ICAM-1 targeted thrombomodulin: an experimental therapeutic for the Acute Respiratory Distress Syndrome

ICAM-1 靶向血栓调节蛋白：急性呼吸窘迫综合征的实验性治疗方法

基本信息

批准号：
9180155
负责人：
Colin Fred Greineder
金额：
$ 13.41万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2016-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9180155
关键词：
Accident and Emergency department Adhesions Adult Respiratory Distress Syndrome Affect Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Area Bacterial Pneumonia Binding Biodistribution Biotechnology Blood Blood Platelets Blood Vessels CD31 Antigens Cell Adhesion Cell Adhesion Molecules Cell Culture System Cell surface Cells Chimeric Proteins Clinical Clinical Trials Coagulation Process Complex Data Development Dose Drug Kinetics Early Diagnosis Emergency Care Emergency Department Physician Endothelial Cells Endothelium Engineering Failure Formulation Functional disorder Generations Genetic Health Human Immune Immunoglobulin Fragments In Vitro Incidence Inflammation Injury Intensive Care Intercellular adhesion molecule 1 Intervention Investigational Therapies Kinetics Laboratories Leukocytes Life Lung Measures Mediating Medical Microfluidics Modeling Monoclonal Antibodies Mus Outcome Pathogenesis Pathway interactions Patients Permeability Pharmaceutical Preparations Plasma Proteins Process Protein C Protein Engineering Proteins Recombinants Role Safety Sepsis Series Severities Signal Transduction Site Surface System Techniques Testing Therapeutic Thrombin Thrombomodulin Thrombosis Time Toxic effect Translations Trauma United States Whole Blood Work abstracting activated Protein C activated protein C receptor career cytokine experience human disease immune activation improved improved outcome in vivo intercellular cell adhesion molecule interest killings lung injury mortality mouse model novel novel therapeutic intervention pre-clinical prevent protective effect receptor research study residence targeted treatment therapeutic target

项目摘要

Project Summary/Abstract The Acute Respiratory Distress Syndrome (ARDS) is a major health concern that affects 200,000 patients a year and kills ~40% of the patients affected. Currently, there are no pharmacologic agents that improve outcome. Patients often present to the Emergency Room relatively early in the course of the illness, suggesting that lung injury might be prevented or even reversed, given timely administration of safe and effective therapeutics. As a practicing Emergency Physician, this clinical experience has motivated me to dedicate my career to the development and translation of biotechnology for the early diagnosis, prognostication, and treatment of ARDS. The current project involves a novel therapeutic approach, which provides protection in a mouse model of lung injury, and proposes three specific aims to further define its mechanism of action and advance its pre-clinical development. In ARDS, there is a reduction in the amount of Thrombomodulin (TM) expressed on the surface of pulmonary endothelial cells. This proteins normally partners with the Endothelial Protein Receptor (EPCR) to activate protein C, which in turn helps to mitigate inflammation, reduce plasma protein leak, and prevent microvessel thrombosis. The therapeutics described in the proposal augment this natural protective mechanism by binding to ICAM-1, an endothelial cell adhesion molecule upregulated in the setting of inflammation, and anchoring recombinant TM to the cell surface. Previous work demonstrates that this approach enables partnering of the targeted therapeutic with naturally expressed EPCR, boosting protein C activation and reducing the severity of lung injury when used prophylactically in a mouse model of ARDS. In the first specific aim, a series of in vitro microfluidic experiments are proposed to: 1. model the complex interactions which occur at the interface of flowing human blood and activated lung endothelium, and 2. clarify how ICAM-targeted TM works to reduce coagulation, immune cell adhesion, and vascular barrier dysfunction in these models. In the second aim, the synthesis and testing of a second generation of ICAM-targeted therapeutics is proposed, with the hypothesis that the new formulation will improve pharmacokinetics and prolong functional activity in the lung. In the third aim, extensive testing of ICAM- targeted TM is proposed in two distinct murine models of ARDS, to determine efficacy, dosing, therapeutic time window, safety, and mechanism of action.

项目概要/摘要急性呼吸窘迫综合症 (ARDS) 是影响 200,000 人的主要健康问题每年都会有大约 40% 的患者死亡。目前，尚无药物制剂可以改善结果。患者通常在治疗过程中相对较早的时间就到急诊室疾病，表明如果及时给予安全的治疗，肺损伤可能是可以预防甚至逆转的和有效的治疗方法。作为一名执业急诊医师，这段临床经历激励着我将我的职业生涯奉献给早期诊断生物技术的开发和转化， ARDS 的预测和治疗。当前的项目涉及一种新颖的治疗方法，在小鼠肺损伤模型中提供保护，并提出三个具体目标来进一步定义其作用机制并推进其临床前开发。在 ARDS 中，血栓调节蛋白 (TM) 表面表达的量减少肺内皮细胞。这种蛋白质通常与内皮蛋白受体 (EPCR) 合作激活蛋白 C，从而有助于减轻炎症、减少血浆蛋白渗漏并预防微血管血栓形成。提案中描述的疗法增强了这种自然保护作用机制是通过与 ICAM-1 结合，ICAM-1 是一种内皮细胞粘附分子，在炎症，并将重组TM锚定到细胞表面。先前的工作表明，这该方法能够将靶向治疗与自然表达的 EPCR 结合起来，从而增强蛋白 C 在 ARDS 小鼠模型中预防性使用时，可激活并降低肺损伤的严重程度。在第一个具体目标中，提出了一系列体外微流体实验： 1. 模拟在流动的人体血液和活化的肺内皮的界面处发生复杂的相互作用， 2. 阐明 ICAM 靶向 TM 如何减少凝血、免疫细胞粘附和血管这些模型中的屏障功能障碍。第二个目标是合成和测试第二代提出了 ICAM 靶向疗法，假设新配方将改善药代动力学并延长肺的功能活性。第三个目标是对 ICAM 进行广泛测试提出在两种不同的 ARDS 小鼠模型中进行靶向 TM，以确定疗效、剂量、治疗时间窗口、安全性和作用机制。