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Novel, Non-antibiotic Therapy for Clostridium difficile-Associated Disease

针对艰难梭菌相关疾病的新型非抗生素疗法

基本信息

批准号：
8047396
负责人：
Gerald P Donovan
金额：
$ 414.37万
依托单位：
PROGENICS PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8047396
关键词：
Address Affect Amino Acids Anaerobic Bacteria Animal Model Antibiotic Therapy Antibiotics Antibodies Antitoxins Area Bacteria Basic Science Biological Biology Cessation of life Clinical Clostridium difficile Colon Development Diarrhea Disease Disease Management Disease Outbreaks Epidemic Epithelial Cells Epitopes Exposure to Frequencies Funding Future Generations Goals Hamsters Healed Hemorrhage Hospital Nursing Hospitals Human In Vitro Incidence Individual Infection Inflammation Intestines Investigational New Drug Application Life Maps Mediating Metronidazole Modeling Monoclonal Antibodies Nursing Homes Outcome Outpatients Pathology Patients Pharmacologic Substance Phase II Clinical Trials Pre-Clinical Model Property Pseudomembranous Colitis Public Health Recurrence Recurrent disease Relapse Reporting Reproduction spores Role Series Severities Structure-Activity Relationship Testing Therapeutic Time Toxic effect Toxicology Toxin Translating Universities Vancomycin combat cost cytotoxic healing in vivo innovation insight manufacturing process meetings mortality novel pathogen pre-clinical preclinical efficacy preclinical study prevent public health relevance research clinical testing response restoration safety study standard of care success therapy design treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Clostridium difficile is an anaerobic, spore-forming bacterium that represents the leading cause of hospital-acquired diarrhea and life-threatening pseudomembranous colitis. C. difficile-associate disease (CDAD) affects more than 750,000 individuals each year in the U.S. and is responsible for more deaths than all other intestinal infections combined. Disease is mediated by two toxins, A and B that are potently cytotoxic and disrupt colonic epithelial cells, leading to inflammation and hemorrhage. CDAD typically is precipitated by disruption of the normal colonic bacterial flora with antibiotics, which provide opportunities for C. difficile to become established. The dramatic rise in CDAD over the past decade has paralleled the increased use of broad-spectrum antibiotics. Recent outbreaks of hypervirulent strains have been reported around the globe. New treatment strategies are urgently needed to combat the worldwide epidemic of C. difficile infections. Our approach to addressing this need has been to discover novel antitoxin monoclonal antibodies (mAbs) that demonstrate unprecedented toxin-neutralizing activity and define unique neutralization epitopes on the C. difficile toxins. These mAbs are 100-fold more potent that current-generation mAbs against hypervirulent strains and are the first to demonstrate complete and durable protection in a stringent animal model of CDAD. Whereas current-generation mAbs have demonstrated clinical promise in preventing recurrent disease but not in treating active disease, our ultrapotent mAbs may have utility in managing a spectrum of CDAD manifestations, including cases of active, severe or life-threatening disease. Our overall goal in this project is to ready our novel mAbs for human testing while elucidating fundamental structure-function relationships within the C. difficile toxins. Our project thus directly addresses Thematic Area 2: "Translating Basic Science Discoveries into New and Better Treatments." Aim 1 of our project seeks to define the novel neutralization epitopes to the level of individual amino acids. This information will provide new insights into C. difficile toxicity and its inhibition. Aim 2 will examine our mAbs in a series of innovative preclinical efficacy studies that will significantly expand our understanding of the potential role of antitoxin mAbs in the management of CDAD. Specific Aims 3 and 4 describe translational activities that are essential steps in readying our novel mAbs for human testing, which will be conducted under separate funding. Success in this project is defined as (1) favorable outcomes in the proposed preclinical mechanistic, efficacy and safety studies; and (2) clearance by FDA for us to conduct first-in-humans studies of our novel mAbs. Success would represent a major milestone in the development of an innovative, antitoxin therapy with unique potential to address some of the most pressing challenges of the C. difficile epidemic. PUBLIC HEALTH RELEVANCE: Clostridium difficile is a spore-forming bacterium that is the leading cause of hospital-acquired diarrhea and is responsible for more deaths per year in the U.S. than all other intestinal infections combined. The dramatic rise in the incidence and severity of C. difficile infections over the past decade have paralleled the increased use of broad- spectrum antibiotics, which provide opportunities for C. difficile to become established. Recently, outbreaks of hypervirulent strains have been reported across the globe. Our approach to meeting this worldwide public health challenge has been to develop novel antitoxin antibodies with unprecedented toxin-neutralizing activity in the best available preclinical models. In this project, we seek to complete key studies to ready our antitoxin antibodies for clinical testing while providing fundamental insight into C. difficile toxicity and its inhibition.

