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

用于治疗耐抗生素肺炎克雷伯菌感染的先导治疗噬菌体混合物的优化、制造和测试

• 批准号: 10674294
• 负责人: Derrick E Fouts
• 金额: $ 92.13万
• 依托单位: J. CRAIG VENTER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-21 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674294
• 关键词: Acute; Address; Antibiotic Resistance; Antibiotic Therapy; Antibodies; B-Lymphocytes; Bacteria; Bacteriophages; Bar Codes; Benchmarking; Blood Circulation; Clinical; Clinical Research; Clinical Trials; Cyclic GMP; Development; Dose; Engineering; Enterobacteriaceae; Formulation; Funding; Future; Genome; Genomics; Goals; Health; Human; Immune response; Immunity; In Vitro; Infection; Inflammation; Investigational Drugs; Investigational New Drug Application; Klebsiella pneumoniae; Label; Lead; Lung infections; Methods; Modeling; Modification; Mus; Pharmaceutical Preparations; Phase I Clinical Trials; Preparation; Production; Public Health; Recording of previous events; Research Institute; Research Personnel; Resistance; Sepsis; Septicemia; Specificity; Staphylococcus aureus; System; T-Lymphocyte; Technology; Testing; Therapeutic; Toxicity Tests; Urinary tract; Virus; Work; Wound Infection; Yeasts; alternative treatment; cGMP production; carbapenem resistance; cellular development; cytokine release syndrome; design; drug testing; efficacy testing; experience; experimental study; genome sequencing; immunoregulation; improved; in vivo; ineffective therapies; innovation; interest; lead candidate; lead optimization; manufacture; microbiome; mortality; mouse development; mouse model; pathogen; pathogenic bacteria; pharmacokinetics and pharmacodynamics; preclinical study; prevent; process optimization; public health relevance; receptor binding; resistant Klebsiella pneumoniae; respiratory; safety testing; scale up; stability testing; synthetic biology; synthetic genomics; therapeutic candidate; treatment strategy; whole genome; wound treatment

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.

项目总结/摘要 由肺炎克雷伯氏菌引起的感染越来越普遍，并且由于无效的治疗而难以治疗。 由于抗生素耐药性的增加而导致的治疗选择。噬菌体，感染并杀死细菌的病毒， 用于有效地治疗和治愈由许多细菌病原体引起的感染。解决 需要新的治疗方法来治疗由克雷伯氏菌引起的伤口和肺部感染。肺炎，我们的小组有 开发了一种5噬菌体先导候选治疗鸡尾酒，能够感染我们100株试验中的53株 面板该提案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 并审查1期临床试验的IND申请。 拟议的工作将通过J.克雷格文特尔研究所（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的合成和噬菌体基因组学的历史，WRAIR开发噬菌体疗法的经验， 小鼠模型的开发，以及APTs cGMP生产能力和噬菌体临床试验经验。 我们的目标是准备我们的主要候选治疗IND提交给FDA将通过三个实现 主要目的：1）优化电极导线治疗，2）进行IND要求的测试，3）优化 并扩大cGMP生产和测试规模。实现这些目标的工作流程是创新的， 利用尖端技术，并涵盖从优化和测试到GMP的整个过程 治疗剂的生产。更重要的是，它将成为开发未来基于噬菌体的 治疗其他重要的细菌病原体。