A Novel Recombinant Protein for Mitigating Acute Radiation Injury

项目描述：这项SBIR第二期提案旨在进一步开发重组人 MFG-E8(rhMFG-E8)作为美国FDA批准的放射医学对策(MCM) 未来。核恐怖主义和重大核电站泄漏可在很大程度上造成急性辐射损伤 比例。目前，可用于治疗急性辐射综合征(ARS)的药物有限。RhMFG-E8是一种 分泌糖蛋白，可维持肠道屏障动态平衡，增强死亡细胞的清除， 并减少炎症。在我们的第一阶段研究中，我们已经表明内源性MFG-E8被下调 辐射损伤后，用大肠杆菌表达的hMFG-E8标记的重组人MFG-E8治疗提高了存活率，体内 大鼠的体重和肠道完整性。然而，表达His的大肠杆菌标记了 蛋白质不适合在人类身上使用。因此，我们使用以下命令生成了无标签的rhMFG-E8 人细胞，显著增强重组人MFG-E8‘S的生物学活性。我们已经证明了无标签的rhMFG-E8 显著改善X射线照射小鼠的存活率、体重和肠道完整性。 我们还测定了重组人MFG-E8‘S的药代动力学、可能的无致突变性和短期(3个月)。 稳定性。基于上述阳性结果，我们推测人细胞表达无标签的重组人MFG-E8 可被开发为一种有效和安全的急性辐射损伤后暴露后缓释剂。在这份提案中， 我们将评估无标签的重组人MFG-E8‘S作为一种放射性MCM对胃肠道急性白血病小鼠的疗效。 放射综合征(GI-ARS)和血液性急性辐射综合征(H-ARS)。此外，我们还将 确定辐射照射后缩短治疗持续时间的治疗窗口和效果 作为重组人MFG-E8‘S的安全性、潜在致瘤性和免疫原性。这些拟议的研究应该提供 重组人MFG-E8作为靶向GI-ARS的新型放射MCM的有效性和安全性的关键信息 联合使用GI-和H-ARS。我们的最终目标是获得FDA的批准，使用rhMFG-E8作为安全和 对患有严重急性呼吸综合征的患者进行有效治疗。

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.