An Antibody Immunoprotectant for Category B Toxins

描述(由申请人提供)：故意传播自然产生的传染病和有毒物质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方面。这些生物恐怖主义威胁大大增加了我们开发针对精选毒剂毒素的防御系统的紧迫感。B类毒素由产气荚膜梭菌表观毒素(ETX)、蓖麻毒素和葡萄球菌肠毒素B(SEB)组成，都是非常有效的，来自常见的、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，并可以以稳定的气雾剂形式传递--它们在战场上或在平民人口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的方法。我们已经在动物模型中识别出可单独保护动物免受致死性ETX、蓖麻毒素和SEB攻击的单抗。这项应用的目标是开发一种针对B类毒素的广谱抗体鸡尾酒(CBT-ab)，在快速且具有成本效益的植物系统中生产，用于预防和暴露后中毒治疗。追求针对这三种毒素的单一产品(单抗将单独制造，然后组合成最终产品)将体现为节省成本和时间。此外，单一的鸡尾酒产品对于临床使用是可取的，因为与B类毒素中毒会导致类似的症状和护理点诊断，以快速识别致病因素通常不是可用的和/或可获得的。这一应用的具体目的是：特定目的#1.评价CBT-ab的体内外。鸡尾酒的预防和暴露后活动将被证明符合提交调查新药(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。专业目标3.完成支持Ind的研究。CBT-ab将根据当前的良好制造规范(CGMP)进行制造和配方。将进行所有支持IND的药理学、毒理学和化学、制造和控制(CMC)研究，最终目标是提交研究性新药(IND)申请，以支持第一阶段人类安全试验。

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.