描述（由申请方提供）：艰难梭菌是一种厌氧孢子形成细菌，是医院获得性腹泻和危及生命的伪膜性结肠炎的主要原因。C.在美国，艰难梭菌相关疾病（CDAD）每年影响超过750，000人，并且比所有其他肠道感染的总和造成更多的死亡。疾病由两种毒素A和B介导，这两种毒素具有强效细胞毒性并破坏结肠上皮细胞，导致炎症和出血。CDAD通常是通过用抗生素破坏正常的结肠细菌植物群而引起的，这为C.很难建立。CDAD在过去十年中的急剧上升已经阻碍了广谱抗生素使用的增加。最近在地球仪各地报告了高毒力菌株的爆发。迫切需要新的治疗策略来对抗世界范围内流行的C。艰难感染。我们解决这一需求的方法是发现新的抗毒素单克隆抗体（mAb），这些抗体表现出前所未有的毒素中和活性，并在C.艰难梭菌毒素这些单克隆抗体是100倍更有效的，目前一代单克隆抗体对高毒力菌株，是第一个证明完全和持久的保护，在严格的动物模型的CDAD。鉴于目前这一代mAb已证明在预防复发性疾病方面有临床前景，但在治疗活动性疾病方面没有，我们的超强效mAb可能在管理一系列CDAD表现方面具有实用性，包括活动性、重度或危及生命的疾病病例。我们在这个项目中的总体目标是准备我们的新单克隆抗体用于人体测试，同时阐明C.艰难梭菌毒素因此，我们的项目直接涉及主题领域2：“将基础科学发现转化为新的更好的治疗方法。" 我们项目的目标1是在单个氨基酸水平上确定新的中和表位。这些信息将为C.艰难梭菌的毒性及其抑制作用。目标2将在一系列创新的临床前功效研究中检查我们的mAb，这将显着扩大我们对抗毒素mAb在CDAD治疗中的潜在作用的理解。具体目标3和4描述了翻译活动，这些活动是准备我们的新型mAb进行人体测试的必要步骤，这些测试将在单独的资助下进行。该项目的成功定义为：（1）在拟议的临床前机制、疗效和安全性研究中取得了有利的结果;以及（2）FDA批准我们对我们的新型mAb进行首次人体研究。成功将是一个重要的里程碑，在开发一种创新的抗毒素疗法，具有独特的潜力，以解决一些最紧迫的挑战，C。艰难的流行病公共卫生关系：艰难梭菌是一种孢子形成细菌，是医院获得性腹泻的主要原因，在美国每年造成的死亡人数超过所有其他肠道感染的总和。C.在过去的十年里，艰难梭菌感染已经阻碍了广谱抗生素的使用，这为艰难梭菌提供了机会。很难建立。最近，地球仪各地都报告了高毒力菌株的爆发。我们应对这一全球公共卫生挑战的方法是在最佳临床前模型中开发具有前所未有的毒素中和活性的新型抗毒素抗体。在这个项目中，我们寻求完成关键的研究，准备我们的抗毒素抗体的临床测试，同时提供基本的洞察C。艰难梭菌的毒性及其抑制作用。