A Monoclonal Cocktail for CDI

CDI 单克隆混合物

• 批准号: 8394486
• 负责人: Andrew C Hiatt
• 金额: $ 30万
• 依托单位: MAPP BIOPHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-07 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394486
• 关键词: Alternative Therapies; Animal Testing; Antibiotic Resistance; Antibodies; Antiviral Agents; Bacteria; Biological Products; Biomass; Budgets; Categories; Clinical; Clinical Data; Clinical Pharmacology; Clinical Protocols; Clinical Trials; Clostridium difficile; Combined Modality Therapy; Combined Vaccines; Contracts; Cyclic GMP; Development; Disease; Economic Burden; Effectiveness; Epidemic; Evaluation; Exhibits; FDA approved; Fermentation; Funding; Goals; Grant; HIV; Hamsters; Hospitals; Human; Immunoglobulins; In Vitro; Individual; Infection; Infectious Agent; Kentucky; Lead; Licensing; Mammalian Cell; Marketing; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Nursing Homes; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Plants; Prevention; Production; Reporting; Research Infrastructure; Safety; Small Business Innovation Research Grant; Specificity; System; Targeted Toxins; Testing; Therapeutic; Therapeutic antibodies; Time; Toxin; Transgenic Mice; Vancomycin; Virulence; Work; base; bioprocess; cost; design; economic cost; human monoclonal antibodies; in vivo; monoclonal antibody production; mortality; novel; pre-clinical; pressure; prevent; prophylactic

DESCRIPTION (provided by applicant): Clostridium difficile associated disease (CDI) is an important cause of morbidity in hospital and nursing home patients, and is being increasingly recognized as an important cause of mortality. Estimates put the economic burden of CDI at 1-3 billion dollars in the U.S. alone. The overall goal of this project is to develop an anti-toxin humn monoclonal antibody product for prevention and/or treatment of C. difficile infection. Due to specificity, stability, safety, and the specific targeting of toxins (as opposed to selective pressre on the bacterium), a mAb product is ideal for prevention and treatment of the diseases caused by C. difficile. Antibodies are the only category of FDA-approved therapeutic that specifically neutralize toxins. We have isolated a panel of neutralizing human monoclonal antibodies (mAbs) that recognize the toxins of C. difficile. In terms of their neutralizing potency in vitro, these mAbs are superior to mAbs previously reported that are in clinical development [1]. Preliminary testing in vivo has demonstrated protection in the hamster model that was superior to vancomycin. We will produce each of our human mAbs against C. difficile toxins A and B (TcdA, TcdB) in a scalable production system that can provide antibodies for therapeutic or prophylactic indications. Each mAb, as well as the combination of mAbs, will be evaluated for effectiveness in preventing and treating C. difficile infection in the hamster model to select the lead mAb cocktail for continued development. Specific Aim #1. Produce quantities of each anti-TcdA and anti-TcdB human mAb for in vitro characterization and animal testing in a novel manufacturing system. Human anti-TcdA and anti-TcdB mAbs have been generated using transgenic mice containing human immunoglobulin loci (HuMab-Mouse(r)). Three anti-TcdA and three anti-TcdB mAbs have been developed under license by Mapp. The mAbs all exhibited potent neutralizing activity and have subsequently been produced in a scalable plant-based system. Combined, these mAbs are potent immunoprotectants in the hamster challenge model. Specific Aim #2. Evaluate individual mAbs and combinations of mAbs in vivo for prevention and treatment of CDI. MAbs produced in Specific Aim #1 will be compared in the hamster model of C. difficile infection. The anti-TcdA mAbs will first be evaluated individually to determine the baseline of protection. Only anti-TcdA has been observed to provide significant protection alone, whereas anti-TcdB may extend the duration and effectiveness of anti-TcdA protection [1]. The best anti- TcdA mAb will then be further tested in combination with each anti-TcdB mAb to determine the synergistic potential of mAb pairs. The best mAb pair will be selected for further development in pre-clinical and clinical protocols largely funded by a Phase II SBIR grant. PUBLIC HEALTH RELEVANCE: The efforts in this proposal will help in the development of a drug product for preventing and/or treating Clostridium difficile infection (CDI), a cause of significant morbidity and mortality in hospitals and nursing homes. The economic cost of CDI has been conservatively estimated at $1-3 billion per year in the U.S. The recent characterization of an epidemic C. difficile strain with increased virulence and antibiotic resistance has made the development of alternative therapies even more pressing.

描述（由申请人提供）：艰难梭菌相关疾病（CDI）是医院和养老院患者发病的重要原因，并且越来越被认为是导致死亡的重要原因。据估计，仅在美国，CDI的经济负担就高达30亿至30亿美元。该项目的总体目标是开发一种用于预防和/或治疗艰难梭菌感染的抗毒素人单克隆抗体产品。由于特异性、稳定性、安全性和毒素的特异性靶向（而不是对细菌的选择性压力），mAb产品是预防和治疗艰难梭菌引起的疾病的理想选择。抗体是fda批准的唯一一种专门中和毒素的治疗药物。我们已经分离出一组识别艰难梭菌毒素的中和性人单克隆抗体（mab）。就其体外中和效力而言，这些单克隆抗体优于先前报道的处于临床开发阶段的单克隆抗体。初步体内试验表明，在仓鼠模型中，万古霉素的保护作用优于万古霉素。我们将在可扩展的生产系统中生产针对艰难梭菌毒素A和B （TcdA, TcdB）的每个人单克隆抗体，可以提供治疗或预防适应症的抗体。将评估每种单抗以及单抗组合在仓鼠模型中预防和治疗艰难梭菌感染的有效性，以选择主要单抗鸡尾酒进行继续开发。明确目标#1。在一个新的生产系统中，生产大量的抗tcda和抗tcdb人单抗，用于体外表征和动物试验。人抗tcda和抗tcdb单克隆抗体是用含有人免疫球蛋白位点的转基因小鼠（HuMab-Mouse(r)）制备的。根据Mapp的许可，已经开发了三种抗tcda和三种抗tcdb单克隆抗体。这些单克隆抗体都表现出强大的中和活性，并随后在可扩展的植物系统中生产。综合起来，这些单克隆抗体在仓鼠攻击模型中是有效的免疫保护剂。具体目标2。评估单克隆抗体和单克隆抗体在体内预防和治疗CDI的作用。在Specific Aim #1中产生的单克隆抗体将在艰难梭菌感染的仓鼠模型中进行比较。首先对抗tcda单克隆抗体进行单独评估，以确定保护基线。只有抗tcda被观察到单独提供显著的保护，而抗tcdb可以延长抗tcda保护的持续时间和有效性。最佳的抗TcdA单抗将与每个抗tcdb单抗联合进行进一步测试，以确定单抗对的协同潜力。将选择最佳的单抗对进行临床前和临床方案的进一步开发，主要由II期SBIR拨款资助。