A Novel Recombinant Protein for Mitigating Acute Radiation Injury

一种用于减轻急性放射损伤的新型重组蛋白

基本信息

批准号：
10376745
负责人：
Wayne Chaung
金额：
$ 97.44万
依托单位：
THERASOURCE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-10 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376745
关键词：
Accidents Acute Apoptosis Bacterial Translocation Biological Biological Assay Blood Body Weight Bone Marrow Cells Clinical Trials Coagulation Process Colony-Forming Units Assay Disasters Dose Drug Kinetics E-Selectin Endothelial Cells Epidermal Growth Factor Escherichia coli Evaluation Exposure to FDA approved Factor VIII Future Glycoproteins Goals Heart Hematopoietic Hepatic Histologic Homeostasis Human Human Milk Inflammation Injury Intestinal permeability Intestines Kidney Lethal Dose 50 Liver Lung Maximum Tolerated Dose Modification Monitor Mus Nuclear Nuclear Power Plants Oncogenic Pharmaceutical Preparations Pharmacology Phase Proteins Radiation Radiation Dose Unit Radiation Dose-Response Relationship Radiation Injuries Radiation Toxicity Radiation exposure Radioactive Rattus Recombinant Proteins Recombinants Regimen Safety Saline Small Business Innovation Research Grant Small Intestines Smooth Muscle Spleen Terrorism Testing Therapeutic Thick Time Toxicokinetics War Whole-Body Irradiation acute toxicity angiogenesis animal efficacy base carcinogenicity cell bank cytokine effective therapy efficacy study gamma irradiation gastrointestinal healing immunogenicity improved intestinal barrier irradiation medical countermeasure mesenteric lymph node milk fat globule nonhuman primate novel novel therapeutics phase 1 study programs protective effect public health relevance subcutaneous treatment duration von Willebrand Factor x-ray irradiation

项目摘要

PROJECT DESCRIPTION: This SBIR Phase II proposal is intended to further develop recombinant human MFG-E8 (rhMFG-E8) as a radiation medical countermeasure (MCM) towards its approval by the FDA in the future. Nuclear terrorism and major nuclear power plant leaks can cause acute radiation injury on a large scale. Currently, there are limited drugs available to treat acute radiation syndrome (ARS). rhMFG-E8 is a secretory glycoprotein that can maintain intestinal barrier homeostasis, enhance the clearance of dying cells, and reduce inflammation. In our Phase I studies, we have shown that endogenous MFG-E8 is downregulated after radiation injury, and treatment with E. coli-expressed His-tagged rhMFG-E8 improved the survival, body weight, and intestinal integrity of rats exposed to gamma irradiation. However, E. coli-expressed His-tagged proteins are inappropriate for the use in humans. Therefore, we have generated tag-free rhMFG-E8 using human cells, significantly enhancing rhMFG-E8’s biological activities. We have shown that tag-free rhMFG-E8 significantly improved the survival, body weight, and intestinal integrity of mice exposed to X-ray irradiation. We also determined rhMFG-E8’s pharmacokinetics, possible lack of mutagenicity, and short-term (3 months) stability. Based on the above positive results, we hypothesize that human cell-expressed tag-free rhMFG-E8 can be developed as an effective and safe post-exposure mitigator of acute radiation injury. In this proposal, we will assess tag-free rhMFG-E8’s efficacy as a radiation MCM in mice with the gastrointestinal acute radiation syndrome (GI-ARS) and hematopoietic acute radiation syndrome (H-ARS). In addition, we will determine the therapeutic window and effects of reduced treatment duration after radiation exposure, as well as rhMFG-E8’s safety and potential oncogenicity and immunogenicity. These proposed studies should provide crucial information on the efficacy and safety of rhMFG-E8 as a novel radiation MCM targeting GI-ARS and combined GI- and H-ARS. Our ultimate goal is to obtain FDA approval to use rhMFG-E8 as a safe and effective treatment for victims suffering from severe ARS.

项目描述：该 SBIR II 期提案旨在开发进一步的重组人 MFG-E8 (rhMFG-E8) 作为一种辐射医疗对策 (MCM)，即将获得 FDA 批准未来，核恐怖主义和重大核电站泄漏可能会造成大量急性辐射损伤。目前，可用于治疗急性放射综合征（ARS）的药物有限。分泌性糖蛋白，可以维持肠道屏障稳态，增强垂死细胞的清除，在我们的 I 期研究中，我们发现内源性 MFG-E8 被下调。放射损伤后，用大肠杆菌表达的 His 标记的 rhMFG-E8 治疗可改善生存率、身体然而，大肠杆菌表达了组氨酸标签。蛋白质不适合在人类中使用，因此，我们使用了无标签的 rhMFG-E8。人类细胞，显着增强rhMFG-E8的生物活性我们已经证明无标签的rhMFG-E8。显着提高了接受 X 射线照射的小鼠的存活率、体重和肠道完整性。我们还确定了 rhMFG-E8 的药代动力学、可能缺乏致突变性和短期（3 个月）基于以上积极结果，我们勇敢地提出了人细胞表达的无标签rhMFG-E8。可以开发为一种有效且安全的急性辐射损伤暴露后缓解剂。我们将评估无标签 rhMFG-E8 作为放射 MCM 在患有急性胃肠道疾病的小鼠中的功效此外，我们还将了解放射综合症（GI-ARS）和造血急性放射综合症（H-ARS）。确定辐射暴露后的治疗窗和减少治疗持续时间的效果，以及由于 rhMFG-E8 的安全性以及潜在的致癌性和免疫原性，这些拟议的研究应该提供。有关 rhMFG-E8 作为一种针对 GI-ARS 的新型放射 MCM 的功效和安全性的重要信息，我们的最终目标是获得 FDA 批准使用 rhMFG-E8 作为安全且可靠的药物。为患有严重 ARS 的受害者提供有效的治疗。