Optimization, Manufacturing and Testing of a Lead Therapeutic Bacteriophage Cocktail for the Treatment of Antibiotic-Resistant Klebsiella pneumoniae Infections

项目摘要/摘要 由肺炎克雷伯氏菌引起的感染日益流行，由于无效而难以治疗 由于抗生素耐药性增加而导致的治疗选择。噬菌体，感染和杀死细菌的病毒，是 用于有效治疗和治愈由多种细菌病原体引起的感染。要解决这个问题 需要新的治疗方法来治疗肺炎克雷伯菌引起的伤口和肺部感染，我们的小组已经 开发了一种5噬菌体候选治疗鸡尾酒，能够感染我们100个菌株中的53个 面板。这项建议的目标是优化我们的铅治疗及其生产，以及进行 成功提交所需的研究前新药(IND)测试和基准测试 以及审查IND的1期临床试验申请。 拟议的工作将通过J.Craig Venter研究所(JCVI)、 沃尔特里德陆军研究所(WRAIR)和适应性噬菌体治疗(APT)。它将利用 JCVI在合成和噬菌体基因组学方面的历史，WRAIR开发噬菌体疗法的经验， 小鼠模型的开发，以及APTS cGMP的生产能力和噬菌体临床试验的经验。 为IND提交给FDA准备我们的主要候选治疗药物的目标将通过三个月实现 主要目标：1)优化铅治疗，2)进行IND要求的测试，3)优化 以及cGMP制造和测试的放大。实现这些目标的工作流程是创新的， 利用尖端技术，涵盖从优化、测试到GMP的整个过程 治疗性产品的制作。更重要的是，它将成为开发未来基于噬菌体的平台 其他重要细菌病原体的治疗。

PROJECT SUMMARY/ABSTRACT Infections caused by Klebsiella pneumoniae are increasingly prevalent and difficult to treat due to ineffective treatment options due to increased antibiotic resistance. Bacteriophages, viruses that infect and kill bacteria, are being used to effectively treat and cure infections caused by a number of bacterial pathogens. To address the need for new treatments for wound and pulmonary infections caused by K. pneumoniae, our group has developed a 5-phage lead candidate therapeutic cocktail that is capable of infecting 53 of our 100-strain test panel. The goal of this proposal is to optimize our lead therapeutic and its production as well as to conduct the required pre-Investigational New Drug (IND) testing and benchmarking necessary for the successful submission and review of an IND application for a phase 1 clinical trial. The proposed work will be conducted through a partnership between the J. Craig Venter Institute (JCVI), the Walter Reed Army Institute of Research (WRAIR) and Adaptive Phage Therapeutics (APT). It will leverage JCVI’s history of synthetic and phage genomics, WRAIR’s experience developing phage therapeutics, development of mouse models, and APTs cGMP production capabilities and experience with phage clinical trials. The goal to prepare our lead candidate therapeutic for IND submission to FDA will materialize through three main objectives: 1) To optimize the lead therapeutic, 2) To conduct IND-required testing, and 3) To optimize and scale-up for cGMP manufacturing and testing. The workflow to achieve these objectives is innovative, utilizing cutting-edge technologies, and encompasses the entire process from optimization and testing to GMP production of the therapeutic. More significantly, it will be a platform for developing future phage-based therapeutics for other important bacterial pathogens.