Human Monoclonal Antibody To Treat P. aeruginosa Infections in Cystic Fibrosis

人单克隆抗体治疗囊性纤维化中的铜绿假单胞菌感染

基本信息

批准号：
8199568
负责人：
Eric John Patzer
金额：
$ 92.24万
依托单位：
ARIDIS PHARMACEUTICALS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8199568
关键词：
Acute Alginates Americas Animals Anti-Bacterial Agents Antibiotic Resistance Binding Biodistribution Biological Assay Bioreactors Carbohydrates Cell Culture Techniques Cell Line Cell surface Clinical Clinical Trials Clinical trial protocol document Communicable Diseases Cyclic GMP Cystic Fibrosis Data Development Development Plans Drug Formulations Drug resistance Engineering Enzyme-Linked Immunosorbent Assay Epitopes Feedback Future Gram-Negative Bacteria Growth Human Immune In Vitro Infection Infection Control Intensive Care Units Investigation Investigational New Drug Application Laboratory Procedures Linezolid Lung Maximum Tolerated Dose Mediating Modeling Monoclonal Antibodies Morbidity - disease rate Mus Nosocomial pneumonia Nursing Homes Patients Phagocytosis Pharmaceutical Preparations Phase Phase I Clinical Trials Pneumonia Principal Investigator Process Production Productivity Pseudomonas aeruginosa Qualifying Quality Control Rattus Regulation Reporting Resistance Respiratory physiology Safety Schedule Small Business Technology Transfer Research Societies Testing Time Tissues Toxic effect Toxicokinetics Toxicology Treatment Efficacy Ventilator Work antimicrobial cell bank clinical lot clinical material clinically relevant cross reactivity cystic fibrosis patients experience human monoclonal antibodies human tissue killings manufacturing process meetings microorganism mortality novel pathogen pre-clinical programs prophylactic research clinical testing scale up

项目摘要

DESCRIPTION (provided by applicant): Over the past two decades, the number of new antimicrobials being developed has experienced a greater than 60% decline, while the number of antibiotic resistant microorganisms has been steadily increasing. Only one new antibacterial drug with a novel mechanism of action (linezolid) has been introduced during this period making the long term outlook for sustained infection control increasingly precarious. One particularly concerning example is a Gram negative bacterium called Pseudomonas aeruginosa in which 30% of clinical isolates from ICU (intensive care unit) or nursing home patients were reported to be resistant to 3 or more drugs. The Infectious Diseases Society of America (IDSA) also identified P. aeruginosa as one of six "superbugs" on the top priority "hit list" of dangerous pathogens that are becoming increasingly drug resistant. P. aeruginosa poses a particularly deadly threat for lung infections in hospital acquired pneumonia (HAP), particularly ventilator associated pneumonia (VAP) cases and in cystic fibrosis (CF) patients. The major hypothesis to be tested in this application is whether a human monoclonal antibody (mAb) targeted against a prevalent cell surface carbohydrate (alginate) on P. aeruginosa can be used clinically to treat P. aeruginosa lung infections resulting in improvement in lung function and a reduction in morbidity and mortality. Preliminary data indicate that these human mAbs recognize an epitope on alginate that is expressed on a broad array of P. aeruginosa clinical isolates. The mAb kills these isolates through an immune mediated process called opsono-phagocytosis and can be used therapeutically to protect animals from lethal lung infections. In this application, we propose to scale-up the manufacturing process for the mAb and produce clinical material for future clinical trials. We propose to test the clinical material in toxicity studies in animals according to Good Laboratory Procedures (GLP) to demonstrate that the mAb is safe to administer to people in human clinical testing. Finally, we propose to schedule a pre-IND (investigational new drug) meeting with the FDA to present and discuss the Mab preclinical data and our proposed clinical plan. Incorporating feedback from the FDA, we will then file an IND application. PUBLIC HEALTH RELEVANCE: The proposed studies will result in further development of a human monoclonal antibody for the treatment of severe bacterial lung infections due to Pseudomonas aeruginosa in patients with hospital acquired pneumonia and cystic fibrosis. Clinical material will be produced, safety data in animals will be generated and an IND will be filed with the FDA.

描述（申请人提供）：在过去的二十年里，正在开发的新抗菌药物的数量下降了 60% 以上，而抗生素耐药微生物的数量却在稳步增加。在此期间，仅推出了一种具有新颖作用机制的新抗菌药物（利奈唑胺），使得持续感染控制的长期前景变得越来越不稳定。一个特别令人担忧的例子是一种称为铜绿假单胞菌的革兰氏阴性细菌，据报道，来自 ICU（重症监护病房）或疗养院患者的临床分离株中有 30% 对 3 种或更多药物具有耐药性。美国传染病学会 (IDSA) 还将铜绿假单胞菌确定为危险病原体最优先“打击名单”中的六种“超级细菌”之一，这些病原体的耐药性日益增强。铜绿假单胞菌对医院获得性肺炎 (HAP)、特别是呼吸机相关性肺炎 (VAP) 病例和囊性纤维化 (CF) 患者的肺部感染构成特别致命的威胁。本申请要测试的主要假设是针对铜绿假单胞菌上普遍存在的细胞表面碳水化合物（藻酸盐）的人单克隆抗体（mAb）是否可以在临床上用于治疗铜绿假单胞菌肺部感染，从而改善肺功能和发病率和死亡率降低。初步数据表明，这些人单克隆抗体可识别藻酸盐上的表位，该表位在多种铜绿假单胞菌临床分离株中表达。单克隆抗体通过称为调理吞噬作用的免疫介导过程杀死这些分离株，并可用于治疗性保护动物免受致命性肺部感染。在此应用中，我们建议扩大单克隆抗体的生产工艺，并生产用于未来临床试验的临床材料。我们建议根据良好实验室程序 (GLP) 在动物毒性研究中测试临床材料，以证明该 mAb 在人体临床测试中可以安全地用于人体。最后，我们建议与 FDA 安排一次 IND（研究新药）会议，以介绍和讨论 Mab 临床前数据和我们提出的临床计划。结合 FDA 的反馈，我们将提交 IND 申请。公共健康相关性：拟议的研究将进一步开发人单克隆抗体，用于治疗医院获得性肺炎和囊性纤维化患者因铜绿假单胞菌引起的严重细菌性肺部感染。将制作临床材料、生成动物安全数据并向 FDA 提交 IND 申请。