rhMFG-E8 as an Effective Adjuvant Therapy for Hemorrhagic Shock

rhMFG-E8 作为失血性休克的有效辅助疗法

基本信息

批准号：
10005406
负责人：
Max Brenner
金额：
$ 50.56万
依托单位：
THERASOURCE, LLC
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：
2016-01-08 至 2022-07-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005406
关键词：
Acidosis Acute Adjuvant Adjuvant Therapy Age-Years American Apoptotic Attenuated Biological Biological Assay Blood Blood flow Cardiac Output Cause of Death Cell Count Cell Death Cells Cessation of life Clinical Trials Death Rate Dose Epidermal Growth Factor Failure Family suidae Future Glycoproteins Goals HMGB1 gene Half-Life Health Care Costs Heart Hemorrhage Hemorrhagic Shock Hemostatic function Hepatic Histologic Histology Human Human Milk Infiltration Inflammation Injury to Kidney Interleukin-6 Intravenous Kidney Lactated Ringer&apos s Solution Length of Stay Lethal Dose 50 Liquid substance Liver Lung Maximum Tolerated Dose Modeling Molecular Monitor Morbidity - disease rate Mus Organ Organ failure Patients Pattern Peripheral Resistance Phase Production Proteins Rattus Recombinants Resuscitation Safety Saline Small Business Innovation Research Grant Small Intestines Survival Rate System TNF gene TdT-Mediated dUTP Nick End Labeling Assay Testing Therapeutic Time Tissues Toxic effect Toxicokinetics Trauma United States base carcinogenicity cell free DNA cytokine drug development functional disability hemodynamics improved liver injury milk fat globule mortality neutrophil novel novel therapeutics organ injury preclinical study pressure prevent public health relevance scale up years of life lost

项目摘要

PROJECT DESCRIPTION: This SBIR Phase II project proposes to further develop recombinant human milk fat globule epidermal growth factor-factor 8 (rhMFG-E8) as a novel and effective adjuvant therapy for hemorrhagic shock, which kills 60,000 Americans every year. Hemorrhagic shock results in cell death, and dying cells release damage-associated molecular patterns (DAMPs). DAMPs promote inflammation, compounding organ injury to cause multiorgan failure, which is an important cause of morbidity and mortality after hemorrhage. MFG-E8 is a secreted glycoprotein that promotes the clearance of dying cells, thus abrogating the release of DAMPs. In our preliminary studies, we have shown that circulating levels of MFG-E8 are reduced in hemorrhaged mice, and that their adjuvant treatment with His-tagged rhMFG-E8 decreases inflammation and improves hemorrhagic shock survival. Since His-tagged biologics are not suitable for the use in human patients, we used a human cell expression system to produce pure tag-free rhMFG-E8, with superior biological activity. In a rat model of hemorrhagic shock, adjuvant treatment with tag-free rhMFG-E8 significantly reduced the number of apoptotic cells in the liver and lungs, circulating levels of proinflammatory cytokines and pulmonary infiltration by activated neutrophils. Tag-free rhMFG-E8 also attenuated renal and hepatic injury and improved hemorrhagic shock survival from 50% to 80%. Additionally, we determined rhMFG-E8’s distribution and elimination half-lifes and its non-carcinogenicity. Therefore, we hypothesize that tag-free rhMFG-E8 can be further developed as a new and effective adjuvant therapy for hemorrhagic shock. To advance the drug development, we will determine tag-free rhMFG-E8’s dose-dependent beneficial effects on organ injury and hemodynamic parameters, as well as its therapeutic window to improve survival after hemorrhage in the rat. We will also examine tag-free rhMFG- E8’s safety profile in the rat and verify its beneficial effects on organ injury, hemodynamic parameters, and survival in a pig model of hemorrhagic shock. These studies will provide critical dosing, time of administration, efficacy, and safety information to further develop tag-free rhMFG-E8 as an adjuvant therapy for hemorrhagic shock. Our future steps will include scaling up production of MFG-E8 and completing efficacy, ADME, and toxicokinetic preclinical studies. We will then file an investigative new drug (IND) application with the FDA to initiate clinical trials. Our ultimate goal is to obtain commercial utilization of tag- free rhMFG-E8 as a safe and effective resuscitation adjuvant for patients with hemorrhagic shock.

项目描述：这项SBIR II期项目提案旨在进一步发展重组人牛奶脂肪球表皮生长因子因子8（RHMFG-E8）作为一种新颖有效的调整疗法出血性休克，每年杀死60,000名美国人。出血性休克导致细胞死亡，并垂死的细胞释放损伤相关的分子模式（湿）。潮湿会促进炎症，使器官损伤导致多器官损伤，这是发病率和出血后的死亡率。 MFG-E8是一种分泌的糖蛋白，可促进垂死细胞的清除，从而消除了潮湿的释放。在我们的初步研究中，我们表明循环水平 MFG-E8在出血的小鼠中降低，并通过His标记的RHMFG-E8调整治疗减少炎症并改善出血性休克存活率。因为他标记的生物制剂不是适合在人类患者中使用，我们使用人类细胞表达系统可产生纯标签 RHMFG-E8，具有出色的生物学活性。在大鼠出血性休克模型中，调整无标记的RHMFG-E8显着减少了肝脏和肺中凋亡细胞的数量，循环活化中性粒细胞的促炎细胞因子和肺部浸润水平。无标签的RHMFG-E8 还减轻了肾脏和肝损伤，并将出血性休克存活率从50％提高到80％。此外，我们确定了RHMFG-E8的分布和消除半插曲及其非癌性。因此，我们假设无标签的RHMFG-E8可以作为新的有效佐剂治疗用于出血性休克。为了推进药物开发，我们将确定无标签 RHMFG-E8对器官损伤和血液动力学参数的剂量依赖性有益作用及其治疗窗口可改善大鼠出血后生存。我们还将检查无标签RHMFG- E8在大鼠中的安全性并验证其对有机损伤，血液动力学参数和在出血性休克模型中的生存。这些研究将提供关键的给药，时间管理，效率和安全信息，以进一步开发无标签的RHMFG-E8作为可调疗法出血性休克。我们的未来步骤将包括扩展MFG-E8的生产并完成有效，ADME和有毒动力学临床前研究。然后，我们将提交调查新药（IND）与FDA的应用启动临床试验。我们的最终目标是获得标签的商业利用 - 免费的RHMFG-E8作为出血性休克患者的安全有效复苏。