Fully Human Anti-Anthrax Toxin MAbs: Product Development

描述（由申请人提供）：该拨款旨在开发一种针对炭疽保护抗原（PA）的全人源单克隆抗体（HuMAb），作为预防和治疗抗毒素。我们已经生成了一组抗pa HuMAbs，从中选择了1个单克隆抗体（mAb 5E8）和1个备用抗体（5D5）进行进一步开发。选择的HuMAbs基于优越的炭疽毒素中和活性，并在PA上定义了一个以前未被识别的中和表位。HuMAb 5E8可延长兔在吸入致死剂量炭疽孢子后的存活时间，在接触炭疽孢子时同时给药（预防作用），在出现炭疽病临床症状后给药（治疗作用）。设想这种抗体的实际用途将是为暴露于炭疽芽孢杆菌的个体提供快速被动免疫。在接触前或接触后的情况下，使用可能是预防性的，但更重要的是，可能对目前没有有效治疗方法的活动性疾病患者有疗效。为了进一步开发这种抗体，我们的目标是：

DESCRIPTION (provided by applicant): This grant proposes to develop a fully human monoclonal antibody (HuMAb) to the anthrax protective antigen (PA) as a prophylactic and therapeutic antitoxin. We have generated a panel of anti-PA HuMAbs, from which 1 monoclonal antibody (mAb 5E8) and one backup antibody (5D5) were selected for further development. The HuMAbs were selected based on superior anthrax toxin neutralizing activity and define a neutralizing epitope on PA that has not been previously recognized. The HuMAb 5E8 affords extended survival to rabbits after inhalation of a lethal dose of anthrax spores, when administered concurrently with the exposure (prophylactic activity) and 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. 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 develop this antibody, we aim to: 1. Develop a manufacturing process including cell line development, purification and formulations strategies. 2. Manufacture sufficient GMP quantities of test article to complete Phase I clinical trials and efficacy studies in appropriate animal models. 3. Investigate the safety and efficacy in in vivo and in vitro models. Perform Phase III pivotal studies in an appropriate animal model. 4. Perform Phase I clinical trials to investigate safety and pharmacokinetics in human subject.