Creation of a Human Recombinant Polyclonal Antibody therapy against Clostridium d

描述（由申请人提供）：本项目的目标是创建一个人重组多克隆抗体（HRPA）治疗C。艰难梭菌相关疾病（CDAD）。在过去的几十年里，C。在美国，艰难梭菌已经成为医院内腹泻的最重要原因，加拿大和欧洲。以前的一线抗生素治疗对新出现的耐药菌株越来越无效，CDAD的死亡率正在上升。迫切需要新的治疗选择。本文提出的CDAD的HRPA疗法将由靶向疾病生物体的多种抗原和表位的几种抗体组成。HRPA疗法的开发是一个复杂的多阶段过程。第一阶段的目标是建立一个小的，但可行的人类抗体库，针对C。很难证明在II期研究中创建更完整的文库用于动物试验的可行性。 该项目第一阶段的具体目标是：1.从三组已知或可能暴露于C的潜在供体中招募受试者。艰难梭菌，获得血液样品并分离浆细胞以克隆抗体基因; 2.使用从每个供体获得的浆细胞的子集产生克隆和表达的抗体的测试文库; 3.优化并进行基于ELISA的识别C.培养物上清液、细菌裂解物和毒素中的艰难梭菌蛋白;和4.分析目的3中产生的抗体文库，并确定II期研究是否需要额外筛选。在第一阶段成功后，第二阶段研究的目标是：1。分析I期获得的抗体的抗体-表位相互作用; 2.进行大规模表达和纯化C.艰难梭菌抗体;和3.进行一系列动物研究，以检查几种抗体混合物在CDAD动物模型中的有效性。在成功完成动物试验后，Excelimmune将寻求通过与大型生物制药公司的战略合作伙伴关系将CDAD治疗产品推向市场。 公共卫生相关性：C.艰难梭菌相关疾病（CDAD）是由于高毒性抗生素抗性菌株的增加而日益严重的公共卫生问题。根据CDC的数据，每年发生约300万例CDAD病例，死亡率约为1- 2.5%，并且这些数字正在上升。该项目的总体目标是开发一种新的CDAD治疗方法，该方法基于使用克隆的人类抗体，可有效治疗该疾病并防止耐药菌株的出现。

DESCRIPTION (provided by applicant): The goal of this project is to create a human recombinant polyclonal antibody (HRPA) therapy against C. difficile associated disease (CDAD). Over the last several decades, C. difficile has become the most important cause of nosocomial diarrhea in the U.S., Canada and Europe. Previously first-line antibiotic treatments are increasingly ineffective against emerging antibiotic-resistant strains and the mortality rate from CDAD is rising. New treatment options are desperately needed. The HRPA therapy for CDAD proposed here will consist of several antibodies targeting multiple antigens and epitopes of the disease organism. Development of an HRPA therapy is a complex, multi-stage process. The phase I goal is to create a small but viable library of human antibodies against C. difficile to demonstrate the feasibility of creating a more complete library in a phase II study for testing in animals. The phase I specific aims for this project are: 1. to recruit subjects from three groups of potential donors with known or likely exposure to C. difficile, obtain blood samples and isolate the plasma cells in order to clone the antibody genes; 2. to generate a test library of cloned and expressed antibodies using a subset of the plasma cells obtained from each donor; 3. to optimize and carry out an ELISA-based screen for antibodies recognizing C. difficile proteins in culture supernatant, bacterial lysate and toxins; and 4. to analyze the antibody library generated in aim 3 and determine whether additional screening will be required for the Phase II study. Following a successful Phase I, the goals of a Phase II study would be: 1. to analyze the antibody-epitope interactions of antibodies obtained in Phase I; 2. to perform large scale expression and purification of C. difficile antibodies; and 3. to carry out a series of animal studies to examine the effectiveness of several antibody cocktails in an animal model of CDAD. Following the successful completion of animal trials, Excelimmune will seek to bring a CDAD therapeutic product to market through strategic partnerships with larger biopharmaceutical companies. PUBLIC HEALTH RELEVANCE: C. difficile associated disease (CDAD) is a growing public health problem due to the rise of highly virulent, antibiotic resistant strains. According to the CDC, approximately 3 million cases of CDAD occur annually, with mortality rates of approximately 1-2.5%, and these numbers are on the rise. The overall goal of this project is to develop a novel therapeutic for CDAD, based on the use of cloned human antibodies that will effectively treat the disease and prevent the rise of resistant strains.