Development of Human Monoclonal Antibody for Treatment of Anthrax Exposure

描述（由申请人提供）：本拨款申请旨在开发一种针对炭疽保护抗原（PA）的全人源单克隆抗体，作为预防和治疗药物。我们利用专有的Xenerex(tm) （SCID小鼠）技术，从炭疽疫苗吸附（AVA）免疫供体中获得了一组高亲和力的全人源单克隆抗体。几种抗体，有效中和PA，三方炭疽外毒素的一个组成部分，彻底表征了体外。该候选抗体AVP-21D9 （lgG1/K）以亚纳摩尔亲和力与PA83结合，并在稳定的重组CHO细胞系中作为分泌分子产生。在大鼠、小鼠、豚鼠和兔子身上获得了概念验证数据。AVP-21D9对经鼻注射炭疽芽孢杆菌（Ames）孢子与次理想剂量环丙沙星联合攻击的豚鼠和小鼠具有剂量依赖的保护作用。此外，AVP-21D9单独在兔孢子攻击模型中非常有效，其中单次皮下剂量AVP-21D9在低至1 mg/kg的剂量下完全保护动物。当治疗延迟至孢子攻击后24或48小时时，单次皮下剂量的抗体仍然分别对80%和60%的存活动物提供显著的保护。显然需要能够阻断炭疽杆菌释放的致病性毒素功能的治疗剂。到目前为止获得的这些令人信服的数据表明，AVP-21D9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-21D9，并完成产品所需的生物安全性和稳定性测试；2)在非人类灵长类动物中试验对雾化炭疽芽孢杆菌的防治效果。这项工作将使AVP-21D9能够提交IND申请，并在人体受试者中进行临床安全性测试。

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.