Use of a Humanized Antibody against Intracellular Bacterial Pathogen

抗细胞内细菌病原体的人源化抗体的用途

基本信息

批准号：
10003580
负责人：
Guoquan Zhang
金额：
$ 18.69万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-23 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10003580
关键词：
Acute Adult Aerosols Animals Antibiotics Antibody-mediated protection B-Lymphocytes Cellular Immunity Centers for Disease Control and Prevention (U.S.)Chronic Chronic Disease Coxiella burnetii Defect Disease Disease Outbreaks Dose Doxycycline Emergency Situation Emergency treatment Exposure to Goals Gram-Negative Bacteria Health Heart Valves Human Immunocompromised Host Immunologics Immunotherapy Individual Infection Lead Life Lipopolysaccharides Monoclonal Antibodies Mus Netherlands Occupational Outcome Study Pathogenicity Patients Phase Prevention Prevention strategy Public Health Q Fever Regimen Reporting Research Risk SCID Mice T-Lymphocyte Testing Therapeutic Vaccination Vaccines Wild Type Mouse Work Zoonoses aerosolized chronic infection design effective therapy flu high risk humanized antibody humanized monoclonal antibodies immunoprophylaxis immunosuppressed innovation macrophage novel strategies pathogen pathogenic bacteria pregnant programs prophylactic

项目摘要

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.

抽象的 Q发烧是一种世界范围内的人畜共患病，是由专性细胞内革兰氏阴性细菌引起的 Coxiella burnetii。人类Q发烧会发展为严重的慢性致命疾病。但是，有在美国，没有可用于预防人类Q发烧的疫苗。另外，很难治疗慢性Q发烧患者患有各种抗生素方案。因此，迫切需要开发紧急替代预防和治疗策略，用于预防和治疗Q发烧。这应用旨在证明单克隆抗体可以用作预防性和针对细胞内细菌病原体的治疗策略。尽管C. burnetii是义务的细胞内细菌病原体，我们最近的工作表明，I期脂多糖特异性的被动转移单克隆抗体1E4对SCID小鼠和 1E4（HUSCFV1E4）的人源化变量片段能够抑制小鼠和人类的伯内特感染。巨噬细胞。这些结果证明了HUSCFV1E4的实用性是一种快速，有效的紧急处理控制Q发烧。因此，本应用的目的是进一步证明使用的可行性 HUSCFV1E4用于针对Q发烧的有效紧急预防和治疗治疗。两个具体的目标旨在测试中心假设，即被动给药HUSCFV1E4将立即提供防止C. burnetii感染。具体目标1将评估HUSCFV1E4的预防功效针对小鼠的伯内特氏菌气溶胶感染。特定目标2将检查HUSCFV1E4是单独的还是组合使用抗生素将更有效地治疗被感染的小鼠。作为这项研究的结果，我们希望证明使用HUSCFV1E4预防和治疗Q发烧有可行性。这将有对人类健康的重大积极影响，因为这是发展有效的关键一步紧急预防性和治疗治疗，用于控制Q发烧。