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（由申请人提供）：葡萄球菌肠毒素 B（SEB；B 类毒剂）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 源自常见的易于接触的细菌，相对容易产生，并且可以以稳定的气雾剂形式递送。 SEB 通过吸入途径表现出严重的毒性；一旦吸入，微克剂量的它会导致广泛的全身损害、多器官系统衰竭，甚至休克和死亡。显然，SEB 的攻击将对平民以及战争时期的战场造成毁灭性的打击。目前，尚无针对 SEB 的预防或治疗方法。 单克隆抗体 (mAb) 是 FDA 批准的一类生物制剂，可以有效中和毒素。由于单克隆抗体具有稳定性、特异性、多功能性和低免疫原性潜力，因此是生物防御相关对策的理想选择。由于第一阶段工作的成功完成，我们已经确定了一种高效的单克隆抗体，可以保护小鼠免受全身和气溶胶的攻击。此外，在这项提案中，我们正在与 Integrated Biotherapeutics（马里兰州盖瑟斯堡）合作，该公司的团队已通过单独的 NIAID 资助确定了一种额外的抗 SEB 单克隆抗体。我们将共同确定这两种单克隆抗体中哪一种最适合持续开发，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免疫保护产品。我们预计最初​​的适应症将用于暴露前和暴露后预防。 该提案的具体目标和里程碑是： 目标 1. 使用基于烟草的快速抗体制造平台 (RAMP) 生产两种候选 mAb。 目标 2. 评估两种 mAb 在非人灵长类动物中针对雾化 SEB 的暴露前和暴露后功效。将选择最有效的单克隆抗体（MB-SEB）进行持续开发。 目标 3. 完成研究性新药 (IND)，使研究能够根据监管要求为 MB-SEB 的临床评估做好准备。使用根据良好生产规范 (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、制造和控制数据），以支持一期安全试验。