Phase I clinical trial of an immunoadhesin antitoxin for anthrax

描述（由申请人提供）：吸入性炭疽，由吸入的炭疽芽孢杆菌孢子引起，即使用抗生素治疗，死亡率也有50%左右。发病机制由两种毒性非共价复合物-水肿毒素和致死毒素介导。这两种复合物的重要组成部分保护性抗原（PA）与介导体内毒素致死的主要哺乳动物受体毛细血管形态发生蛋白-2 （CMG2）结合。我们利用烟草表达系统制备了人CMG2和人IgG Fc细胞外结构域的融合，并证明了其在兔吸入性炭疽的预防和治疗上的有效性。我们的重组蛋白PBI-220与PA结合，阻止其与细胞表面CMG2结合，从而阻断毒性。值得注意的是，PBI-220在体外试验中可以中和被抗PA单克隆抗体难以中和的工程PA变体，这使得它可能优于其他正在开发的炭疽治疗药物。我们预计PBI-220可用于暴露于炭疽杆菌或有暴露风险的个体的暴露前和暴露后预防，并可用于治疗表现出吸入性炭疽体征或症状的个体。我们正在根据FDA的“动物规则”开发PBI-220，该规则适用于不能在伦理上测试人类疗效的药物。我们已经完成了PBI-220在大鼠和食蟹猕猴身上的毒理学试验，并正在开发cGMP生产工艺。我们正在与杜兰国家灵长类动物研究中心的研究人员合作，评估PBI-220在食蟹猴吸入性炭疽模型中的治疗效果。我们计划在大鼠和食蟹猕猴身上进行GLP毒理学试验。所有这些非临床活动将在未来12个月内完成。开发PBI-220的下一步是在健康志愿者中进行安全测试。我们建议进行一项剂量范围、安慰剂对照的临床试验，以测试单次静脉输注PBI-220的耐受性（包括免疫原性）和药代动力学。这项计划拨款的目的是：1)选择临床地点并确定研究设计；2)完成所有基本研究文件，包括研究者手册、知情同意书、病例报告表、研究操作手册、基本研究文件收集（根据ICH-E6和FDA法规）、统计分析计划、监测计划、药房和实验室手册以及数据管理计划；3)准备与FDA的ind前会议。

DESCRIPTION (provided by applicant): Inhalational anthrax, caused by inhaled Bacillus anthracis spores, has a ~50% fatality rate even when treated with antibiotics. Pathogenesis is mediated by two toxic noncovalent complexes - edema toxin and lethal toxin. An essential component of both complexes, protective antigen (PA), binds to the major mammalian receptor that mediates toxin lethality in vivo, capillary morphogenesis protein-2 (CMG2). We have produced a fusion of the extracellular domain of human CMG2 and human IgG Fc, using a tobacco expression system, and demonstrated its effectiveness in treating inhalational anthrax in rabbits, both prophylactically and therapeutically. Our recombinant protein, PBI-220, binds to PA, blocks it from binding to cell-surface CMG2 and thus blocks toxicity. Significantly, PBI-220 neutralizes engineered PA variants that are poorly neutralized by anti-PA monoclonal antibodies in an in vitro assay, making it potentially superior to other anthrax therapeutics under development. We expect PBI-220 to be indicated for the pre- and post-exposure prophylaxis of individuals exposed to, or at risk of exposure to B. anthracis, and for the treatment of individual displaying signs or symptoms of inhalational anthrax. We are developing PBI-220 under FDA's "Animal Rule" for drugs that cannot be ethically tested for efficacy in humans. We have already completed pilot toxicology studies of PBI-220 in rats and cynomolgus macaques, and are developing a cGMP manufacturing process. We are collaborating with researchers the Tulane National Primate Research Center to evaluate PBI-220 as a treatment in a cynomolgus macaque model of inhalational anthrax. We have scheduled GLP toxicology testing in rats and cynomolgus macaques. All of these non-clinical activities will be completed in the next 12 months. The next step in the development of PBI-220 is to conduct safety testing in healthy volunteers. We are proposing a dose-ranging, placebo-controlled clinical trial to test the tolerability (including immunogenicity) and pharmacokinetics of a single intravenous infusion of PBI-220. The aims of this planning grant are 1) to select a clinical site and finalize the study design; 2) to complete all essential study documents, including an Investigator's Brochure, Informed Consent forms, Case Report forms, Study Manual of Operations, Essential Study Document collection (per ICH-E6 and FDA regulations), Statistical Analysis Plans, Monitoring Plans, Pharmacy and Laboratory Manuals and Data Management Plans; and 3) to prepare for a Pre-IND meeting with FDA.