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

• 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
• 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' 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

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：该 SBIR 二期项目提议进一步开发重组人 乳脂球表皮生长因子-因子 8 (rhMFG-E8) 作为一种新型有效的辅助疗法 失血性休克每年夺去 60,000 名美国人的生命。失血性休克导致细胞死亡，并且 垂死细胞释放损伤相关分子模式（DAMP）。 DAMP 会促进炎症， 复合器官损伤导致多器官功能衰竭，是导致发病和死亡的重要原因 出血后死亡。 MFG-E8 是一种分泌性糖蛋白，可促进死亡细胞的清除， 从而取消 DAMP 的释放。在我们的初步研究中，我们已经表明循环水平 MFG-E8 在出血小鼠中减少，并且用 His 标记的 rhMFG-E8 进行辅助治疗 减少炎症并提高失血性休克的生存率。由于 His 标记的生物制剂不 适合在人类患者中使用，我们使用人类细胞表达系统生产纯无标签 rhMFG-E8，具有优越的生物活性。在失血性休克的大鼠模型中，辅助治疗 无标签 rhMFG-E8 显着减少了肝脏和肺部的凋亡细胞数量，循环 促炎细胞因子的水平和活化的中性粒细胞的肺部浸润。无标签 rhMFG-E8 还减轻了肾脏和肝脏损伤，并将失血性休克生存率从 50% 提高到 80%。 此外，我们还确定了 rhMFG-E8 的分布和消除半衰期及其非致癌性。 因此，我们假设无标签的 rhMFG-E8 可以进一步开发为一种新的有效的 失血性休克的辅助治疗。为了推进药物开发，我们将确定无标签 rhMFG-E8 对器官损伤和血流动力学参数的剂量依赖性有益作用及其 治疗窗口以提高大鼠出血后的存活率。我们还将检查无标签的 rhMFG- E8 在大鼠中的安全性并验证其对器官损伤、血流动力学参数和 失血性休克猪模型的存活率。这些研究将提供关键剂量、时间 管理、功效和安全性信息，以进一步开发无标签 rhMFG-E8 作为辅助疗法 用于失血性休克。我们未来的步骤将包括扩大 MFG-E8 的生产规模并完成 功效、ADME 和毒代动力学临床前研究。然后我们将提交新药研究 (IND) 向 FDA 申请启动临床试验。我们的最终目标是获得标签的商业利用 免费rhMFG-E8作为失血性休克患者安全有效的复苏辅助剂。