Development of a novel antibody therapy for clostridium difficile infection

开发针对艰难梭菌感染的新型抗体疗法

基本信息

批准号：
7962084
负责人：
IRVING NACHAMKIN
金额：
$ 20万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2010-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7962084
关键词：
Affinity Alloantigen Alternative Therapies Animal Diseases Animal Model Animals Antibiotic Therapy Antibiotics Antibodies Antibody Affinity Antibody Therapy Antigens Autoantibodies Bacillus (bacterium)Blood Cells Cloning Clostridium difficile Colitis Community Hospitals Community-Acquired Infections Development Diarrhea Disease Engineering Environment Epitopes Hamsters Healthcare Hospital Costs Human Human Cloning Human Development Immune response Immune system Immunotherapy In Vitro Individual Infection Infectious Agent Isoantibodies Lead Length of Stay Methods Modeling Modification Monoclonal Antibodies Monomeric GTP-Binding Proteins Organism Pathogenesis Patients Phage Display Population Prevention Property Proteins Public Health Reagent Refractory Reproduction spores Research Personnel Risk Specificity System Techniques Technology Testing Therapeutic Therapeutic Uses Therapeutic antibodies Tissues Toxin United States Virulent Work antimicrobial drug base gastrointestinal epithelium gastrointestinal infection glycosylation human disease human monoclonal antibodies novel prevent protective effect public health relevance

项目摘要

DESCRIPTION (provided by applicant): Clostridium difficile is a common cause of both hospital- and community acquired gastrointestinal infection that may occur after patients have been treated for other infections with a variety of antimicrobial agents. While mostly causing antibiotic-associated diarrhea, C. difficile infection may cause more severe disease and may be refractory to current standard forms of therapy. In recent years, a more virulent strain of C. difficile has emerged that has caused serious disease in some patients. The pathogenesis of C. difficile infection, while not completely understood, involves the action of two toxins, toxin-A (TcdA) and toxin-B (TcdB), produced by the organism, on the gut epithelium. There is very good evidence showing that antibodies against TcdA and TcdB have protective effects against disease in humans and in animal models of C. difficile colitis. The purpose of the current study is to develop an antibody-based immunotherapy for C. difficile infection by cloning human monoclonal antibodies (mAbs) from individuals with C. difficile and determine whether these antibodies can protect against disease using a hamster model of infection. The antibodies will be produced in vitro by cloning patients' antibodies using a phage display system, a technique for which Dr. Donald Siegel, Co- Investigator of the study, is among the pioneers. Toxin specific antibodies will be produced in vitro and will be tested for the ability of these antibodies to protect animals from developing C. difficile colitis. Use of this technology over the past 15 years has produced human monoclonal antibodies with specificities against a large number of human auto- and alloantigens, and human infectious agents. Thus, phage display technology is an ideal approach for producing completely human proteins in a way that exploits the human immune system's ability to generate large repertoires of high affinity, antigen selected, antibodies with varying specificities for disease- associated epitopes. Given the multitude of antibodies that will be developed in this proposal, the strategy will provide enough reagents for characterization and allow us to choose optimal antibodies (or combinations of antibodies) as lead compounds for therapeutic use. PUBLIC HEALTH RELEVANCE: C difficile is one of the most common causes of antibiotic associated diarrhea in healthcare settings as is being increasingly recognized as a community acquired infection. Patients with nosocomially acquired C. difficile disease incur significantly higher hospital costs and length of stay and has been estimated to exceed 1 billion dollars in the US. Thus, C. difficile disease is of considerable public health concern.

描述（由申请人提供）：艰难梭菌是医院和社区获得性胃肠道感染的常见原因，这种感染可能在患者接受各种抗菌药物治疗其他感染后发生。虽然艰难梭菌感染主要引起抗生素相关性腹泻，但它也可能引起更严重的疾病，并且可能对当前的标准治疗形式无效。近年来，出现了一种毒性更强的艰难梭菌菌株，已导致一些患者出现严重疾病。艰难梭菌感染的发病机制虽然尚未完全了解，但涉及生物体产生的两种毒素：毒素 A (TcdA) 和毒素 B (TcdB) 对肠道上皮的作用。有充分的证据表明，针对 TcdA 和 TcdB 的抗体对人类和艰难梭菌结肠炎动物模型中的疾病具有保护作用。当前研究的目的是通过克隆来自艰难梭菌个体的人单克隆抗体（mAb）来开发一种基于抗体的艰难梭菌感染免疫疗法，并确定这些抗体是否可以使用仓鼠感染模型来预防疾病。这些抗体将通过使用噬菌体展示系统克隆患者的抗体在体外产生，该研究的共同研究员唐纳德·西格尔博士是这项技术的先驱之一。毒素特异性抗体将在体外产生，并将测试这些抗体保护动物免受艰难梭菌结肠炎的能力。过去 15 年中，该技术的应用已生产出具有针对大量人类自身抗原和同种异体抗原以及人类传染原的特异性的人类单克隆抗体。因此，噬菌体展示技术是生产完全人类蛋白质的理想方法，其方式是利用人类免疫系统的能力来产生大量高亲和力、抗原选择的抗体，对疾病相关表位具有不同的特异性。鉴于本提案中将开发多种抗体，该策略将提供足够的试剂用于表征，并允许我们选择最佳抗体（或抗体组合）作为治疗用途的先导化合物。公共卫生相关性：艰难梭菌是医疗机构中抗生素相关性腹泻的最常见原因之一，并且越来越多地被认为是社区获得性感染。患有医院获得性艰难梭菌疾病的患者的住院费用和住院时间显着增加，在美国估计超过 10 亿美元。因此，艰难梭菌疾病引起了相当大的公共卫生关注。