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: 9252365
• 负责人: ALAN THOMAS JOHNSON
• 金额: $ 160.03万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252365
• 关键词: Address; Adenylate Cyclase; Alpha Cell; 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; Complex; Cyclic AMP; Development; Disease; Dose; Edema; Engineering; Ensure; Event; Formulation; Germination; Goals; Grant; Human; Immunotherapeutic agent; Infection; Inhalation Exposure; Intensive Care; Intoxication; Lead; Left; Mainstreaming; Mediating; Metalloproteases; Modeling; Modernization; 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; 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; clinical candidate; cost; design; edema factor; extracellular; genotoxicity; improved; in vivo; inhibitor/antagonist; manufacturing process; meetings; metabolic abnormality assessment; mortality; mouse model; novel; pre-clinical; preclinical development; prophylactic; public health relevance; resistant strain; 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建议研究的目标是确定一种临床候选药物，该药物在暴露后吸入炭疽热的动物模型中显示出体内疗效，并具有适合用于人类作为炭疽致命因子中毒解毒剂的安全性。2001年通过美国邮件进行的炭疽孢子袭击导致了11例吸入性炭疽病确诊病例。尽管给予了一线抗生素和现代重症监护支持，这些患者中只有6人幸存下来。高死亡率，加上普遍的恐慌和可观的清理费用，鲜明地定义了这一生物恐怖事件的严重性和炭疽病对国家安全构成的极端威胁。目前可用于治疗炭疽的治疗药物，如抗生素和免疫治疗剂(疫苗和单抗)，在暴露前给予动物模型时显示出完全保护作用。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下降，这表明毒血症仍然是对宿主生存的威胁。炭疽病的复杂发病机制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的来源，生物制剂可以阻止毒素进入细胞，但目前还没有治疗方法可以解除细胞中已存在的毒素的武装。Panthera已经确定了具有皮摩尔效力的新型炭疽致命因子抑制剂(LFIs)，并在大鼠、小鼠和兔的炭疽模型上证明了体内疗效。与仅作用于细胞外的生物制剂不同，这些LFI旨在通过细胞内和细胞外作用来缓解早期和晚期毒血症。小分子LFIs还应提供一种对抗炭疽杆菌抗药性菌株(增强剂)和新型病毒载体的对策，这些新型病毒载体被设计为输送细胞内的炭疽LF毒素(高级剂)。拟议项目的具体目标是：1)完成先导优化研究并选择临床前候选者；2)进行足以与FDA召开IND前会议的早期IND研究；以及3)完成向FDA提交IND所需的其余IND研究。为了实现这些目标，我们组建了一支在细菌毒素和炭疽病领域处于领先地位的科学家团队。这个专家合作者团队为我们提供了独特的动物模型：炭疽病的老鼠毒素和小鼠孢子攻击模型(Leppla Lab；NIH)，以及炭疽病兔吸入孢子感染的模型(Peterson Lab；UTMB)。