Antibody therapy for pneumococcal disease

肺炎球菌疾病的抗体治疗

基本信息

批准号：
10053301
负责人：
Liise-anne Pirofski
金额：
$ 41.75万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-11-10 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053301
关键词：
AIDS/HIV problem Address Adult Agglutination Antibiotic Resistance Antibiotics Antibodies Antibody Response Antibody Therapy Antibody-mediated protection Antigens Apoptosis B-Lymphocytes Binding Biological Assay Child Childhood Clinical Medicine Conjugate Vaccines Data Drug resistance Elderly Empyema Epitopes Equilibrium Gene Expression Gene Expression Profiling Goals Herd Immunity Human Immunity Immunization Immunotherapy In Vitro Infant Infection Inflammation Inflammation Mediators Knowledge Learning Lung Lung Inflammation Mediating Modeling Monoclonal Antibodies Mus Oligosaccharides Passive Immunotherapy Patients Phagocytes Pneumococcal Infections Pneumococcal Pneumonia Pneumococcal vaccine Pneumonia Polysaccharides Pre-Clinical Model Prevention Public Health Risk Sepsis Serotyping Specificity Streptococcus pneumoniae Testing Transgenic Mice Transgenic Organisms Vaccines Work base community acquired pneumonia disorder risk high risk human monoclonal antibodies immunogenic improved in vitro activity in vivo innovation interest macrophage mortality mortality risk novel novel strategies pathogen prevent response vaccine efficacy

项目摘要

ABSTRACT Pneumococcal polysaccharide (PPS conjugate vaccines (PCV) have had remarkable impact in preventing invasive pneumococcal disease (IPD), but there is still a gap in treatment and prevention of pneumococcal disease as current vaccines are less effective for pneumonia than IPD and less immunogenic in patients most at risk for disease. My group has a longstanding interest in vaccine-elicited PPS antibodies and how they work. We made the paradigm-shifting discovery that while some PPS3 monoclonal antibodies (MAbs) that protect mice from serotype 3 (ST3) pneumococcus mediate phagocyte killing of ST3 in vitro (opsonic), others do not (non-opsonic). These MAb types have distinct PPS3 specificities and require different effectors and FcγRs to protect mice from ST3 pneumonia. Opsonic antibodies induce early lung bacterial clearance, but non-opsonic MAbs do not, instead they reduce lung inflammation. These findings challenge prevailing dogma that vaccine efficacy is solely a function of opsonic antibodies and show there is still much to learn about how PPS antibodies mediate protection. The goal of this application is to make human monoclonal antibodies (huMAbs) to treat ST3 pneumonia. Ultimately, we wish to develop a multi-ST huMAb cocktail, but ST3 will be our first target as PCV13 is less effective for ST3, an important cause of pneumonia that still carries higher risk of death than other STs. We hypothesize huMAbs that balance ST3 clearance and control of host inflammation will provide the most protection. We will generate PPS3 huMAbs from pneumococcal vaccine recipients, use a novel ST3 glycan array to identify huMAb PPS3 epitopes, and determine their functional activities in vitro and efficacies against ST3 in vivo in colonization, pneumonia, and sepsis models in normal and human (hu)FcγR transgenic mice. This will identify candidate huMAbs to advance for therapy, reveal potentially new correlates of protection, and identify potential adjunctive PPS3 antigens to enhance vaccine efficacy for pneumonia. This project will advance understanding of mechanisms of antibody action and have a major impact on clinical medicine and public health by removing roadblocks to prevention and treatment of pneumococcal pneumonia with ideas and an approach that can be applied to any pathogen.

