Safety and efficacy of an anti-claudin-5 monoclonal antibody to increase blood-brain barrier permeability for drug delivery to the brain in a non-human primate
Safety and efficacy of an anti-claudin-5 monoclonal antibody to increase blood-brain barrier permeability for drug delivery to the brain in a non-human primate
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DOI：
10.1016/j.jconrel.2021.06.009
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发表时间：
2021-06-17
影响因子：
10.8
通讯作者：
Kondoh, Masuo
中科院分区：
文献类型：
--
作者：
Tachibana, Keisuke;Hashimoto, Yosuke;Kondoh, Masuo
紧密连接蛋白-5（Claudin-5，CLDN-5）是血脑屏障中紧密连接密封的重要组成部分。先前，我们表明，通过抗CLDN-5单克隆抗体（mAb）在体外调节CLDN-5可能有助于增加血脑屏障的渗透性以将药物递送至大脑。基于这些发现，我们在此检查了抗CLDN-5 mAb在非人灵长类动物中的安全性和有效性。向食蟹猴静脉内施用抗CLDN-5 mAb，然后施用荧光素染料（376 Da），并检查脑脊液中染料的浓度。当mAb以3.0 mg/ kg给药时，脑脊液中染料浓度增加，未观察到行为变化或炎症或肝或肾损伤的血浆生物标志物变化。然而，接受6 mg/kg mAb的猴出现惊厥，随后对该动物进行的组织病理学检查显示肝、肺和肾血管舒张;肺出血;脑水肿。总之，我们的数据表明，CLDN-5可能是增强药物向大脑递送的潜在靶标，但抗CLDN-5 mAb的治疗窗口可能较窄，无法分离疗效和毒性。
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.