An Antibody Immunoprotectant for Category B Toxins

B 类毒素的抗体免疫保护剂

• 批准号: 8268955
• 负责人: Larry Zeitlin
• 金额: $ 117.22万
• 依托单位: MAPP BIOPHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-08 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268955
• 关键词: Academia; Aerosols; Affect; Animal Model; Antibodies; Bacteria; Benchmarking; Biological Products; Biological Response Modifier Therapy; Bioterrorism; Categories; Chad; Chemistry; Clinical; Clostridium perfringens; Clostridium perfringens epsilon toxin; Collaborations; Controlled Study; Development; Dimensions; Drug Formulations; Ensure; Exposure to; FDA approved; Goals; Human; Immunotherapeutic agent; In Vitro; Industry; Institutes; International; Intoxication; Investigation; Investigational New Drug Application; Iowa; Kentucky; Monoclonal Antibodies; Morbidity - disease rate; Performance; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Plants; Population; Preclinical Testing; Prevention; Preventive; Production; Ricin; Running; Safety; Savings; Staphylococcal Enterotoxin B; Symptoms; System; Testing; Therapeutic; Time; Toxin; Universities; bioprocess; cost; cost effective; drug development; in vivo; liquid formulation; manufacturing process development; member; mortality; point-of-care diagnostics; prevent; product development

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. PUBLIC HEALTH RELEVANCE: The efforts in this application will help in the development of a drug for preventing and/or treating the morbidity and mortality caused by exposure to the Category B toxins (C. perfringens epsilon toxin, ricin, and staphylococcal enterotoxin B) which may be used as bioweapons. No FDA-approved preventive or treatment currently exists for any of these toxins.

描述（由申请人提供）：故意传播自然发生的传染和有毒药物的潜力为这些代理商传统上带来的威胁增加了一个严重的新维度。这些生物恐怖主义威胁大大增加了我们对针对特定毒剂毒素的防御性的紧迫感。 B类毒素由灌注梭状芽胞杆菌氏蛋白酶毒素（ETX），易感蛋白和葡萄球菌肠毒素B（SEB）组成，都是非常有效的，均来自常见的，易于获得的植物（Ricin）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传递 - 它们在战场上或平民中用作生物武器，将导致灾难性的发病率和死亡率。目前，AE尚无预防性或治疗药物暴露于这些毒素的情况。我们已经确定了单克隆抗体（mAb），它们在动物模型中单独预防致命的ETX，ricin和SEB挑战。该应用的目的是开发针对B类毒素（CBT-AB）的广谱抗体鸡尾酒，该鸡尾酒是在快速且具有成本效益的植物系统中制造的，用于预防和暴露后侵入性治疗中毒。使用这三种毒素来追求单个产品（将单独制造单独制造，然后合并到最终产品中），这将表现为节省成本和时间。此外，需要单一的鸡尾酒产品用于临床用途，因为与B类毒素中毒会导致类似的症状和护理点诊断，以迅速识别该因子剂通常不可用和/或无法使用。该应用程序的具体目的是：特定目标＃1。评估体外和体内CBT-AB。鸡尾酒的预防和暴露后活动将被证明，以满足提交调查新药（IND）申请的要求。特定目标＃2。确定CBT-AB公式。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曲线。特定目标＃3。完整的辅助研究。 CBT-AB将根据当前良好的制造实践（CGMP）制造和制造。将进行所有辅助药理学，毒理学以及化学，制造和控制（CMC）研究，最终目标是提出研究新药物（IND）申请以支持1期人类安全试验。 公共卫生相关性：本申请中的努力将有助于开发一种药物，以预防和/或治疗暴露于B类毒素（C. perpringens epsilon毒素，ricin和ricin和葡萄球菌肠毒素B）引起的发病率和死亡率，这些发病率和死亡率可用作Bioweapons。这些毒素中的任何一种目前都不存在FDA批准的预防或治疗。