Phase I clinical trial of an immunoadhesin antitoxin for anthrax

描述(申请人提供)：吸入性炭疽病，由吸入的炭疽芽胞引起，即使用抗生素治疗也有大约50%的死亡率。致病机制由两种有毒的非共价复合体--水肿性毒素和致死性毒素介导。保护性抗原(PA)是这两种复合体的基本成分，它与体内介导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胞外区和人免疫球蛋白Fc的融合，并证明了其在预防和治疗兔吸入性炭疽病方面的有效性。我们的重组蛋白PBI-220与PA结合，阻止其与细胞表面CMG2结合，从而阻止毒性。值得注意的是，PBI-220在体外试验中中和了抗PA单抗难以中和的工程PA变体，使其潜在地优于其他正在开发的炭疽疗法。我们预计PBI-220将用于暴露于炭疽杆菌或处于暴露风险中的个人暴露前和暴露后的预防，以及用于显示吸入性炭疽体征或症状的个人的治疗。我们正在根据FDA的“动物规则”开发PBI-220，用于无法在人体上进行疗效伦理测试的药物。我们已经完成了PBI-220在老鼠和食蟹猴身上的初步毒理学研究，并正在开发一种cGMP的制造工艺。我们正在与杜兰国家灵长类研究中心的研究人员合作，评估PBI-220作为食蟹猴吸入性炭疽模型的治疗方法。我们已经安排了在老鼠和食蟹猴身上进行GLP毒理学测试。所有这些非临床活动都将在未来12个月内完成。开发PBI-220的下一步是在健康志愿者身上进行安全性测试。我们建议进行一项剂量范围、安慰剂对照的临床试验，以测试单次静脉注射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)选择临床地点并最终确定研究设计；2)完成所有基本研究文件，包括研究人员手册、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的规定)、统计分析计划、监测计划、药学和实验室手册以及数据管理计划；以及3)为IND前与FDA的会议做准备。

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.