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: 6818888
• 负责人: ISRAEL LOWY
• 金额: $ 78.11万
• 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 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6818888
• 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）： 这项资助旨在研究炭疽保护性抗原（PA）的全人单克隆抗体（HuMAbs）作为预防和治疗性抗毒素的潜在效用和作用机制。对于免疫接种，Medarex，Inc.使用其专有的HuMab小鼠，该小鼠表达转基因人抗体基因并具有灭活的鼠抗体基因座。这些小鼠产生完全人的亲和力成熟的抗体，其通过杂交瘤和转染瘤技术分离和产生。根据与USAMRIID和达特茅斯大学的CRADA，Medarex，Inc.已经开发了一组HuMAb，其在体外细胞毒性测定中与炭疽毒素反应并有效中和炭疽毒素，已经在PA-63上定义了新的中和表位，并在吸入性炭疽兔模型中提供保护和治疗。 从该组中，选择1种单克隆抗体（mAb 5E 8）和1种备用抗体（5D 5）用于进一步开发。基于巨噬细胞中上级炭疽毒素中和活性选择HuMAb。在吸入致死剂量的炭疽孢子后，当与暴露同时给药（预防/暴露后预防活性），甚至在炭疽病临床体征发作后给药（治疗活性）时，HuMab 5E 8可延长家兔的存活期。这种抗体的预期实际用途将是为有暴露于炭疽杆菌和随后严重疾病风险的个体提供快速被动免疫。 在暴露前或暴露后的情况下，该用途可以是预防性的，但更重要的是，可以在治疗患有目前没有有效疗法的活动性疾病的个体中具有功效。 为了进一步研究该抗体的效用和作用机制，Medarex，Inc.目的是：1.进一步明确HuMab 5E 8和其他抗PA单克隆抗体所赋予的保护作用的具体机制; 2.建立适合于治疗活性研究的吸入性炭疽动物模型; 3.研究HuMab 5E 8在吸入性炭疽治疗模型中的活性;和4.研究抗体对感染天然免疫力形成和PA疫苗免疫原性的影响。