An Antibody Immunoprotectant for Category B Toxins

说明（由申请方提供）：天然存在的传染性和毒性物剂有意传播的可能性给这些物剂传统上构成的威胁增加了一个新的严重层面。这些生物恐怖主义威胁大大增加了我们对发展防御选择代理毒素的紧迫感。B类毒素包括产气荚膜梭菌肠毒素（ETX）、蓖麻毒素和葡萄球菌肠毒素B（SE B），这些毒素都非常强效，来源于常见的、容易获得的植物（蓖麻毒素）和细菌（SE B和ETX）。这些毒素比较容易生产，可以以稳定的气溶胶形式投放-在战场上或在平民中用作生物武器，将导致毁灭性的发病率和死亡率。目前还没有预防或治疗暴露于这些毒素。我们已经确定了单克隆抗体（mAb），分别保护对致命的ETX，蓖麻毒素，和SEB的挑战，在动物模型。本申请的目的是开发一种针对B类毒素的广谱抗体混合物（CBT-ab），在快速且具有成本效益的工厂系统中生产，用于预防和暴露后中毒治疗。针对这三种毒素的单一产品（mAb将单独生产，然后组合成最终产品）将节省成本和时间。此外，由于B类毒素的中毒导致类似的症状，因此单一混合物产品对于临床应用是理想的，并且通常不能获得和/或获得用于快速鉴定致病剂的护理点诊断。本申请的具体目标是：具体目标#1。在体外和体内评价CBT-ab。将证明混合制剂的预防和暴露后活性，以满足新药研究（IND）申请的提交要求。具体目标#2确定CBT-ab制剂。将确定鸡尾酒的最佳液体制剂，以确保最终产品具有适当的稳定性特征。特殊目标#3。完成IND赋能研究。CBT-ab将按照现行药品生产质量管理规范（cGMP）进行生产和配制。将进行所有IND使能药理学、毒理学和化学、生产和控制（CMC）研究，最终目标是提交研究性新药（IND）申请，以支持1期人体安全性试验。

Description (provided by the applicant): The potential for intentional dissemination of naturally occurring infectious and toxic agents adds a serious new dimension to the threats traditionally posed by these agents. These bioterrorism threats have greatly increased our sense of urgency for developing defenses against Select Agent toxins. The Category B toxins, which consist of Clostridium perfringens epsilon toxin (ETX), ricin, and staphylococcal enterotoxin B (SEB), are all extraordinarily potent, and are derived from common, readily-accessible plants (ricin) and bacteria (SEB and ETX). These toxins are relatively easily produced, and can be delivered in a stable aerosol form -- their use as bioweapons on the battlefield or in civilian populations would result in devastating morbidity and mortality. There ae currently no preventives or therapeutics for exposure to these toxins. We have identified monoclonal antibodies (mAbs) that individually protect against lethal ETX, ricin, and SEB challenge in animal models. The goal of this application is development of a broad-spectrum antibody cocktail against the Category B toxins (CBT-ab), manufactured in a rapid and cost-effective plant system, for prevention and post-exposure treatment of intoxication. Pursuing a single product (the mAbs will be manufactured individually and then combined into the final product) against these three toxins will manifest as savings in costs and time. Further, a single cocktail product is desirable for clinical use since intoxication with the Category B toxins result in similar symptoms and point of care diagnostics to rapidly identify the causative agent are not generally available and/or accessible. The Specific Aims of this application are: Specific Aim #1. Evaluate CBT-ab in vitro and in vivo. The preventive and post-exposure activity of the cocktail will be demonstrated to satisfy requirements for submission of an Investigation New Drug (IND) application. Specific Aim #2. Identify a CBT-ab formulation. An optimal liquid formulation for the cocktail will be identified to ensure an appropriate stability profile for the final product. Speciic Aim #3. Complete IND-enabling studies. CBT-ab will be manufactured and formulated under current Good Manufacturing Practices (cGMP). All IND-enabling pharmacology, toxicology, and Chemistry, Manufacturing and Controls (CMC) studies will be performed, with a final goal of filing an Investigational New Drug (IND) application to support a Phase 1 human safety trial.