抽象的肺炎球菌多糖（PPS结合疫苗（PCV））在预防肺炎球菌多糖（PPS结合疫苗（PCV））方面具有显着效果侵袭性肺炎球菌病（IPD），但肺炎球菌的治疗和预防仍存在差距因为目前的疫苗对肺炎的效果不如 IPD，而且对大多数患者的免疫原性也较低我的团队长期以来对疫苗引发的 PPS 抗体及其工作原理很感兴趣。我们做出了范式转变的发现，虽然一些 PPS3 单克隆抗体 (MAb) 可以保护血清型 3 (ST3) 肺炎球菌小鼠在体外（调理性）介导吞噬细胞杀死 ST3，而其他小鼠则不会（非调理性）这些 MAb 类型具有不同的 PPS3 特异性，需要不同的效应子和 FcγR 来发挥作用。调理性抗体可保护小鼠免受 ST3 肺炎，诱导早期肺部细菌清除，但非调理性抗体。单克隆抗体不仅不会减少肺部炎症，反而会减少肺部炎症。这些发现挑战了疫苗接种的普遍观念。功效仅是调理性抗体的一个功能，并且表明关于 PPS 如何发挥作用还有很多东西需要了解该应用的目标是制造人类单克隆抗体（huMAb）。最终，我们希望开发一种多 ST huMAb 混合物，但 ST3 将是我们的第一个。 PCV13 对 ST3 的效果较差，ST3 是肺炎的一个重要原因，但死亡风险仍然较高与其他 ST 相比，我们勇敢地使用能够平衡 ST3 清除和宿主炎症控制的 huMAb。我们将从肺炎球菌疫苗接种者中产生 PPS3 huMAb，并使用新型 ST3 聚糖阵列可鉴定 huMAb PPS3 表位，并确定其体外功能活性和在正常和人 (hu)FcγR 定植、肺炎和脓毒症模型中体内对抗 ST3 的功效这将鉴定出候选的 huMAb 以用于治疗，揭示潜在的新相关性。保护，并确定潜在的辅助 PPS3 抗原以增强肺炎疫苗的功效。该项目将促进对抗体作用机制的理解并对临床产生重大影响消除肺炎球菌肺炎预防和治疗的障碍，促进医学和公共卫生具有可应用于任何病原体的想法和方法。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Post-severe Acute Respiratory Syndrome Coronavirus 2 Monoclonal Antibody Treatment Hospitalizations as a Sentinel for Emergence of Viral Variants in New York City.

严重急性呼吸系统综合症冠状病毒 2 后单克隆抗体治疗住院作为纽约市出现病毒变种的哨兵。

DOI：
发表时间：
2021-08
期刊：
影响因子：
4.2
作者：
Cowman, Kelsie;Guo, Yi;Pirofski, Liise;Wong, David;Bao, Hongkai;Chen, Victor;Hopkins, Una;Andrews, Erin;Hamel, Joseph;Keller, Marla;Bellin, Eran;Thota, Raja;Davis, Patricia;Rodriguez, Edwin Torres;Suthar, Pooja;Allen, Lauren;Rossi, Ja
通讯作者：
Rossi, Ja

A replication-competent vesicular stomatitis virus for studies of SARS-CoV-2 spike-mediated cell entry and its inhibition.

一种具有复制能力的水泡性口炎病毒，用于研究 SARS-CoV-2 刺突介导的细胞进入及其抑制。

DOI：
发表时间：
2020-05-20
期刊：
影响因子：
0
作者：
Dieterle, M Eugenia;Haslwanter, Denise;Bortz 3rd, Robert H;Wirchnianski, Ariel S;Lasso, Gorka;Vergnolle, Olivia;Abbasi, Shawn A;Fels, J Maximilian;Laudermilch, Ethan;Florez, Catalina;Mengotto, Amanda;Kimmel, Duncan;Malonis, Ryan J;Georgiev, G
通讯作者：
Georgiev, G

Implications of Coronavirus Disease 2019 (COVID-19) Antibody Dynamics for Immunity and Convalescent Plasma Therapy.

2019 年冠状病毒病 (COVID-19) 抗体动态对免疫和恢复期血浆治疗的影响。

DOI：
发表时间：
2021-08-02
期刊：
影响因子：
0
作者：
Casadevall, Arturo;Joyner, Michael J;Pirofski, Liise
通讯作者：
Pirofski, Liise

A Replication-Competent Vesicular Stomatitis Virus for Studies of SARS-CoV-2 Spike-Mediated Cell Entry and Its Inhibition.

一种具有复制能力的水泡性口炎病毒，用于研究 SARS-CoV-2 刺突介导的细胞进入及其抑制。

DOI：
发表时间：
2020
期刊：
影响因子：
30.3
作者：
Dieterle, M Eugenia;Haslwanter, Denise;Bortz 3rd, Robert H;Wirchnianski, Ariel S;Lasso, Gorka;Vergnolle, Olivia;Abbasi, Shawn A;Fels, J Maximilian;Laudermilch, Ethan;Florez, Catalina;Mengotto, Amanda;Kimmel, Duncan;Malonis, Ryan J;Georgiev, G
通讯作者：
Georgiev, G

Help is on the way: Monoclonal antibody therapy for multi-drug resistant bacteria.

帮助即将到来：针对多重耐药细菌的单克隆抗体疗法。