期刊
JOURNAL OF CONTROLLED RELEASE
卷 336, 期 -, 页码 105-111出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2021.06.009
关键词
Claudin-5; Tight junction; Drug delivery to the brain; Non-human primate; Safety evaluation
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [21H03354, 20H03392, 19H04468, 18K19400, 18H03190, 24390042]
- Japan Agency for Medical Research and Development [JP21am0101084, JP21am0101123]
- COCKPI-T Fund
- Project MEET
- Osaka University Graduate School of Medicine
- Tanabe Mitsubishi Pharma Corporation
- Grants-in-Aid for Scientific Research [20H03392, 19H04468, 18H03190, 18K19400, 21H03354] Funding Source: KAKEN
The study suggests that CLDN-5 may be a potential target for enhancing drug delivery to the brain, but the therapeutic window of the anti-CLDN-5 mAb may be narrow.
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 narrow for separating efficacy and toxicity.
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