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: 9202013
• 负责人: Weng-Lang Yang
• 金额: $ 22.25万
• 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/9202013
• 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; 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; Functional disorder; Future; Gamma counter; Goals; Half-Life; Heart; Hospitalization; Human; Human Milk; Inflammation; Injury; Interleukin-1 beta; Interleukin-18; Interleukin-6; 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; Pharmaceutical Preparations; Phase; Plasmids; Property; Proteins; Quality Control; Radioactivity; Rattus; Recombinant Proteins; Recombinants; Renal Blood Flow; Renal Tissue; Renal function; Reperfusion Therapy; Saline; Serum-Free Culture Media; Site; Skin; Small Business Innovation Research Grant; Small Intestines; Spleen; Staging; Staining method; Stains; Stomach; Survival Rate; Suspension substance; Suspensions; System; TNF gene; TdT-Mediated dUTP Nick End Labeling Assay; Therapeutic; Time; Tissues; Toxicology; Tubular formation; Urine; Western Blotting; absorption; cancer surgery; cytokine; effective therapy; heart valve replacement; improved; injured; intravenous administration; intravenous injection; male; milk fat globule; mortality; neutrophil; novel; novel therapeutics; post gamma-globulins; preclinical study; public health relevance; recombinant antihemophilic factor VIII; 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：该项目的主要目标是证明以下项目的可行性： 开发重组人乳脂肪球表皮生长因子-因子 8 (rhMFG-E8) 作为一种新型和 对于因肾功能低下而导致缺血的急性肾损伤（AKI）患者的有效治疗 灌注。 AKI 是住院时间延长和死亡率增加的主要原因。常发生缺血性 AKI 与涉及体外循环的心脏手术相关的肾血流量减少的结果， 特别是冠状动脉搭桥术和瓣膜置换术。尽管经常会缩短寿命， 且并发症费用昂贵，目前临床上尚无 FDA 批准的药物可用于治疗缺血性 AKI。 MFG-E8 是一种蛋白质，可促进炎症促进的死亡细胞的清除，并减少 组织损伤性中性粒细胞涌入受伤部位。在初步研究中，我们使用重组 小鼠 MFG-E8 治疗由严重肾缺血再灌注引起的 AKI 小鼠。治疗用 重组小鼠 MFG-E8 显着减轻肾功能障碍，降低促炎水平 细胞因子，并减少中性粒细胞的肾脏浸润。因此，我们假设rhMFG-E8可以 开发作为治疗缺血性 AKI 患者的新型有效生物药物。确实，行政 His 标记的 rhMFG-E8 将缺血性 AKI 小鼠的 10 天存活率从 47% 提高到 68%。自从 His 标记的蛋白质不适合在人类中使用，我们已经开始生产一种可药物化的、类人的蛋白质 使用哺乳动物中国仓鼠卵巢 (CHO) 细胞表达糖基化、无组氨酸标签的 rhMFG-E8 系统。在这个项目中，我们将表达、纯化和表征 CHO 表达的 rhMFG-E8。我们接下来 确定 CHO 表达的 rhMFG-E8 减轻肾损伤并提高术后生存率的功效 缺血性 AKI 及其在健康和 AKI 动物中的药代动力学 (PK) 特征。我们未来的步骤（SBIR II 期及以后）包括完成临床前和安全性研究、建立 ADME 和安全性 研究，确定第二个物种的功效，并提交研究性新药 (IND) 申请 与 FDA 合作启动临床试验。我们的最终目标是获得 rhMFG-E8 作为药物的商业利用 安全有效的生物药物治疗缺血性 AKI 患者。