Roy Chad J, Ehrbar Dylan J, Bohorova Natasha, Bohorov Ognian, Kim Do, Pauly Michael, Whaley Kevin, Rong Yinghui, Torres-Velez Fernando J, Vitetta Ellen S, Didier Peter J, Doyle-Meyers Lara, Zeitlin Larry, Mantis Nicholas J
Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA.
Division of Infectious Disease, Wadsworth Center, New York State Department of Health, Albany, New York, USA.
JCI Insight. 2019 Jan 10;4(1):e124771. doi: 10.1172/jci.insight.124771.
Ricin toxin (RT) ranks at the top of the list of bioweapons of concern to civilian and military personnel alike, due to its high potential for morbidity and mortality after inhalation. In nonhuman primates, aerosolized ricin triggers severe acute respiratory distress characterized by perivascular and alveolar edema, neutrophilic infiltration, and severe necrotizing bronchiolitis and alveolitis. There are currently no approved countermeasures for ricin intoxication. Here, we report the therapeutic potential of a humanized mAb against an immunodominant epitope on ricin's enzymatic A chain (RTA). Rhesus macaques that received i.v. huPB10 4 hours after a lethal dose of ricin aerosol exposure survived toxin challenge, whereas control animals succumbed to ricin intoxication within 30 hours. Antibody intervention at 12 hours resulted in the survival of 1 of 5 monkeys. Changes in proinflammatory cytokine, chemokine, and growth factor profiles in bronchial alveolar lavage fluids before and after toxin challenge successfully clustered animals by treatment group and survival, indicating a relationship between local tissue damage and experimental outcome. This study represents the first demonstration, to our knowledge, in nonhuman primates that the lethal effects of inhalational ricin exposure can be negated by a drug candidate, and it opens up a path forward for product development.
蓖麻毒素（RT）因其吸入后具有很高的发病和致死潜力，在民用和军事人员所关注的生物武器名单中位居榜首。在非人类灵长类动物中，雾化的蓖麻毒素会引发严重的急性呼吸窘迫，其特征为血管周围和肺泡水肿、嗜中性粒细胞浸润以及严重的坏死性细支气管炎和肺泡炎。目前尚无针对蓖麻毒素中毒的获批对策。在此，我们报告了一种针对蓖麻毒素酶促A链（RTA）上一个免疫显性表位的人源化单克隆抗体的治疗潜力。在接受致死剂量的蓖麻毒素气溶胶暴露4小时后静脉注射huPB10的恒河猴在毒素攻击中存活下来，而对照动物在30小时内死于蓖麻毒素中毒。在12小时进行抗体干预，5只猴子中有1只存活。毒素攻击前后支气管肺泡灌洗液中促炎细胞因子、趋化因子和生长因子谱的变化成功地按治疗组和存活情况对动物进行了聚类，表明局部组织损伤与实验结果之间存在关联。据我们所知，本研究首次在非人类灵长类动物中证明吸入蓖麻毒素暴露的致死效应可被一种候选药物抵消，为产品开发开辟了一条前进道路。
