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）： 该资助计划研究针对炭疽保护性抗原（PA）的全人单克隆抗体（HuMAb）作为预防性和治疗性抗毒素的潜在用途和作用机制。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类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源的、亲和力成熟的抗体，这些抗体是通过杂交瘤和转染瘤技术分离和产生的。根据与 USAMRIID 和达特茅斯大学的 CRADA，Medarex, Inc. 开发了一组 HuMAb，可在体外细胞毒性测定中与炭疽毒素发生反应并有效中和炭疽毒素，在 PA-63 上定义了一种新型中和表位，并在吸入性炭疽兔模型。 从该组中，选择了 1 种单克隆抗体 (mAb 5E8) 和 1 种备用抗体 (5D5) 进行进一步开发。 HuMAb 的选择是基于巨噬细胞中卓越的炭疽毒素中和活性。当兔子吸入致死剂量的炭疽孢子后，与暴露同时给药（预防/暴露后预防活动），甚至在炭疽病临床症状出现后给药（治疗活性），HuMab 5E8 可延长兔子的存活时间。 ）。该抗体的预期实际用途将是为有接触炭疽杆菌并导致严重疾病风险的个体提供快速被动免疫。 该用途可能在暴露前或暴露后情况下起到预防作用，但更重要的是，可能对治疗目前尚无有效疗法的活动性疾病个体有效。 为了进一步研究该抗体的用途和作用机制，Medarex, Inc. 的目标是： 1. 进一步明确 HuMab 5E8 和其他抗 PA 单克隆抗体所赋予的具体保护机制； 2. 开发适合治疗活性研究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； 4. 研究抗体对自然感染免疫发展和 PA 疫苗免疫原性的影响。

项目成果

Prophylaxis and therapy of inhalational anthrax by a novel monoclonal antibody to protective antigen that mimics vaccine-induced immunity.

通过模拟疫苗诱导免疫的新型保护性抗原单克隆抗体来预防和治疗吸入性炭疽。

• 发表时间: 2006-10
• 影响因子: 3.1
• 作者: Vitale, Laura;Blanset, Diann;Lowy, Israel;O'Neill, Thomas;Goldstein, Joel;Little, Stephen F;Andrews, Gerard P;Dorough, Gary;Taylor, Ronald K;Keler, Tibor
• 通讯作者: Keler, Tibor