Humanized Monoclonal Antibody to Treat Acinetobacter Infections

 描述（由申请人提供）：国家监测数据证实，50%的A.从美国重症监护病房分离的鲍曼不动杆菌是极端耐药性（XDR），远远高于其他病原体。至少23，000和75，000例XDR A。鲍曼不动杆菌感染每年分别在美国和全球（在发达国家）发生。这些感染导致美国和全球每年约10，000和30，000例死亡以及3.9亿美元和7.42亿美元的额外医疗费用。此外，与其他耐药细菌相比，几乎没有抗生素在管道中处理XDR A。鲍曼不动杆菌。迫切需要新的预防和治疗战略。我们将研制一种治疗性单克隆抗体来治疗A.鲍曼不动杆菌感染，作为抗生素的辅助药物。在一系列的致病机制研究中，我们发现A.鲍曼不动杆菌的毒力是由先天免疫介导的清除的初始逃避驱动的，导致驱动脓毒症综合征的持续的LPS-TLR 4活化。因此，增强先天免疫介导的清除是一种有前途的免疫治疗策略，以改善感染的结果。此外，用A.鲍曼不动杆菌提高了受感染小鼠的存活率，验证了该方法。我们有一种单克隆抗体，BioAIM 1，它可以结合多种A.鲍曼不动杆菌以及多克隆免疫血清，并且在XDR A的其它致命模型中几乎完全具有保护性。鲍曼不动杆菌败血症和吸入性肺炎是鲍曼不动杆菌最常见的临床症状。鲍曼不动杆菌感染在资助STTR赠款的第一阶段，我们使MAb人源化。在第二阶段，我们寻求将其推向IND申请：目标1。为我们的候选MAb建立GMP生产。GMP规模扩大将由STC Biologics确定。GMP工艺将包括建立主细胞库，完成规模放大，包括初始GMP样生产运行，随后重复运行和最终50 L反应器运行，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进行药物治疗。目标2.完成临床前毒性研究以支持IND申请。毒性研究是根据FDA指南设计的，其执行将由合格的供应商承包。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样材料的临床前毒性研究，目标为第2年。在完成资助后，我们将能够提交IND，以便随后启动I期临床试验。单克隆抗体一旦开发出来，其影响将是显著改善高致死性、XDR和泛耐药（PDR）A的存活率和发病率。鲍曼不动杆菌感染。考虑到没有新的抗生素在开发中来治疗A。鲍曼不动杆菌。

 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.