Use of a Humanized Antibody against Intracellular Bacterial Pathogen

摘要 Q热是一种由专性细胞内革兰氏阴性细菌引起的世界性人畜共患疾病， 伯氏柯克斯体。人类Q热可能发展成一种严重的慢性疾病，可能是致命的。然而，还有 在美国，尚无预防人类Q热的疫苗上市。此外，它很难治疗。 慢性Q热患者使用不同的抗生素方案。因此，迫切需要开发一种 Q热的紧急替代预防和治疗策略。这 应用目的是证明单抗可以作为一种预防和治疗手段 针对细胞内细菌病原体的治疗策略。尽管伯氏梭菌是专性胞内细菌 细菌病原体，我们最近的工作表明，被动转移的一种I相内毒素是特异的 单抗1E4对SCID小鼠和小鼠的伯氏梭菌气溶胶感染具有显著的保护作用 人源化的1E4可变区(HucFv1E4)能够抑制小鼠和人的伯氏弧菌感染 巨噬细胞。这些结果证明了hucFv1E4作为一种快速、有效的紧急治疗方法的实用性 用来控制Q热。因此，本申请的目的是进一步证明使用 HUCCFv1E4，用于对Q热进行有效的紧急预防和治疗。两个具体目标 旨在测试被动注射hucFv1E4将立即提供 对伯氏梭菌感染的保护。具体目标1将评估hucFv1E4的预防效果 抗小鼠伯氏梭状芽胞杆菌气溶胶感染。特定目标2将检查hucFv1E4是单独还是组合 用抗生素治疗感染伯氏梭菌的小鼠会更有效。作为这项研究的结果， 我们希望证明使用hucFv1E4预防和治疗Q热的可行性。这将会有 对人类健康产生重大积极影响，因为这是朝着有效发展的关键一步 控制Q热的紧急预防和治疗。

Abstract Q fever is a worldwide zoonotic disease that is caused by the obligate intracellular Gram-negative bacterium, Coxiella burnetii. Human Q fever can develop into a severe chronic, potentially fatal disease. However, there is no vaccine commercially available for prevention of human Q fever in the US. Additionally, it is difficult to treat chronic Q fever patients with various antibiotic regimens. Therefore, there is an urgent need to develop an emergency alternative prophylactic and therapeutic strategy for prevention and treatment of Q fever. This application aims to prove the concept that monoclonal antibody can be utilized as a prophylactic and therapeutic strategy against intracellular bacterial pathogens. Despite C. burnetii being an obligate intracellular bacterial pathogen, our recent work demonstrated that passive transfer of a phase I lipopolysaccharide specific monoclonal antibody 1E4 conferred significant protection against C. burnetii aerosol infection in SCID mice and a humanized variable fragment of 1E4 (huscFv1E4) was able to inhibit C. burnetii infection in mice and human macrophages. These results demonstrate the utilities of huscFv1E4 as a rapid, effective emergency treatment for control of Q fever. Thus, the objective of this application is to further prove the feasibility of using huscFv1E4 for effective emergency prophylactic and therapeutic treatment against Q fever. Two specific aims were designed to test the central hypothesis that passive administration of huscFv1E4 will provide immediate protection against C. burnetii infection. Specific Aim 1 will evaluate the prophylactic efficacy of huscFv1E4 against C. burnetii aerosol infection in mice. Specific Aim 2 will examine if huscFv1E4 alone or combination with antibiotic would be more effective for treatment of C. burnetii infected mice. As an outcome of this study, we expect to prove the feasibility of using huscFv1E4 for prevention and treatment of Q fever. This will have significant positive effects on human health, because it is the critical step towards developing effective emergency prophylactic and therapeutic treatments for control of Q fever.