RBC-mediated mopping of cytokines for the treatment of pneumonia

红细胞介导的细胞因子清除治疗肺炎

基本信息

批准号：
10353073
负责人：
Jacob Brenner
金额：
$ 20.31万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10353073
关键词：
Acute Adherence Adult Respiratory Distress Syndrome Air Sacs American Animal Model Anti-Inflammatory Agents Antibiotics Antibodies Antiviral Agents Bacteria Bacterial DNA Bacterial Pneumonia Binding Binding Proteins Biodistribution Blood Blood Circulation Blood capillaries COVID-19 Cause of Death Cell Therapy Cell surface Cells Cellular Assay Cessation of life Chimeric Proteins Complement 3b Receptors Creatinine Critical Care Cytolysis DNA Data Disease Distant Drug Delivery Systems Drug Kinetics Endothelial Cells Endotoxins Engineering Erythrocytes Extravasation Focal Infection GYPA gene HMGB Proteins HMGB1 gene Immune Immune response Immune system Immunotherapy In Vitro Infection Inflammation Inflammation Mediators Inflammatory Infusion procedures Interleukin-6 Klebsiella Kupffer Cells Letters Leukocytes Liposomes Liver Lung Lung infections Measures Mediating Mediator of activation protein Mentors Methods Microbe Minority Mitochondrial DNA Monoclonal Antibodies Mus Organ Output Patients Physicians Pneumonia Positioning Attribute Production Property Protein Engineering Proteins Publishing Pulmonary Pathology Sepsis Site Sterility Surface T cell therapy TNF gene Technology Testing Therapeutic Therapeutic Effect Thrombomodulin Time Tissues Toxin Travel Viral Pneumonia Virus combat cytokine cytokine release syndrome design experience fighting lung injury microbial mouse model nanometer nanoparticle novel therapeutics particle pneumonia model pneumonia treatment preservation prevent prototype side effect therapeutic protein

项目摘要

ABSTRACT / SUMMARY Despite the advent of antibiotics and antivirals, pneumonia remains a major killer. In typical years, it kills >50,000 Americans, and in the last year, nearly 10x that amount due to COVID-19. The reason for these deaths is rarely because we cannot stop microbial expansion. Rather, it is due to the host response, in which local inflammation in the lungs causes a very high concentration of pro-inflammatory cytokines to spill into the blood, whereupon the cytokines travel to and damage remote organs. To eliminate excessive cytokines, many antibodies have been developed to bind and neutralize cytokines. However, these antibodies extravasate into the infected tissue (lungs), where they also inhibit the beneficial function of these cytokines, which is the orchestration of leukocytes to clear the microbes. To prevent this problem and the subsequent microbial overgrowth, there is a need to engineer therapeutics that only quench cytokines in the bloodstream, and not in the infected tissues that rely upon cytokines for microbial clearance. To accomplish this, we have developed RBC-Mops. RBC-Mops bind and quench cytokines, but only in the bloodstream, with no extravasation into infected tissues. We will build and test RBC-Mops across two Aims: In Aim 1, we will test RBC-Mops ability to bind their targets in vitro, evaluate for damage to RBCs themselves, and determine the pharmacokinetics and biodistribution of RBC-Mops in naive mice. In Aim 1, we will test RBC-Mops in the Klebsiella mouse model of pneumonia, evaluating benefits to the lungs and remote organs, while also investigating potential side effects. This R21 is designed to produce and validate the prototype RBC-Mop within 2 years. After that, we will apply for an R01 to further the translational potential of RBC-Mops and better understand their mechanisms. Eventually, we hope to develop a combination of RBC-Mops that can eliminate cytokines and other circulating toxins, to ameliorate a large range of acute illnesses, including viral pneumonia (COVID-19), sepsis, and sterile cytokine release syndromes produced by immunological therapies.

摘要 /摘要尽管抗生素和抗病毒药出现了，但肺炎仍然是主要杀手。在典型的几年中，杀死> 50,000名美国人，在去年，由于19号造成的近10倍。这些原因死亡很少是因为我们无法停止微生物扩张。相反，这是由于主机的响应，其中肺部局部炎症会导致非常高浓度的促炎细胞因子溢出血液，因此细胞因子传播并损坏偏远的器官。为了消除过多的细胞因子，已经开发了许多抗体来结合和中和细胞因子。但是，这些抗体会外出进入感染组织（肺），它们也抑制这些细胞因子的有益功能，即白细胞的编排以清除微生物。到防止此问题和随后的微生物过度生长，需要设计治疗剂仅在血液中淬灭细胞因子，而不在依赖细胞因子的微生物的感染组织中清除。为此，我们开发了RBC-MOPS。 RBC-mops结合并淬灭细胞因子，但仅在血液没有渗入被感染的组织。我们将构建和测试两个目的：在AIM 1中，我们将测试RBC-MOPS在体外绑定目标的能力，评估对RBC的损害自己，并确定幼稚小鼠中RBC-mops的药代动力学和生物分布。在AIM 1中，我们将在肺炎的克雷伯菌小鼠模型中测试RBC-mops，评估肺部和遥控器的益处器官，同时还研究潜在的副作用。该R21旨在在2年内生产和验证原型RBC-MOP。之后，我们将申请R01来进一步推动RBC-MOPS的翻译潜力，并更好地了解其机制。最终，我们希望开发出可以消除细胞因子和其他循环的RBC-mops的组合毒素，改善各种急性疾病，包括病毒性肺炎（Covid-19），败血症和无菌性疾病免疫疗法产生的细胞因子释放综合征。