Use of a Humanized Antibody against Intracellular Bacterial Pathogen

点击翻译按钮获取中文摘要

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.