Human monoclonal antibody therapy for HUS

人类单克隆抗体治疗 HUS

• 批准号: 6845031
• 负责人: HOWARD TRACHTMAN
• 金额: $ 92.92万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6845031
• 关键词: Escherichia coli 0157:H7; Escherichia coli infections; adult human (21+); antitoxins; bioterrorism /chemical warfare; clinical research; clinical trial phase I; clinical trial phase II; cooperative study; diarrhea; enteritis; hemolytic anemia; human genetic material tag; human subject; human therapy evaluation; immunologic substance development /preparation; immunopharmacology; immunotherapy; laboratory mouse; monoclonal antibody; nonhuman therapy evaluation; orphan disease /drug; patient oriented research; pharmacokinetics; renal failure; shiga toxin; swine

DESCRIPTION (provided by applicant): This application targets the development of immunotherapy against diarrhea-associated hemolytic uremic syndrome (D+HUS). This disease is caused by Shiga toxin-producing E. coli (STEC), primarily the O157:H7 serotype. These bacteria are virulent Category B pathogens, associated primarily with food and waterborne acquired disease with relevance to potential bioterrorism. D+HUS is a life-threatening illness in children and the elderly that is heralded by the sudden onset of pallor and oliguria. The acute mortality rate remains 3-5% and nearly 25% of patients develop serious extra-renal complications. There is no treatment for D+HUS that ameliorates the disease course or reduces the need for acute dialysis support. Because D+HUS is an orphan disease, federal funding is urgently required to facilitate the development of effective therapeutic agents. There are no current NIH-funded clinical trials to assess novel treatments for D+HUS. Our team has developed and characterized a panel of neutralizing human monoclonal antibodies (Hu-MAb) which are highly active in vitro and in vivo against Shiga toxins 1 and 2. These antibodies have undergone extensive preclinical evaluation in an appropriate animal model. This application is designed to test the hypothesis that administration of a Hu-MAb to Stx2 will: (1) be safely tolerated by healthy adult volunteers and a test cohort of children with STEC enteritis and D+HUS; and (2) ameliorate the clinical severity and disease course in patients with D+HUS. The Specific Aims of this application are: (1) Manufacture of Phase I GMP clinical material, namely a Hu-MAb to Stx2, for use in Phase I and II clinical trials, confirm efficacy in an experimental model, and file an IND application (Interval 1); (2) Performance of a comprehensive Phase I placebo-controlled, dose escalation and pharmacokinetic study of Hu-MAb to Stx2 in healthy adult volunteers and in a sample cohort of children with STEC enteritis and D+HUS (Interval 2); and (3) Performance of a Phase II study of Hu-MAb to Stx2 in children with D+HUS (amelioration) (Interval 3). The significance of this application is that it may facilitate the development of a safe and effective immunotherapeutic biological product that can be given to individuals exposed to an accidental or deliberate (bioterrorism) STEC contamination of food or water sources.

描述（由申请人提供）：本申请针对针对腹泻相关溶血性尿毒症综合征（D+HUS）的免疫疗法的发展。该疾病是由志贺毒素产生的大肠杆菌（STEC）引起的，主要是O157：H7血清型。这些细菌是B类病原体，主要与食物和水生成的疾病有关，与潜在的生物恐怖主义有关。 D+HUS是儿童和老年人的一种威胁生命的疾病，这是由于苍白和寡核突然发作所预告的。急性死亡率保持3-5％，近25％的患者出现严重的肾上腺外并发症。没有针对D+HUS的治疗方法可以改善疾病病程或减少对急性透析支持的需求。由于D+HUS是一种孤儿疾病，因此迫切需要联邦资金来促进有效的治疗剂的发展。当前没有NIH资助的临床试验来评估D+HUS的新型治疗方法。 我们的团队已经开发并表征了一个中和人类单克隆抗体（HU-MAB）的小组，这些抗体在体外高活性和对志贺毒素1和2的体内。这些抗体在适当的动物模型中经历了广泛的临床前评估。该应用旨在检验以下假设：将HU-MAB施用到STX2将：（1）健康的成年志愿者和一组STEC肠炎和D+HUS的儿童安全耐受； （2）改善D+HUS患者的临床严重程度和疾病病程。 该应用程序的具体目的是：（1）制造I期GMP临床材料，即HU-MAB到STX2，用于I阶段和II期临床试验，确认实验模型中的功效，并提交IND应用程序（间隔1）; （2）在健康的成人志愿者和STEC肠炎和D+HUS的儿童样本中，HU-MAB至STX2的全面的I期安慰剂对照，剂量升级和药代动力学研究（Intervel 2）； （3）在D+HUS儿童（安装）儿童中HU-MAB至STX2的II期研究（间隔3）。该应用的意义在于，它可能有助于开发安全有效的免疫治疗生物学产品，该产品可以给予暴露于意外或故意（生物恐怖主义）食品或水源污染的个人。