Final preclinical development of an immunoadhesin therapy for inhalation anthrax

描述（由申请方提供）：由吸入炭疽芽孢杆菌孢子引起的吸入性炭疽，即使使用抗生素治疗，致死率也约为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。我们正在开发PBI-220作为被动免疫疗法，以补充吸入性炭疽治疗期间抗生素的使用。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。我们正在与加尔维斯顿国家实验室和杜兰国家灵长类动物研究中心的研究人员合作，评估PBI-220和抗生素治疗在兔子疾病晚期的益处，并评估PBI-220作为吸入性炭疽病食蟹猴模型的治疗方法。这笔赠款将推进我们的PBI-220产品开发计划，完成准备新药研究（IND）申请所需的生产和临床前动物研究，从而实现人体安全性试验。赠款目标包括：1）开发污染植物蛋白的定量测定，以确保药物产品中这些蛋白的最低水平，如人类治疗所需; 2）在两种动物物种中进行GLP安全性研究（大鼠和猴子），其药物产品的质量与将用于第一次人体临床试验的药物产品的质量相同; 4）开发用于临床样本分析的免疫测定法（药物和抗药抗体的定量）和5）完成成功向FDA提交IND申请所需的基准。

Description (provided by the 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 non-covalent complexes - edema toxin and lethal toxin. An essential component of both complexes, protective antigen (PA), binds to the major mammalian receptor which 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 are developing PBI-220 as a passive immunotherapy to complement the use of antibiotics during treatment of inhalational anthrax. 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 at the Galveston National Laboratory and the Tulane National Primate Research Center to evaluate the benefits of combining PBI-220 and antibiotic treatment in late stages of disease in rabbits and to evaluate PBI-220 as a treatment in a cynomolgus macaque model of inhalational anthrax. This grant will advance our Product Development Plan for PBI-220 by completing the manufacturing and pre-clinical animal studies required for preparing an Investigational New Drug (IND) application, thus enabling human safety trials. Grant objectives include: 1) Develop a quantitative assay for contaminating plant proteins, to assure a minimal level of these proteins in the drug product, as required for human therapeutics; 2) Conduct GLP safety studies in two animal species (rats and monkeys) with drug product of the same quality as will be used in the first human clinical trial; 3 Produce PBI-220 under cGMP for Phase 1 clinical trial(s); 4) Develop immunoassays for clinical sample analyses (quantification of drug and anti-drug antibodies) and 5) Complete required benchmarks for successful submission of an IND application to FDA.