An Antibody Immunoprotectant for Category B Toxins

描述（由申请人提供）：自然发生的传染性和毒性物质有意传播的可能性，为这些物质传统上构成的威胁增加了一个严重的新层面。这些生物恐怖主义威胁极大地增加了我们开发针对精选特工毒素的防御措施的紧迫感。B类毒素由产气荚膜梭菌毒素（ETX）、蓖麻毒素和葡萄球菌肠毒素B （SEB）组成，它们都是非常有效的，来源于常见的、容易获得的植物（蓖麻毒素）和细菌（SEB和ETX）。这些毒素相对容易产生，并且可以以稳定的气溶胶形式输送——在战场上或在平民中作为生物武器使用将导致毁灭性的发病率和死亡率。目前还没有预防或治疗接触这些毒素的方法。我们已经鉴定出单克隆抗体（mab），在动物模型中单独保护免受致命的ETX，蓖麻毒素和SEB的攻击。本申请的目标是开发一种针对B类毒素（CBT-ab）的广谱抗体鸡尾酒，在快速和具有成本效益的植物系统中制造，用于中毒的预防和暴露后治疗。追求针对这三种毒素的单一产品（单克隆抗体将单独生产，然后组合成最终产品）将节省成本和时间。此外，由于B类毒素中毒会导致类似的症状，并且通常无法获得和/或无法获得快速确定病原体的护理点诊断，因此临床使用单一鸡尾酒产品是可取的。此应用程序的具体目标是：具体目标#1。评估体内和体外的CBT-ab。将证明鸡尾酒的预防和暴露后活性，以满足提交新药调查（IND）申请的要求。具体目标2。确定CBT-ab配方。将确定鸡尾酒的最佳液体配方，以确保最终产品的适当稳定性。明确目标#3。完成ind启用研究。CBT-ab将按照现行的良好生产规范（cGMP）进行生产和配制。所有支持IND的药理学、毒理学、化学、制造和控制（CMC）研究将进行，最终目标是提交新药研究（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.