DEVELOPMENT OF AN ANTIDOTE FOR E COLI 0157--H7 VEROTOXIN

大肠杆菌0157--H7维罗毒素解毒剂的研制

• 批准号: 2148351
• 负责人: NISHA V PADHYE
• 金额: $ 7.25万
• 依托单位: OPHIDIAN PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-06-01 至 1995-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2148351
• 关键词: Escherichia coli; Escherichia coli infections; antibacterial antibody; antitoxins; bacterial food poisoning; bacterial toxins; bioassay; chickens; disease /disorder model; drug administration routes; drug design /synthesis /production; drug screening /evaluation; immunochemistry; laboratory mouse; nonhuman therapy evaluation; parenteral feedings; uremias; western blottings

E. coli Ol57:H7 is an emerging food-borne pathogen with substantial morbidity and mortality. There are an estimated 20,000 cases of E. coli 0157:H7 infection per year in the United States. However, only 11 states require reporting of the cases to the State Health Department; hence, the actual number of cases is likely to be much higher. Twenty-two percent of children acquiring E. coli Ol57:H7 infection develop potentially fatal complications, such as hemolytic uremic syndrome (HUS). Patients who develop complications must be hospitalized for long periods, and often require life-long kidney dialysis or kidney transplants. HUS is believed to be caused by verotoxins produced by the offending bacterium, and there are no antitoxins available for clinical use. Ophidian Pharmaceuticals herein proposes to develop E. coli Ol57:H7 antiverotoxin using proprietary methods for the large-scale production of therapeutic polyclonal antibodies from eggs of hyperimmune hens. High-purity avian antitoxins have been shown to have superior toxin- neutralizing potency when used in either a parenteral or enteral dosing regimen. Hens will be immunized with pure E. coli O157:H7 verotoxins, followed by preparation of yolk immunoglobulin fractions. The resulting antibodies will be characterized in vitro by immunochemical analysis and by toxin neutralization in a vero cell assay. The therapeutic efficacy of antiverotoxin will be assessed in vivo in a mouse HUS model using either enteral or parenteral antiverotoxin administration. These studies will i) provide experimental evidence for the therapeutic utility of antiverotoxin antibodies in E. coli O157:H7 disease, such as HUS, and ii) determine if disease progression can be arrested by antiverotoxin enterally administered and/or whether antiverotoxin is effective when given parenterally.

大肠杆菌 Ol57:H7 是一种新兴的食源性病原体，具有大量的 发病率和死亡率。估计有 20,000 例大肠杆菌病例。 美国每年都有大肠杆菌 0157:H7 感染。然而，仅 11个州要求向州卫生部门报告病例 部门;因此，实际病例数可能会很多 更高。 22% 的儿童感染大肠杆菌 Ol57:H7 感染会产生潜在致命的并发症，例如 溶血性尿毒症综合征（HUS）。出现并发症的患者 必须长期住院，并且往往需要终生 肾透析或肾移植。 HUS 被认为是由 由有害细菌产生的维罗毒素，并且没有 抗毒素可供临床使用。奥菲迪安制药公司 本文建议使用大肠杆菌 Ol57:H7 来开发抗蛇毒素 用于大规模生产治疗药物的专有方法 来自超免疫母鸡鸡蛋的多克隆抗体。高纯度 禽类抗毒素已被证明具有优越的毒素 用于肠外或肠内给药时的中和效力 给药方案。母鸡将接受纯大肠杆菌 O157:H7 免疫 维罗毒素，然后制备卵黄免疫球蛋白 分数。所得抗体将在体外进行表征 通过免疫化学分析和 Vero 中的毒素中和 细胞测定。抗蛇毒的治疗效果为 使用肠内或肠内途径在小鼠 HUS 模型中进行体内评估 肠外抗蛇毒素给药。这些研究将 i) 为治疗效用提供实验证据 大肠杆菌 O157:H7 疾病中的抗蛇毒素抗体，例如 HUS、 ii) 确定是否可以通过以下方式阻止疾病进展 肠内施用抗蛇毒素和/或是否使用抗蛇毒素 肠外给药时有效。