Humanized Monoclonal Antibody to Treat Acinetobacter Infections

 描述(申请人提供)：国家监测数据证实，来自美国重症监护病房的鲍曼不动杆菌分离物中有50%是极端耐药(XDR)，远远高于其他病原体。美国和全球(发达国家)每年分别至少发生23,000例和75,000例鲍曼不动杆菌XDR感染病例。这些感染每年在美国和全球导致约10,000和30,000人死亡，额外的医疗费用分别为3.9亿美元和7.42亿美元。此外，与其他耐药细菌不同的是，几乎没有抗生素正在研制中，以应对鲍曼不动杆菌。迫切需要新的预防和治疗战略。我们将开发一种治疗性的单抗来治疗鲍曼不动杆菌感染，作为抗生素的辅助。在一系列的发病机制研究中，我们发现鲍曼不动杆菌的毒力是由于最初逃避天然免疫介导的清除，导致持续的内毒素-TLR4激活，从而导致败血症综合征。因此，加强天然免疫介导的清除是一种很有前途的免疫治疗策略，可以改善感染的预后。此外，针对鲍曼不动杆菌的多克隆免疫血清被动免疫提高了受感染小鼠的存活率，验证了该方法。我们有一种单抗BioAIM1，它可以结合多种鲍曼不动杆菌以及多克隆免疫血清的表面，在鲍曼不动杆菌细菌性败血症和吸入性肺炎的其他致命模型中几乎完全具有保护作用，这是鲍曼不动杆菌感染最常见的临床症状。在STTR资助的第一阶段，我们使MAB人性化。在第二阶段，我们寻求将其推进到IND备案：目标1。为我们的候选MAB建立GMP生产。GMP规模化将由STC生物公司建立。GMP过程将包括建立一个主细胞库，完成规模扩大，包括最初的类似GMP的生产运行，然后重复运行和最后50个L反应堆运行，以及稳定性研究。我们将确认其体外和体内活性。 生产的材料。我们经验丰富的团队将管理供应商，他们曾带领之前的公司进行IPO，并通过NDA/BLA服用药物。目的2.完成临床前毒性研究以支持IND应用。毒性研究已经根据FDA的指导进行了设计，并将把执行工作外包给合格的供应商。我们将与FDA举行IND前会议，以确认我们的毒性研究计划和未来的I期临床试验。完成使用GMP类材料的临床前毒性研究，目标是在第二年。在资金完成后，我们将准备提交IND，允许随后启动I期临床试验。一旦开发出单抗，其影响将显著提高鲍曼不动杆菌感染的高致命性、XDR和泛耐药(PDR)感染的存活率和发病率。考虑到治疗鲍曼不动杆菌的新抗生素的开发中缺乏新的抗生素，这种影响将特别大。

 DESCRIPTION (provided by applicant): National surveillance data confirm that 50% of A. baumannii isolates from US intensive care units are extreme drug resistance (XDR), far higher than other pathogens. At least 23,000 and 75,000 cases of XDR A. baumannii infections occur annually in the US and globally (in developed countries), respectively. These infections result in ~10,000 and 30,000 deaths and excess healthcare costs of $390 million and $742 million in the US and globally, annually. Furthermore, in contrast to other resistant bacteria, virtually no antibiotics are in the pipeline to deal with XDR A. baumannii. New prevention and treatment strategies are critically needed. We will develop a therapeutic monoclonal antibody to treat A. baumannii infections, as an adjunct to antibiotics. In a series of pathogenesis studies, we found that A. baumannii virulence was driven by an initial evasion of innate immune-mediated clearance, resulting in sustained LPS-TLR4 activation that drove sepsis syndrome. Thus enhancement of innate immune mediated clearance was a promising immune-therapeutic strategy to improve outcomes from infection. Furthermore, passive immunization with polyclonal immune serum targeting A. baumannii improved survival of infected recipient mice, validating the approach. We have a MAb, BioAIM1 that binds to the surface of multiple strains of A. baumannii as well as polyclonal immune serum, and is nearly completely protective in otherwise fatal models of XDR A. baumannii bacteremic sepsis and aspiration pneumonia, the most common clinical syndromes of A. baumannii infection. During phase I of the funded STTR grant, we humanized the MAb. In phase II, we seek to advance it towards IND filing: Aim 1. Establish GMP manufacturing for our candidate MAbs. GMP scale up will be established by STC Biologics. The GMP process will include establishment of a master cell bank, completion of scale up including an initial GMP-like manufacturing run followed by repeat runs and a final 50 L reactor run, as well as stability studies. We will confirm the in vitro and in vivo activity of the material produced. Our highly experienced team, which has taken prior companies to IPO and taken drugs through NDA/BLA, will manage the vendor. Aim 2. Complete pre-clinical toxicity studies to support an IND application. Toxicity studies have been designed based on FDA guidance, and their execution will be contracted to a qualified vendor. We will hold a pre-IND meeting with the FDA to confirm our plans for toxicity studies and the future phase I clinical tria. Completion of pre-clinical toxicity studies using GMP-like material and will be targeted for year 2. Upon completion of funding we will be positioned to file an IND that will allow subsequent initiation of a phase I clinical trial. The impact of the MAb once developed will be to markedly improve survival and morbidity from highly lethal, XDR and pan-drug resistant (PDR) A. baumannii infections. The impact will be particularly great given the absence of new antibiotics in development to treat A. baumannii.