Therapeutic Intervention of Pneumonic Plague by Monoclonal Antibodies to LcrV

鼠疫耶尔森氏菌是肺鼠疫的病原体，也是A类选择性病原体。有 目前还没有获得许可的鼠疫疫苗，尽管这种细菌对几种抗生素敏感，但最近 多重耐药Y.鼠疫提出了继续研究和开发 新的治疗方法来防止鼠疫的复发在一项由五大湖区域教育中心资助的合作中， 一直致力于改进LcrV作为一种单亚单位疫苗，能够保护小鼠和大鼠免受高水平的免疫。 攻毒剂量Y.肺鼠疫模型中的鼠疫。在我们努力识别免疫相关性的过程中， 保护，我们确定了LcrV抗体的关键作用，并发现这些抗体也可以保护 被动转移模型中的小鼠。我们已经鉴定了三个LcrV表位，它们可以产生保护性的 抗体和至少5个非中和性LcrV表位。中和强度 通过对这些表位的单克隆抗体的检测，发现腺鼠疫与抗原相关 结合亲和力以及抗体同种型，其中IgG1是最具保护性的。在这个新的机遇中 应用，我们建议研究三种单克隆抗体的治疗潜力，每种 结合到一个独特的中和表位，在布朗挪威大鼠肺鼠疫，并开始 将其作为暴露后的治疗选择。我们不仅将描述疗效， 结合和细菌清除，这可能会导致未来的医疗发展的改善， 应对鼠疫威胁的措施。

Yersinia pestis is the causative agent of pneumonic plague and a category A select agent. There are currently no licensed vaccines for plague, and though the bacterium is sensitive to several antibiotics, recent emergence of mUlti-drug resistant Y. pestis has raised the need to continue research and development of new therapeutics to prevent resurgent plague. In a collaboration funded by the Great Lakes RCE, we have been working on improving LcrV as a single subunit vaccine capable of protecting mice and rats against high challenge doses of Y. pestis in pneumonic plague modeis. In our efforts to identify immune correlates of protection, we defined a critical role for antibodies to LcrV and found these antibodies could aiso protect mice in a passive transfer model. We have identified three LcrV epitopes which can generate protective antibodies and at least five LcrV epitopes that were non-neutralizing. The strength of neutralization of bubonic plague by individual monoclonal antibodies to these epitopes was found to correlate with antigen binding affinity as well as antibody isotype, with IgG1 being the most protective. In this New Opportunities application, we propose to investigate the therapeutic potential of three monoclonal antibodies to LcrV, each binding to a distinct neutralizing epitope, against pneumonic plague in the Brown Norway rat and begin to develop this as a post-exposure treatment option. We will not only characterize efficacy but also antigen binding and bacterial clearance which may lead to future improvements in the development of medical countermeasures to the threat of plague.