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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.

摘要 Q热是一种世界性的人畜共患病，由专性细胞内革兰氏阴性菌引起，贝氏柯克斯体人类Q热可发展成为一种严重的慢性、可能致命的疾病。不过有在美国没有商业上可用于预防人类Q热的疫苗。此外，它很难治疗慢性Q热患者使用各种抗生素方案。因此，迫切需要制定一项预防和治疗Q热的紧急替代预防和治疗策略。这本申请旨在证明单克隆抗体可用作预防剂的概念，针对细胞内细菌病原体的治疗策略。尽管C.贝氏菌是一种专性细胞内细菌病原体，我们最近的工作表明，被动转移的I相脂多糖特异性，单克隆抗体1E4对C.在SCID小鼠中的贝氏气溶胶感染， 1E4的人源化可变片段（huscFv1E4）能够抑制C.小鼠和人的贝氏体感染巨噬细胞这些结果证明了huscFv1E4作为快速、有效的紧急治疗的效用控制Q热因此，本申请的目的是进一步证明使用 huscFv1E4对Q热的有效紧急预防和治疗。两个具体目标设计用于检验中心假设，即被动给予huscFv1E4将提供立即的针对C.的保护贝氏体感染特异性目的1将评价huscFv1E4的预防功效针对C.贝氏气溶胶感染小鼠。具体目标2将检查huscFv1E4单独或组合联合抗生素治疗C.贝氏体感染小鼠。作为这项研究的结果，我们希望证明huscFv1E4用于预防和治疗Q热的可行性。这将具有对人类健康产生重大积极影响，因为这是发展有效的控制Q热的紧急预防和治疗。