Post-exposure immunotherapy for ricin exposure

项目摘要 蓖麻毒素是一种B类毒素，由于其易于获得、传播和高潜力， 暴露后的发病率和死亡率。蓖麻毒素是蓖麻子植物自然产生的， 蓖麻，这是种植在世界各地的工业水平。蓖麻毒素占到5%， 蓖麻籽的总干重，并且可以使用几个简单的富集步骤提取。蓖麻毒素 在注射、吸入或注射后， 它被用作生物恐怖主义的代理人。蓖麻毒素以前是由 美国、前苏联、伊拉克和其他可能的国家， 最近在一些美国政府设施中被发现。有 目前没有预防或治疗蓖麻毒素暴露的方法-这是一个未得到满足的主要问题。 需要保护平民和军队。 Mapp团队与Nicholas Mantis博士（沃兹沃斯中心，奥尔巴尼，纽约）合作 Chad Roy博士（Tulane National Primate Research Center，Covington，LA）已经发现了一种 大量高效抗蓖麻毒素单克隆抗体（mAb）。这些单克隆抗体，无论是在其原始 完全鼠状态，当与人恒定区嵌合时，或当完全人源化时， 在蓖麻毒素攻击之前和之后给药时，证明了对小鼠的保护作用。此外， 这些单克隆抗体，人源化PB 10（hPB 10），已经显示出保护非人灵长类动物（NHP）免受 气雾剂攻击治疗-这是第一次证明NHP的保护， 致命气雾剂的治疗方法。我们现在已经有证据表明mAb混合物 由一个RTA和一个RTB mAb组成的单克隆抗体可以提供改善的效力并延长治疗时间。 窗口我们测试的mAb混合物的体外和体内效力上级任何 先前描述的单个mAb，这与在以下条件下起作用的mAb的组合一致： 中毒过程中的不同步骤抗RTB mAb干扰蓖麻毒素与靶标的结合 细胞，而抗RTA单克隆抗体被提议阻断蓖麻毒素细胞内运输。 将蓖麻毒素医学对策推向临床的具体目的是：1）工程，生产， 2）人源化前导RTA/RTB mAb混合物， 制造以支持目标#3; 3）确定电极导线的预防和治疗有效性 在恒河猴气溶胶激发模型中RTA/RTB组合。这些数据与 化学、制造和控制（CMC）信息将构成预 与FDA举行的研究性新药（IND）会议，以征求关于继续开发 该产品.

PROJECT SUMMARY Ricin is a category B toxin due to its ease of acquisition, dissemination, and the high potential for morbidity and mortality after exposure. Ricin is naturally produced by the castor bean plant, Ricinus communis, which is cultivated on industrial levels worldwide. Ricin constitutes up to 5% of the total dry weight of the castor bean and can be extracted using several simple enrichment steps. Ricin in semi-purified or purified form is extremely toxic to humans following injection, inhalation, or ingestion and has been used as an agent of bioterrorism. Ricin was previously weaponized by the United States, the former Soviet Union, Iraq and likely other countries, has been used in assassinations and was recently detected in a number of U.S. government facilities. There are currently no methods of preventing or treating ricin exposure – this represents a major unmet need for protection of civilians and military forces. The Mapp team, in collaboration with Dr. Nicholas Mantis (Wadsworth Center, Albany, NY) and Dr. Chad Roy (Tulane National Primate Research Center, Covington, LA), has identified a number of highly potent anti-ricin monoclonal antibodies (mAbs). These mAbs, either in their original fully murine state, when chimerized with human constant regions, or when fully humanized, have demonstrated protection of mice when administered prior to and after ricin challenge. Further, one of these mAbs, humanized PB10 (hPB10), has been shown to protect non-human primates (NHPs) from aerosol challenge therapeutically – this is the first demonstration of protection of NHPs by a therapeutic against a lethal aerosol challenge. We have now generated evidence that a mAb cocktail consisting of one RTA and one RTB mAb may provide improved potency and extend the therapeutic window. The in vitro and in vivo potency of the mAb cocktails we have tested is superior to any individual mAb previously described, which is consistent with the combination of mAbs functioning at different steps in the intoxication process. Anti-RTB mAbs interfere with ricin attachment to target cells, while anti-RTA mAbs are proposed to block ricin intracellular trafficking. The Specific Aims to advance a ricin medical countermeasure to the clinic are: 1) Engineer, produce, and down-select from the panel of RTA/RTB mAbs; 2) Humanize the lead RTA/RTB mAb cocktail and manufacture to support Aim #3; 3) Determine the prophylactic and therapeutic efficacy of the lead RTA/RTB combination in the rhesus macaque aerosol challenge model. These data combined with the Chemistry, Manufacturing and Control (CMC) information will form the basis of a pre- Investigational New Drug (IND) meeting with the FDA to solicit guidance on continued development of the product.