Exploiting Fc-engineering to dissect mechanisms of anti-microbial action of M. tuberculosis-specific antibodies

利用 Fc 工程剖析结核分枝杆菌特异性抗体的抗微生物作用机制

• 批准号: 9911087
• 负责人: Edward Buford Irvine
• 金额: $ 3.15万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911087
• 关键词: Antibodies; Antibody Specificity; Antibody Therapy; Antigens; BCG Live; Bacteria; Bacterial Adhesins; Biological Assay; CD4 Positive T Lymphocytes; Cause of Death; Cells; Cellular Immunity; Chemicals; Chemosensitization; Communication; Complement; Coupled; Data; Development; Disease; Drug resistance; Educational process of instructing; Engineering; Environment; Epidemic; Fc Receptor; Fellowship; Fluorescence Microscopy; Generations; Growth; Heat shock proteins; Human; Humoral Immunities; IgG Receptors; Immune; Immune response; Immune system; Immunity; Immunologics; Immunology; Individual; Infection; Infectious Agent; Innate Immune Response; Innate Immune System; Institutes; Libraries; Lung; Mediating; Mediator of activation protein; Modification; Monoclonal Antibodies; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Nature; Phagocytosis; Physiological; Publishing; Pulmonary Tuberculosis; Receptor Signaling; Regimen; Research; Research Project Grants; Role; Science; Serologic tests; Signal Pathway; Signal Transduction; Surface; Surface Antigens; Surveys; System; T-Lymphocyte; Testing; Therapeutic; Time; Training; Tuberculosis; Tuberculosis Vaccines; Vaccine Design; Vaccines; Whole Blood; Wild Type Mouse; Work; antibody engineering; antibody-dependent cell cytotoxicity; antimicrobial; base; design; disorder control; emerging antibiotic resistance; experimental study; fight against; heparin-binding hemagglutinin; in vitro Assay; in vivo; innate immune function; innate immune pathways; innovation; insight; lipoarabinomannan; macrophage; microbial; neutrophil; novel vaccines; prevent; success; therapeutic development

Project Summary Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the leading cause of death from a single infectious agent globally. While TB is curable, the intensive chemotherapeutic regimen coupled with the emergence of antibiotic resistance, has highlighted the need for an efficacious tuberculosis vaccine, as well as for the development of therapeutics robust to drug resistance. Bacillus Calmette-Guérin (BCG), developed in 1921, remains the only licensed TB vaccine to date, and does not effectively protect against the development of pulmonary TB. Consequently, innovative approaches to therapeutic and vaccine design are needed to curb the ongoing tuberculosis epidemic. Remarkably, despite the critical nature of the humoral immune response to protection by a majority of approved vaccines, humoral immunity to Mtb remains understudied. However, emerging evidence supports a role for antibodies in Mtb restriction. Antibodies can block the progression of infection and prevent spread. Moreover, mice unable to signal through activating Fc- gamma receptors have increased bacterial burden in the lung following Mtb infection, as well as decreased survival compared to wild-type mice. These data strongly implicate a role for antibodies, and more critically for the antibody constant domain (Fc), in protection; however, the Fc-mediated functions able to drive protection remain extensively unclear. Thus, this work aims explore antibody Fc-mediated mechanisms of Mtb control. We hypothesize that antibodies targeting surface exposed Mtb antigens direct the innate immune system to restrict Mtb growth in an Fc-dependent manner, and we plan to test this hypothesis using rationally designed Fc-engineered libraries of monoclonal antibodies, which allow the probing of individual Fc-enhancements and modifications for their impact on antibody anti-microbial activity. These antibody Fc-libraries will be tested in a systematic and rigorous set of in vitro assays, designed to capture potentially disparate mechanisms of antibody action. Aim 1 will identify the functions of antibodies able to drive Mtb growth restriction in whole- blood when present at the time of infection; Aim 2 will explore the intracellular mechanisms of antibody action in limiting Mtb survival within its host macrophage, the primary niche of the bacterium during infection. Overall, if successful, this work will contribute to our understanding of how antibodies may contribute to Mtb disease control, and thus help guide the next generation of vaccines and/or therapeutics against this global killer. This work will primarily be carried out at the Ragon Institute of MGH, MIT, and Harvard, a world leader in immunology research. Moreover, in parallel with the described research project, this fellowship will provide abundant teaching and science communication opportunities, to collectively encompass a comprehensive, systematic graduate training plan.

项目摘要 结核分枝杆菌(Mtb)是结核病(TB)的病原体，是由 全球范围内只有一种单一的感染源。虽然结核病是可以治愈的，但强化化疗方案与 抗生素耐药性的出现也突显了有效的结核病疫苗的必要性。 至于耐药治疗的发展。卡介苗(BCG) 在1921年，仍然是迄今为止唯一获得许可的结核病疫苗，并不能有效地预防 肺结核病的发展。因此，治疗和疫苗设计的创新方法是 这是遏制目前结核病流行所必需的。值得注意的是，尽管幽默的批判性 对大多数批准疫苗保护的免疫反应，对结核分枝杆菌的体液免疫仍然存在 未得到充分研究。然而，新出现的证据支持抗体在结核分枝杆菌限制中的作用。抗体可以 阻止感染的进展，防止传播。此外，无法通过激活Fc-来发出信号的小鼠 在结核分枝杆菌感染后，伽玛受体增加了肺部的细菌负荷，同时减少了 与野生型小鼠相比，存活率更高。这些数据强烈地暗示了抗体的作用，更关键的是 保护中的抗体恒定域(Fc)；然而，Fc介导的功能能够驱动保护 目前仍很不清楚。因此，本工作旨在探索抗体Fc介导的结核分枝杆菌控制机制。 我们假设，针对表面暴露的结核分枝杆菌抗原的抗体引导先天免疫系统 以依赖于FC的方式限制结核分枝杆菌的增长，我们计划使用合理设计的 Fc设计的单抗抗体库，允许探测单个Fc增强和 修饰对抗体抗微生物活性的影响。这些抗体Fc库将在 一套系统和严格的体外分析，旨在捕捉潜在的不同机制 抗体作用。目标1将确定能够驱动结核分枝杆菌生长限制的抗体的功能 感染时存在的血液；目标2将探索抗体作用的细胞内机制 限制结核分枝杆菌在宿主巨噬细胞内的存活，巨噬细胞是细菌在感染期间的主要生态位。总的来说， 如果成功，这项工作将有助于我们理解抗体如何导致结核分枝杆菌病。 控制，从而帮助指导下一代针对这一全球杀手的疫苗和/或疗法。这 工作将主要在麻省理工学院拉贡研究所和哈佛大学进行，哈佛大学是世界领先的 免疫学研究。此外，在所述研究项目的同时，该研究金将提供 丰富的教学和科学交流机会，共同涵盖全面、 系统的研究生培养计划。