelhardt
Jun 30, 2019·NeuroImage·Ying MengNir Lipsman
May 23, 2020·Drug Discovery Today·Yosuke HashimotoMasuo Kondoh
Jul 25, 2020·Scientific Reports·Hannah W SongEric V Shusta