A Novel Recombinant Protein for Mitigating Acute Radiation Injury

项目描述：本SBIR II期提案旨在进一步开发重组人 MFG-E8（rhMFG-E8）作为一种辐射医疗对策（MCM），以获得FDA的批准， 未来核恐怖主义和重大核电站泄漏可造成大面积的急性辐射损伤， 规模目前，可用于治疗急性放射综合征（ARS）的药物有限。rhMFG-E8是一种 分泌性糖蛋白，可维持肠屏障稳态，增强垂死细胞的清除， 减少炎症。在我们的I期研究中，我们已经表明内源性MFG-E8被下调， 放射损伤后，用E.大肠杆菌表达的His标记的rhMFG-E8提高了存活率， 体重和肠道完整性。而E.大肠杆菌表达的His标记的 蛋白质不适合用于人类。因此，我们使用以下方法产生了无标签的rhMFG-E8： 人细胞，显著增强rhMFG-E8的生物活性。我们已经表明，无标签rhMFG-E8 显著改善了暴露于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，以及短期（3个月） 稳定基于上述阳性结果，我们假设人细胞表达的无标签rhMFG-E8 可开发为急性辐射损伤的有效和安全的暴露后缓解剂。在这一提议中， 我们将评估无标签rhMFG-E8作为放射MCM在患有胃肠道急性炎症的小鼠中的功效。 放射综合征（GI-ARS）和造血急性放射综合征（H-ARS）。此外，我们将 确定治疗窗口和辐射暴露后减少治疗持续时间的影响，以及 rhMFG-E8的安全性、潜在的致瘤性和免疫原性。这些拟议的研究应提供 关于rhMFG-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， GI和H-ARS的组合。我们的最终目标是获得FDA的批准，使用rhMFG-E8作为一种安全， 为患有严重急性呼吸窘迫综合征的受害者提供有效治疗。

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.