Development of Fully Human mAbs as Anthrax Antitoxins

开发全人单克隆抗体作为炭疽抗毒素

• 批准号: 7112285
• 负责人: ISRAEL LOWY
• 金额: $ 76.6万
• 依托单位: MEDAREX, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112285
• 关键词: Bacillus anthracis; Macaca fascicularis; anthrax toxin; antibody receptor; antitoxins; ciprofloxacin; confocal scanning microscopy; cooperative study; immune response; immunity; immunologic substance development /preparation; laboratory rabbit; monoclonal antibody; neutralizing antibody; passive immunization; pharmacokinetics

DESCRIPTION (provided by applicant): This grant proposes to investigate the potential utility and mechanism of action of fully human monoclonal antibodies (HuMAbs) to the anthrax protective antigen (PA) as prophylactic and therapeutic antitoxins. For immunization, Medarex, Inc. uses its proprietary HuMab mice, which express transgenic human antibody genes and have an inactivated murine antibody locus. These mice produce fully human, affinity-matured antibodies, which are isolated and produced by hybridoma and transfectoma technology. Under a CRADA with USAMRIID and Dartmouth University, Medarex, Inc. has developed a panel of HuMAbs that react with and potently neutralize Anthrax toxin in in vitro cytotoxicity assays, have defined a novel neutralizing epitope on PA-63, and provide protection and therapy in an inhalational anthrax rabbit model. From this panel, 1 monoclonal antibody (mAb 5E8) and 1 backup antibody (5D5) were selected for further development. The HuMAbs were selected based on superior anthrax toxin neutralizing activity in macrophages. The HuMab 5E8 affords extended survival to rabbits after inhalation of a lethal dose of anthrax spores, when administered concurrently with the exposure (prophylaxis / post-exposure prophylaxis activity), and even when given after the onset of clinical signs of anthrax disease (therapeutic activity). The envisioned practical usage of this antibody will be to provide rapid passive immunity to individuals at risk for exposure to Bacillus anthracis and ensuing serious disease. The usage may be prophylactic in pre- or post-exposure situations, but more importantly, may have efficacy in treatment of individuals with active disease for which there is no current effective therapy. To further investigate the utility and mechanisms of action of this antibody, Medarex, Inc. aims to: 1. Further define the specific mechanism(s) of protection conferred by HuMab 5E8 and other anti-PA monoclonal antibodies; 2. Develop current animal models of inhalation anthrax amenable for the investigation of therapeutic activity; 3. Investigate the activity of HuMab 5E8 in therapeutic models of inhalation anthrax; and 4. Investigate the effect of the antibody on the development of natural immunity to infection and on the immunogenicity of the PA vaccine.

描述(由申请人提供)： 这笔赠款建议调查针对炭疽保护性抗原(PA)的全人单抗(HuMAbs)作为预防和治疗性抗毒素的潜在用途和作用机制。Medarex公司使用其专利的HuMab小鼠进行免疫，这种小鼠表达转基因人类抗体基因，并具有灭活的小鼠抗体基因。这些小鼠产生完全人类的、亲和力成熟的抗体，这些抗体是通过杂交瘤和转基因瘤技术分离和生产的。在与USAMRIID和达特茅斯大学的CRADA合作下，Medarex，Inc.开发了一组在体外细胞毒性测试中与炭疽毒素反应并有效中和炭疽毒素的HuMAb，定义了PA-63上的新中和表位，并在吸入性炭疽兔模型中提供保护和治疗。从中筛选出1株单抗(MAb5E8)和1株备用抗体(5D5)用于进一步的研究。HuMAb是基于在巨噬细胞中具有良好的炭疽毒素中和活性而选择的。HuMab 5E8在吸入致命剂量的炭疽孢子后，如果与暴露同时给予(预防/暴露后预防活性)，甚至在炭疽病临床症状出现后给予(治疗活性)，则可延长兔子的存活时间。这种抗体的预期实际用途将是为接触炭疽芽孢杆菌和随后发生严重疾病的风险个人提供快速被动免疫。在暴露前或暴露后的情况下，这种使用可能是预防性的，但更重要的是，可能对患有活动性疾病的个人具有疗效，目前尚无有效的治疗方法。为了进一步研究这种抗体的用途和作用机制，Medarex公司的目标是：1.进一步确定HuMab 5E8和其他抗PA单抗提供保护的特定机制(S)；2.建立适合于研究治疗活性的现有吸入性炭疽动物模型；3.研究HuMab 5E8在吸入性炭疽治疗模型中的活性；以及4.调查抗体对自然免疫发展和PA疫苗免疫原性的影响。