Fully Human Anti-Anthrax Toxin MAbs: Product Development

描述（由申请人提供）：该资助计划开发炭疽保护性抗原（PA）的全人单克隆抗体（HuMAb），作为预防和治疗性抗毒素。我们已经生成了一组抗PA HuMAb，从中选择了1种单克隆抗体（mAb 5E8）和1种备用抗体（5D5）用于进一步开发。基于上级炭疽毒素中和活性选择HuMAb，并在PA上定义先前未识别的中和表位。HuMAb 5E8在吸入致死剂量的炭疽孢子后，与暴露同时给药（预防活性）和在炭疽病临床体征发作后给药（治疗活性），可延长家兔的存活期。这种抗体的预期实际用途是为有接触炭疽杆菌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。为了进一步开发这种抗体，我们的目标是： 1.开发生产工艺，包括细胞系开发、纯化和配方策略。 2.生产足够GMP数量的供试品，以在适当的动物模型中完成I期临床试验和有效性研究。 3.在体内和体外模型中研究安全性和有效性。在适当的动物模型中进行III期关键研究。 4.进行I期临床试验，以研究人类受试者的安全性和药代动力学。

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.