A Novel Recombinant Protein as an Effective Therapy for Acute Kidney Injury

一种新型重组蛋白可有效治疗急性肾损伤

• 批准号: 9314562
• 负责人: Weng-Lang Yang
• 金额: $ 11.28万
• 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: 2016-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9314562
• 关键词: ADME Study; Acute Renal Failure with Renal Papillary Necrosis; Adult; Animals; Apoptotic; Area Under Curve; Attenuated; Bilateral; Binding; Biological; Biological Assay; Blood; Blood Urea Nitrogen; Blood flow; Brain; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cell Adhesion; Cells; Cessation of life; Chinese Hamster; Chinese Hamster Ovary Cell; Clinical; Clinical Trials; Closure by clamp; Complication; Coronary Artery Bypass; Coronary artery; Creatinine; Dose; Drops; Drug Kinetics; Drug or chemical Tissue Distribution; Eosine Yellowish; Epidermal Growth Factor; Excretory function; FDA approved; Factor VIII; Functional disorder; Future; Gamma counter; Goals; Half-Life; Heart; Histologic; Hospitalization; Human; Human Milk; Hydrophobicity; Inflammation; Injection of therapeutic agent; Injury; Interleukin-1 beta; Interleukin-18; Interleukin-6; Intravenous; Investigational New Drug Application; Ion Exchange; Ischemia; Kidney; LCN2 gene; Label; Large Intestine; Length of Stay; Life; Liver; Lung; Mass Spectrum Analysis; Measures; Metabolism; Modeling; Monitor; Mus; Muscle; Neutrophil Infiltration; Normal saline; Operative Surgical Procedures; Ovary; Patients; Peptide Signal Sequences; Perfusion; Peroxidases; Phagocytes; Pharmaceutical Preparations; Phase; Plasmids; Property; Proteins; Quality Control; Radioactivity; Rattus; Recombinant Proteins; Recombinants; Renal Blood Flow; Renal Tissue; Renal function; Reperfusion Therapy; Saline; Serum; Site; Skin; Small Business Innovation Research Grant; Small Intestines; Spleen; Staining method; Stains; Stomach; Survival Rate; Suspensions; System; TNF gene; TdT-Mediated dUTP Nick End Labeling Assay; Therapeutic; Time; Tissues; Toxicology; Treatment Efficacy; Tubular formation; Urine; Western Blotting; absorption; cancer surgery; cost; cytokine; effective therapy; heart valve replacement; improved; injured; male; milk fat globule; mortality; neutrophil; novel; novel therapeutics; post gamma-globulins; preclinical study; public health relevance; renal ischemia; safety study; secretory protein; urinary; valve replacement

PROJECT DESCRIPTION: The primary objective of this project is to demonstrate the feasibility of developing recombinant human milk fat globule epidermal growth factor-factor 8 (rhMFG-E8) as a novel and effective therapeutic for patients with acute kidney injury (AKI) associated with ischemia due to low renal perfusion. AKI is a major cause of prolonged hospitalization and increased mortality. Ischemic AKI often results from decreased renal blood flow associated with cardiac surgery involving cardiopulmonary bypass, especially coronary artery bypass graft and valve replacement. Despite being a frequent, life-shortening, and costly complication, no FDA-approved drugs are currently clinically available to treat ischemic AKI. MFG-E8 is a protein that promotes the clearance of inflammation-promoting dying cells and decreases the influx of tissue-damaging neutrophils to the injured site. In the preliminary study, we used recombinant mouse MFG-E8 to treat mice with AKI induced by severe renal ischemia-reperfusion. Treatment with recombinant mouse MFG-E8 significantly attenuated renal dysfunction, decreased levels of proinflammatory cytokines, and reduced kidney infiltration by neutrophils. Therefore, we hypothesize that rhMFG-E8 can be developed as a new and effective biologic drug to treat patients with ischemic AKI. Indeed, administration of His-tagged rhMFG-E8 increased the 10-day survival of mice with ischemic AKI from 47% to 68%. Since His-tagged proteins are not suited for use in humans, we have started to produce a druggable, human-like glycosylated, His tag-free rhMFG-E8 using a mammalian Chinese hamster ovary (CHO) cell expression system. In this project we will express, purify, and characterize CHO-expressed rhMFG-E8. We will next determine CHO-expressed rhMFG-E8's efficacy to attenuate renal injury and improve survival after ischemic AKI, and its pharmacokinetic (PK) profile in healthy and AKI animals. Our future steps (SBIR Phase II and beyond) include completing preclinical and safety studies, establishing ADME and safety studies, determining efficacy in a second species, and filing an investigational new drug (IND) application with the FDA to initiate clinical trials. Our ultimate goal is to obtain commercial utilization of rhMFG-E8 as a safe and effective biologic drug to treat patients with ischemic AKI.

项目描述：该项目的主要目的是证明 将重组的人牛奶脂肪球表皮生长因子因子8（Rhmfg-e8）作为一种新颖和 急性肾损伤患者（AKI）与缺血有关的有效治疗 灌注。 AKI是长期住院和死亡率增加的主要原因。缺血性aki经常 与心脏手术相关的肾脏血流减少的结果，涉及心肺旁路， 特别是冠状动脉搭桥移植物和瓣膜替代。尽管频繁，生活差，但 和昂贵的并发症，目前尚无FDA批准的药物可用于治疗缺血性AKI。 MFG-E8是一种蛋白质，可促进促进炎症的垂死细胞的清除，并减少 组织受伤的中性粒细胞流入受伤部位。在初步研究中，我们使用了重组 小鼠MFG-E8用严重的肾脏缺血再灌注引起的AKI治疗小鼠。与 重组小鼠MFG-E8显着减弱肾功能障碍，促炎水平降低 细胞因子和嗜中性粒细胞减少肾脏浸润。因此，我们假设RHMFG-E8可以是 开发为一种新的有效的生物药，用于治疗缺血性AKI患者。确实，行政管理 在HIS标记的RHMFG-E8中，缺血性AKI的小鼠10天生存率从47％增加到68％。自从 用他的标签蛋白不适合在人类中使用，我们已经开始产生一种可吸毒的，人类的样子 糖基化，他使用哺乳动物中国仓鼠卵巢（CHO）细胞表达的他的无标签RHMFG-E8 系统。在这个项目中，我们将表达，净化和表征CHO表达的RHMFG-E8。我们接下来 确定CHO表达的RHMFG-E8对减轻肾脏损伤并改善生存的功效 缺血性AKI及其在健康和AKI动物中的药代动力学（PK）谱。我们的未来步骤（Sbir 第二阶段及以后）包括完成临床前和安全研究，建立ADME和安全 研究，确定第二种的功效，并提交研究新药（IND） 使用FDA启动临床试验。我们的最终目标是获得RHMFG-E8的商业利用 安全有效的生物学药物治疗缺血性AKI患者。