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：
7271057
负责人：
Eric John Patzer
金额：
$ 30万
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 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7271057
关键词：
Acute Acute Pneumonia Aerosols Alginates Animal Model Antibodies Bacterial Infections Breathing Carboxylic Acids Cell Line Charge Chinese Hamster Ovary Cell Chronic Compatible Condition Cultured Cells Cystic Fibrosis Data Data Protection Development Disease Dose Drug Formulations Epitopes Goals Human Immune Immune response Immunotherapeutic agent In Vitro Infection Inhalators Intervention Life Liquid substance Lung Lung diseases Methods Modeling Monoclonal Antibodies Mus Nebulizer Nosocomial Infections Organism Oropharyngeal Pathology Patients Phase Polysaccharides Powder dose form Preclinical Testing Principal Investigator Process Production Pseudomonas aeruginosa Respiratory Failure Respiratory physiology Route Study models Surface System Temperature Testing Transgenic Organisms Uronic Acids Wild Type Mouse airway inflammation base cost effective cystic fibrosis mouse cystic fibrosis patients design human monoclonal antibodies killings monomer mucoid physical property portability pre-clinical programs research clinical testing response

项目摘要

DESCRIPTION (provided by applicant): Cystic Fibrosis (CF) is an autosomal recessive disorder, which leads to the abnormal composition and physical properties of airway secretions in CF patients. Additionally, the lungs of CF patients are particularly susceptible to chronic bacterial infections with >80% of CF patients becoming chronically infected by 18 years of life with mucoid forms of Pseudomonas aeruginosa that over-produce the surface polysaccharide alginate. The long term goal of this project (which is outside the scope of this application) is to investigate the use of alginate specific monoclonal antibodies (mAb) as an immunotherapeutic to treat chronic P. aeruginosa lung infections in CF patients. The major hypothesis to be tested is whether alginate specific mAbs can be used to reduce P. aeruginosa lung infections and result in improvement in lung function. One key observation of P. aeruginosa infections in CF is that the infection fails to elicit opsonic/protective antibodies in patients. This ineffective immune response allows the organism to escape elimination by acquired host immune defenses and underlies the progressive decline in lung function. The alginate-specific human mAbs are both opsonic and protective against both mucoid strains of P. aeruginosa as well as classical non- mucoid strains isolated from patients with nosocomial infections. Preliminary data indicate that these human mAbs recognize an epitope on alginate that is defined by the highly charged carboxylic acid component of the uronic acid monomers that make up alginate, and represent a broadly reactive epitope that may be an effective target for immunotherapeutic intervention. In this application, we propose further preclinical development of alginate-based immunotherapeutics by preparing and testing the protective activities of a human mAb against acute P. aeruginosa pulmonary infection in wild-type (WT) mice and chronic P. aeruginosa oropharyngeal colonization and lung disease in transgenic CF mice. We will first develop cell culture processes to provide sufficient quantities of a mAb to perform preclinical testing in animal models and to determine whether the existing cell lines expressing mAb will be adequate to provide sufficient quantities for clinical testing. We will also investigate whether a mAb can be formulated and delivered optimally as a liquid in a mouse inhalation model. The studies proposed in this application are designed to further development of a human monoclonal antibody to treat chronic Pseudomonas aeruginosa lung infections of CF patients. At present, 80-95% of CF patients ultimately succumb to respiratory failure due to chronic P. aeruginosa infection and airway inflammation.

描述（申请人提供）：囊性纤维化（CF）是一种常染色体隐性遗传疾病，导致CF患者气道分泌物的成分和物理性质异常。此外，CF患者的肺部特别容易受到慢性细菌感染，超过80%的CF患者在18岁之前就被粘液形式的铜绿假单胞菌慢性感染，这些铜绿假单胞菌过度产生表面多糖藻酸盐。该项目的长期目标（不属于本申请的范围）是研究使用藻酸盐特异性单克隆抗体 (mAb) 作为免疫治疗药物来治疗 CF 患者的慢性铜绿假单胞菌肺部感染。要测试的主要假设是藻酸盐特异性单克隆抗体是否可用于减少铜绿假单胞菌肺部感染并改善肺功能。 CF 中铜绿假单胞菌感染的一项重要观察结果是，感染无法在患者体内引发调理/保护性抗体。这种无效的免疫反应使生物体能够逃脱获得性宿主免疫防御的消除，并导致肺功能逐渐下降。藻酸盐特异性人单克隆抗体既具有调理作用，又能针对铜绿假单胞菌的粘液样菌株以及从医院感染患者中分离出的经典非粘液样菌株发挥保护作用。初步数据表明，这些人单克隆抗体识别藻酸盐上的表位，该表位由构成藻酸盐的糖醛酸单体的高电荷羧酸成分定义，并且代表了广泛反应性表位，可能是免疫治疗干预的有效靶标。在本申请中，我们建议通过制备和测试人单克隆抗体对野生型（WT）小鼠急性铜绿假单胞菌肺部感染以及慢性铜绿假单胞菌口咽定植和肺部疾病的保护活性，进一步开发基于藻酸盐的免疫疗法。在转基因 CF 小鼠中。我们将首先开发细胞培养工艺，以提供足够数量的 mAb 在动物模型中进行临床前测试，并确定表达 mAb 的现有细胞系是否足以为临床测试提供足够的数量。我们还将研究是否可以在小鼠吸入模型中以液体形式配制和输送单克隆抗体。本申请中提出的研究旨在进一步开发人单克隆抗体来治疗 CF 患者的慢性铜绿假单胞菌肺部感染。目前，80-95%的CF患者最终因慢性铜绿假单胞菌感染和气道炎症而死于呼吸衰竭。