Development of Human Monoclonal Antibody for Treatment of Anthrax Exposure

用于治疗炭疽暴露的人单克隆抗体的开发

• 批准号: 7135433
• 负责人: Wolfgang W Scholz
• 金额: $ 205.89万
• 依托单位: AVANIR PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7135433
• 关键词: CHO cells; antibody; cell bank /registry; cell line; guinea pigs; human; monoclonal antibody; neutralizing antibody; spores; tissue /cell culture; toxin

DESCRIPTION (provided by applicant): This grant application proposes to develop a fully human monoclonal antibody to the anthrax protective antigen (PA) as prophylactic and therapeutic drug substance. We have generated a panel of high affinity, fully human monoclonal antibodies, derived from Anthrax Vaccine Adsorbed (AVA) immune donors using proprietary Xenerex(tm) (SCID mouse) technology. Several antibodies that potently neutralize PA, a component of the tripartite anthrax exotoxins were thoroughly characterized in vitro. The lead candidate antibody selected for further development, AVP-21D9 (lgG1/K), binds to PA83 with sub-nanomolar affinity, and is produced as a secreted molecule from a stable recombinant CHO cell line. Proof-of-concept data were obtained in rats, mice, guinea pigs and rabbits. AVP-21D9 shows a dose-dependent protection of guinea pigs and mice challenged with intranasal administered B. anthracis (Ames) spores in combination with a sub-optimal dose of ciprofloxacin. Furthermore, AVP-21D9 alone is highly effective in a rabbit spore challenge model, where a single subcutaneous dose of AVP-21D9 fully protects animals at doses as low as 1 mg/kg. When treatment is delayed to 24 or 48 hrs post spore challenge, a single subcutaneous dose of antibodies still provides significant protection with 80 % and 60% surviving animals, respectively. There is a clear need for therapeutic agents that block the function of pathogenic toxins released by B. anthracis. These compelling data obtained so far suggest that AVP-21D9 will have a significant therapeutic benefit and merits further development. Thus, we aim to 1) produce cGMP grade purified AVP-21D9, and complete the required biosafety and stability testing of the product; 2) test efficacy against aerosolized B. anthracis spores in nonhuman primates. This work will enable the filing of an IND application, and to move AVP-21D9 into clinical safety testing in human subjects.

描述（由申请人提供）：本授权申请拟开发炭疽保护性抗原（PA）的全人源单克隆抗体，作为预防和治疗药物。我们使用专有的Xenerex（TM）（SCID小鼠）技术从炭疽疫苗吸附（AVA）免疫供体中产生了一组高亲和力的全人单克隆抗体。几种抗体，有力地中和PA，一个组成部分的三方炭疽外毒素进行了彻底的特点在体外。选择用于进一步开发的主要候选抗体AVP-21 D9（IgG 1/K）以亚纳摩尔亲和力与PA 83结合，并作为分泌分子从稳定的重组CHO细胞系中产生。在大鼠、小鼠、豚鼠和家兔中获得了概念验证数据。AVP-21 D9对鼻内给药B的豚鼠和小鼠具有剂量依赖性保护作用。炭疽（艾姆斯）孢子与次优剂量的环丙沙星的组合。此外，单独的AVP-21 D9在兔孢子攻击模型中是高度有效的，其中单次皮下剂量的AVP-21 D9在低至lmg/kg的剂量下完全保护动物。当处理延迟至孢子攻击后24或48小时时，单次皮下剂量的抗体仍然提供显著的保护，分别有80%和60%的动物存活。显然需要阻断由B释放的致病毒素的功能的治疗剂。炭疽病迄今为止获得的这些令人信服的数据表明，AVP-21 D9将具有显著的治疗益处，值得进一步开发。因此，我们的目标是1）生产cGMP级纯化AVP-21 D9，并完成产品所需的生物安全性和稳定性测试; 2）测试对雾化B的有效性。非人类灵长类动物体内的炭疽孢子。这项工作将使IND申请的提交成为可能，并将AVP-21 D9转移到人类受试者的临床安全性测试中。