Phase I clinical trial of an immunoadhesin antitoxin for anthrax

炭疽免疫粘附素抗毒素的 I 期临床试验

• 批准号: 8469692
• 负责人: KEITH WYCOFF
• 金额: $ 18.78万
• 依托单位: PLANET BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-16 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469692
• 关键词: Adverse event; Affinity; Allergic Reaction; American; Anthrax Attack; Anthrax antitoxin; Anthrax disease; Antibiotics; Antibodies; Antigens; Area; Bacillus anthracis; Bacillus anthracis spore; Binding; Biotechnology; Blood Pressure; Blood capillaries; Body Temperature; Breathing; Case Report Form; Cell surface; Chimeric Proteins; Ciprofloxacin; Clinical; Clinical Trials; Collection; Complement; Complex; Consent Forms; Controlled Clinical Trials; Cyclic GMP; Data; Development; Dose; Double-Blind Method; Drug Kinetics; Edema; Effectiveness; Electrocardiogram; Engineering; Evaluation; Exposure to; Extracellular Domain; Funding; Goals; Grant; Half-Life; Heart Rate; Human; Immunoglobulin G; Individual; Industry; Infection; Injectable; Intravenous; Intravenous infusion procedures; Laboratories; Licensing; Logistics; Macaca; Manuals; Mediating; Methods; Modeling; Monitor; Monoclonal Antibodies; Morphogenesis; Oryctolagus cuniculus; Outcome; Pamphlets; Passive Immunotherapy; Pathogenesis; Pharmaceutical Preparations; Pharmacy facility; Phase I Clinical Trials; Physical Examination; Placebo Control; Planets; Plants; Primates; Property; Prophylactic treatment; Proteins; Randomized; Rattus; Recombinant Proteins; Recombinants; Regulation; Research; Research Design; Research Personnel; Risk; Safety; Schedule; Serious Adverse Event; Serum; Site; Symptoms; System; Teleconferences; Testing; Therapeutic; Time; Tobacco; Toxic effect; Toxicology; Toxin; Urinalysis; Variant; animal rule; anthrax lethal factor; antigen binding; base; capillary; clinical research site; data management; design; dosage; efficacy testing; expectation; healthy volunteer; human study; immunogenic; immunogenicity; in vitro Assay; in vivo; intravenous administration; laboratory manuals; manufacturing process; meetings; nonhuman primate; operation; phase 1 study; prophylactic; public health relevance; receptor; respiratory; safety testing

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.

描述（由申请人提供）：吸入性炭疽，由吸入炭疽芽孢杆菌孢子引起，即使用抗生素治疗，死亡率也约为50%。发病机制是由两种毒性非共价复合物介导的-水肿毒素和致死毒素。这两种复合物的基本组分保护性抗原（PA）结合于介导毒素体内致死性的主要哺乳动物受体毛细血管形态发生蛋白-2（CMG 2）。我们已经使用烟草表达系统产生了人CMG 2的胞外结构域和人IgG Fc的融合物，并证明了其在治疗兔吸入性炭疽中的有效性，包括免疫学和治疗学。我们的重组蛋白PBI-220与PA结合，阻止其与细胞表面CMG 2结合，从而阻止毒性。值得注意的是，PBI-220中和了在体外试验中被抗PA单克隆抗体中和较差的工程化PA变体，使其可能上级正在开发的其他炭疽治疗剂。 我们预期PBI-220适用于暴露于或有暴露于B风险的个体的暴露前和暴露后预防。炭疽病，以及用于治疗表现出吸入性炭疽病的体征或症状的个体。我们正在根据FDA的“动物规则”开发PBI-220，用于无法在人类中进行伦理测试的药物。我们已经完成了PBI-220在大鼠和食蟹猴中的初步毒理学研究，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作为吸入性炭疽病食蟹猴模型的治疗方法。我们计划在大鼠和食蟹猴中进行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。PBI-220开发的下一步是在健康志愿者中进行安全性测试。我们提出了一个剂量范围，安慰剂对照的临床试验，以测试耐受性（包括免疫原性）和单次静脉输注PBI-220的药代动力学。该计划补助金的目的是1）选择临床研究中心并最终确定研究设计; 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、监查计划、药房和实验室手册以及数据管理计划;和3）准备与FDA的Pre-IND会议。