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（由申请人提供）：在过去的二十年中，开发的新抗菌剂的数量降低了60％以上，而抗生素耐药的微生物数量一直在稳步增加。在此期间，仅引入了一种新的具有新型作用机理（LineZolid）的新抗菌药物，这使得持续感染控制的长期前景越来越不稳定。一个特别有用的例子是一种称为铜绿假单胞菌的革兰氏阴性细菌，其中30％来自ICU（重症监护病房）或疗养院患者的临床分离株具有对3种或多种药物的耐药性。美国传染病学会（IDSA）还确定了铜绿假单胞菌是六个“超级细菌”，这是危险病原体的首要优先级“命中”清单，这些病原体变得越来越耐药。铜绿假单胞菌对医院获得的肺炎（HAP），特别是呼吸机相关肺炎（VAP）病例和囊性纤维化（CF）患者构成了特别致命的威胁。在此应用中要检验的主要假设是，是否可以在铜绿假单胞菌上针对普遍的细胞表面碳水化合物（藻酸盐）靶向的人单克隆抗体（MAB），可以在临床上用于治疗铜绿假单胞菌肺肺部感染，从而改善肺部功能，并降低肺部功能和降低疾病的发病率和死亡率。初步数据表明，这些人物mAB识别藻酸盐上的表位，该表位在一系列铜绿假单胞菌临床分离株上表达。 MAB通过称为Opsono-吞噬作用的免疫介导过程杀死这些分离株，可以在治疗上用于保护动物免受致命的肺部感染。在此应用程序中，我们建议扩大MAB的制造过程，并生产用于将来临床试验的临床材料。我们建议根据良好的实验室程序（GLP）测试动物毒性研究的临床材料，以证明对人类临床测试中的人进行MAB安全性。最后，我们建议安排与FDA会议的预先印度（研究新药），以介绍和讨论MAB临床前数据和我们提出的临床计划。结合了FDA的反馈，我们将提交一个IND应用程序。公共卫生相关性：拟议的研究将导致人类单克隆抗体的进一步发展，用于治疗由于铜绿假单胞菌而导致的严重细菌性肺部感染，该抗体因铜绿假单胞菌而在医院中获得的肺炎和囊性纤维化。将生产临床材料，将生成动物的安全数据，并将与FDA一起提交IND。