IND Enabling Studies for Small Molecule Anthrax Lethal Factor Inhibitors

小分子炭疽致死因子抑制剂的 IND 启用研究

• 批准号: 8826678
• 负责人: ALAN THOMAS JOHNSON
• 金额: $ 159.35万
• 依托单位: HAWAII BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826678
• 关键词: Address; Adenylate Cyclase; Animal Model; Animals; Anthrax Attack; Anthrax disease; Anthrax exposure; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antidotes; Antigens; Bacillus anthracis; Bacillus anthracis spore; Back; Bacteria; Bacterial Toxins; Binding Proteins; Biological Products; Bioterrorism; Breathing; Calmodulin; Cell physiology; Cell surface; Cells; Cessation of life; Clinical; Complement Factor B; Complex; Cyclic AMP; Development; Disease; Dose; Drug Formulations; Edema; Engineering; Ensure; Event; Germination; Goals; Grant; Human; Immunotherapeutic agent; Infection; Inhalation Exposure; Inhibitory Concentration 50; Intensive Care; Intoxication; Lead; Left; MEKs; Mainstreaming; Mediating; Metalloproteases; Modeling; Monoclonal Antibodies; Mus; National Security; Oryctolagus cuniculus; Panic; Panthera; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Play; Preparation; Proteins; Rattus; Reproduction spores; Request for Proposals; Research; Research Support; Role; Safety; Scientist; Septic Toxemia; Septicemia; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Source; Staging; Survival Rate; System; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Toxin; United States National Institutes of Health; Vaccines; Vegetative States; Viral Vector; Virulence Factors; Zinc; analytical method; anthrax lethal factor; cost; design; edema factor; genotoxicity; improved; in vivo; inhibitor/antagonist; manufacturing process; meetings; metabolic abnormality assessment; mortality; mouse model; novel; pre-clinical; prophylactic; public health relevance; resistant strain; safety study; small molecule; weapons

DESCRIPTION (provided by applicant): PanThera's goal for the proposed research is to identify a clinical candidate that demonstrates in vivo efficacy in animal models of post-exposure inhalation anthrax and has a safety profile suitable for use in humans as an antidote to anthrax lethal factor intoxication. The 2001 anthrax spore attack via the U.S. mail caused 11 confirmed cases of inhalation anthrax. Despite the administration of frontline antibiotics and modern day intensive care support, only six of these patients survived. This high mortality rate, along with the widespread panic and considerable cleanup cost, starkly defined the seriousness of this bioterrorist event and the extreme threat anthrax poses to national security. Therapeutics currently available to treat anthrax, such as antibiotics and immunotherapeutic agents (vaccines and monoclonal antibodies), show complete protection in animal models when administered pre-exposure. However, their protective capability diminishes dramatically as post-exposure treatment delay times increase, suggesting that toxemia remains a threat to host survival. The complex pathogenesis of anthrax disease includes both bacterial and toxin components, although antibiotics can clear the system of bacteria and shut off the source of the toxins, and biological agents can block the transport of toxins into the cells, no therapeutic is currently available to disarm the toxins already present in the cells. PanThera has identified novel anthrax lethal factor inhibitors (LFIs) with picomolar potency and demonstrated in vivo efficacy in rat, mouse, and rabbit models of anthrax. These LFIs are designed to mitigate both early and late-stage toxemia by acting intracellularly and extracellularly, in contrast to biologics which ac only extracellularly. Small molecule LFIs should also provide a countermeasure against antibiotic resistant strains of B. anthracis (Enhanced Agents) and against novel viral vectors engineered to deliver intracellular anthrax LF toxin (Advanced Agents). The specific aims of the proposed project are: 1) complete lead optimization studies and select a preclinical candidate; 2) conduct early IND-enabling studies sufficient for a pre-IND meeting with the FDA; and 3) complete the remaining IND studies needed for submission of an IND to the FDA. To achieve these aims we have assembled a team of scientists who are leaders in the field of bacterial toxins and anthrax disease. This team of expert collaborators provides us with unique animal models: rat toxin and mouse spore challenge models of anthrax (Leppla lab; NIH), as well as a rabbit inhalation spore challenge model of anthrax infection (Peterson lab; UTMB).

描述（由申请人提供）：PanThera 拟议研究的目标是确定一种临床候选药物，该候选药物在暴露后吸入性炭疽动物模型中表现出体内功效，并且具有适合在人类中用作炭疽致死因子解毒剂的安全性中毒。 2001年通过美国邮件发生的炭疽孢子袭击事件导致11例吸入性炭疽确诊病例。尽管使用了一线抗生素和现代重症监护支持，但其中只有六名患者幸存。如此高的死亡率，加上广泛的恐慌和巨大的清理成本，赤裸裸地定义了这一生物恐怖事件的严重性以及炭疽对国家安全构成的极端威胁。 目前可用于治疗炭疽的疗法，例如抗生素和免疫治疗剂（疫苗和单克隆抗体），在暴露前施用时在动物模型中显示出完全的保护作用。然而，随着暴露后治疗延迟时间的增加，它们的保护能力急剧减弱，这表明毒血症仍然对宿主生存构成威胁。炭疽病的发病机制复杂，包括细菌和毒素成分，尽管抗生素可以清除细菌系统并切断毒素来源，生物制剂可以阻止毒素转运至细胞内，但目前尚无治疗方法可以解除武装。细胞中已经存在的毒素。 PanThera 已鉴定出具有皮摩尔效力的新型炭疽致死因子抑制剂 (LFI)，并在大鼠、小鼠和兔炭疽模型中证明了体内功效。这些 LFI 旨在通过细胞内和细胞外作用来减轻早期和晚期毒血症，与仅作用于细胞外的生物制剂相反。小分子 LFI 还应提供针对炭疽芽孢杆菌抗生素抗性菌株（增强剂）和针对经工程改造以输送细胞内炭疽 LF 毒素的新型病毒载体（高级剂）的对策。 该项目的具体目标是：1）完成先导化合物优化研究并选择临床前候选药物； 2) 进行足以与 FDA 举行 IND 前会议的早期 IND 支持研究； 3) 完成向 FDA 提交 IND 所需的剩余 IND 研究。为了实现这些目标，我们组建了一个科学家团队，他们是细菌毒素和炭疽病领域的领导者。这个专家合作团队为我们提供了独特的动物模型：炭疽的大鼠毒素和小鼠孢子激发模型（Leppla 实验室；NIH），以及炭疽感染的兔子吸入孢子激发模型（Peterson 实验室；UTMB）。