An SEB Immunoprotectant

描述（由申请方提供）：葡萄球菌肠毒素B（SE B; B类制剂）是一种通常引起典型食物中毒并可引起非月经中毒性休克综合征（TSS）的毒素，已被研究为潜在的生物战剂。重要的是，SEB来源于常见的容易获得的细菌，相对容易产生，并且可以以稳定的气溶胶形式递送。SEB通过吸入途径表现出严重的毒性;一旦吸入，其在微克剂量下引起广泛的全身性损伤、多器官系统衰竭、甚至休克和死亡。显然，SEB的袭击将对平民以及战争时期的战场造成毁灭性影响。目前，没有针对SEB的预防或治疗药物。 单克隆抗体（mAb）是一类FDA批准的生物制剂，可以有效地中和毒素。由于其稳定性、特异性、多功能性和低免疫原性，mAb是生物防御相关对策的理想选择。由于我们成功完成了第1阶段的工作，我们已经确定了一种高度有效的mAb，可以保护小鼠免受全身和气溶胶攻击。此外，在本提案中，我们与Integrated Biotherapeutics（盖瑟斯堡，MD）合作，后者的团队通过单独的NIAID资助确定了一种额外的抗SEB mAb。我们将共同确定这两种mAb中哪一种最适合继续开发，从而为NIH节省成本。 本项目的长期目标是开发一种安全有效的SEB免疫保护剂产品。我们预计最初的适应症将是暴露前和暴露后预防。 本提案的具体目标和宗旨是： 目标1。使用基于本氏烟草的快速抗体制造平台（RAMP）生产两种候选mAb。 目标2.评价两种mAb在非人灵长类动物中对雾化SEB的暴露前和暴露后有效性。将选择最有效的mAb（命名为MB-SEB）进行继续开发。 目标3.完成新药临床试验申请（IND），使研究能够按照监管要求为MB-SEB的临床评价做好准备。使用按照药品生产质量管理规范（GMP）生产的RAMP mAb，将进行提交IND申请所需的研究（药理学和毒理学;化学、生产和控制数据），以支持I期安全性试验。

DESCRIPTION (provided by applicant): Staphylococcal enterotoxin B (SEB; Category B agent), a toxin that commonly causes classic food poisoning and can cause a non-menstrual toxic shock syndrome (TSS), has been studied as a potential biological warfare agent. Importantly, SEB is derived from common readily accessible bacteria, is relatively easily produced, and can be delivered in a stable aerosol form. SEB exhibits severe toxicity by the inhalation route; once inhaled it causes widespread systemic damage, multi- organ system failure, and even shock and death at microgram doses. Clearly, an SEB attack would be devastating to civilian populations as well as on the battlefield during times of war. Currently, there are no preventatives or therapeutics available against SEB. Monoclonal antibodies (mAbs) are a class of FDA-approved biologics that can potently neutralize toxins. Because of their stability, specificity, versatility, and low potential for immunogenicity, mAbs are ideal for biodefense-related countermeasures. As a result of successful completion of our Phase 1 efforts, we have identified a highly potent mAb that protects mice from systemic and aerosol challenge. Further, in this proposal we are combining forces with Integrated Biotherapeutics (Gaithersburg, MD) whose team has identified an additional anti-SEB mAb via separate NIAID funding. Together we will determine which of the two mAbs is the most appropriate for continued development, resulting in cost-savings for NIH. The Long Range Objective of this project is to develop a safe and effective immunoprotectant product for SEB. We expect the initial indication will be for pre- and post-exposure prophylaxis. The Specific Aims and Milestones of this proposal are: Aim 1. Produce the two candidate mAbs using a Nicotiana benthamiana based rapid antibody manufacturing platform (RAMP). Aim 2. Evaluate the pre- and post-exposure efficacy of the two mAbs in non-human primates against aerosolized SEB. The most efficacious mAb, to be designated MB-SEB, will be chosen for continued development. Aim 3. Complete Investigational New Drug (IND) enabling studies to prepare for clinical evaluation of MB-SEB in accordance with regulatory requirements. Using RAMP mAb produced under Good Manufacturing Practice (GMP), the studies necessary (pharmacology and toxicology; chemistry, manufacturing and control data) to submit an IND application will be performed to support a Phase 1 safety trial.