An SEB Immunoprotectant

SEB 免疫保护剂

• 批准号: 8711005
• 负责人: Kevin John Whaley
• 金额: $ 100万
• 依托单位: MAPP BIOPHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-10 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711005
• 关键词: Aerosols; Antibodies; Bacteria; Biological Response Modifier Therapy; Biological Warfare; Breathing; Categories; Cessation of life; Chemistry; Cost Savings; Data; Development; Dose; Drug Formulations; Exhibits; Exposure to; FDA approved; Failure; Food Poisoning; Funding; Investigational Drugs; Investigational New Drug Application; Military Personnel; Monoclonal Antibodies; Mus; National Institute of Allergy and Infectious Disease; Nicotiana; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Population; Prophylactic treatment; Route; Safety; Shock; Specificity; Staphylococcal Enterotoxin B; Testing; Therapeutic; Time; Toxic Shock Syndrome; Toxic effect; Toxin; United States National Institutes of Health; War; aerosolized; base; biodefense; body system; immunogenicity; meetings; nonhuman primate; prevent; public health relevance; research clinical testing; stability testing

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.

描述(申请人提供)：葡萄球菌肠毒素B(SEB；B类制剂)，一种通常引起经典食物中毒并可引起非经期中毒性休克综合征(TSS)的毒素，已被研究为潜在的生物战剂。重要的是，SEB来自常见的容易接触的细菌，相对容易生产，并可以以稳定的气雾剂形式提供。SEB通过吸入途径表现出严重毒性；一旦吸入，会引起广泛的全身损害，多器官系统衰竭，甚至微克剂量的休克和死亡。显然，SEB的攻击将对平民人口以及战争期间的战场造成毁灭性的打击。目前，还没有针对SEB的预防或治疗方法。 单抗是FDA批准的一类能够有效中和毒素的生物制品。由于其稳定性、特异性、通用性和低免疫原性，mAbs是生物防御相关对策的理想选择。作为我们成功完成第一阶段工作的结果，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雾剂的攻击。此外，在这项提案中，我们正在与综合生物疗法公司(马里兰州盖瑟斯堡)联合，该公司的团队已经通过单独的NIAID资金确定了另一种抗SEB单抗。我们将共同确定两种单抗中哪一种最适合继续开发，从而为NIH节省成本。 该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的预防。 这项建议的具体目标和里程碑是： 目的1.利用烟草快速抗体制造平台(RAMP)制备两株候选单抗。 目的2.评价两种单抗在非人灵长类动物体内暴露前后抗SEB雾化作用的效果。最有效的单抗将被命名为MB-SEB，将被选择用于继续开发。 目的3.完成研究性新药(IND)，使研究能够根据法规要求为MB-SEB的临床评估做准备。使用根据良好制造规范(GMP)生产的RAMP单抗，将进行提交IND申请所需的研究(药理学和毒理学；化学、制造和控制数据)，以支持第一阶段安全试验。