GM-CSF analogs for treating acute radiation syndrome

描述（由申请人提供）： 放射/核医学对策的发展，以治疗急性辐射综合征（ARS）是一个高度优先的研究领域NIAID。骨髓是对辐射损伤最敏感的组织之一，骨髓造血功能受损是过度辐射暴露的最初临床体征之一，通常导致死亡。粒细胞-巨噬细胞集落刺激因子（GM-CSF）是一种14 kDa的细胞因子，可刺激骨髓细胞分裂和分化为中性粒细胞和巨噬细胞。重组人GM-CSF用于治疗癌症患者中化疗诱导的中性粒细胞减少症并加速移植后的骨髓恢复。最近的研究表明，造血因子如GM-CSF可以加速白色血细胞的恢复，并提高ARS动物模型的存活率。GM-CSF在人体中的半衰期较短，需要每天给药，并且可能无法优化该蛋白质对患者的治疗益处。不需要频繁给药的长效GM-CSF类似物可以在核紧急情况下提供显著的治疗优势，其中医护人员的时间将非常宝贵，并且患者的每日给药可能被证明是困难的。我们开发了一种长效的人GM-CSF类似物使用位点特异性聚乙二醇化技术。我们还开发了我们的主要人GM-CSF类似物的鼠GM-CSF类似物，用于测试蛋白质在啮齿动物中的功效（人GM-CSF在啮齿动物中无活性）。我们的长效PEG-GM-CSF类似物在大鼠中具有比GM-CSF更长的半衰期，并且在加速化疗治疗的大鼠中的中性粒细胞恢复方面比GM-CSF显著更有效。SBIR第一阶段资助的主要目的是证明使用这种新型长效GM-CSF类似物加速白色血细胞恢复和提高ARS小鼠模型存活率的可行性。这些研究将使用鼠PEG GM-CSF蛋白。此外，我们将在GLP（药物非临床研究质量管理规范）条件下优化人PEG-GM-CSF蛋白质的生产工艺，并在IND启动、GLP动物药理学和毒理学研究中测量蛋白质的安全性和药代动力学特性，这是FDA在人体中测试化合物之前要求的。我们的长效GM-CSF类似物的改进特性可能为医生提供更有效和更方便的治疗ARS造血并发症的疗法，并提高该患者群体的总生存率。公共卫生相关性：放射/核医学对策的发展，以治疗急性辐射综合征（ARS）是一个高度优先的研究领域NIAID。SBIR第一阶段资助的主要目标是证明使用新型长效GM-CSF类似物改善ARS小鼠模型存活率的可行性。此外，我们还将在GLP（良好实验室规范）条件下优化蛋白质的生产工艺，并在人体测试该化合物之前进行食品和药物管理局要求的许多GLP动物安全性和毒理学研究。我们的长效GM-CSF类似物可能被证明有助于提高因辐射/核灾难而暴露于致命剂量辐射的人的生存率。

DESCRIPTION (provided by applicant): Development of radiological/nuclear medical countermeasures to treat Acute Radiation Syndrome (ARS) is a high priority research area for NIAID. Bone marrow is one of the most sensitive tissues to radiation damage and impaired bone marrow hematopoiesis is one of the first clinical signs of excessive radiation exposure, often leading to death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a 14 kDa cytokine that stimulates bone marrow cells to divide and differentiate into neutrophils and macrophages. Recombinant human GM-CSF is used to treat chemotherapy- induced neutropenia in cancer patients and accelerate bone marrow recovery following transplantation. Recent studies suggest that hematopoietic factors such as GM-CSF can accelerate white blood cell recovery and improves survival in animal models of ARS. GM-CSF has a short half-life in humans, which necessitates daily dosing, and may not optimize therapeutic benefits of the protein for patients. Long-acting GM-CSF analogs that do not require frequent dosing could provide significant treatment advantages in a nuclear emergency scenario, where healthcare worker time will be at a premium and daily dosing of patients may prove difficult. We developed a long-acting human GM-CSF analog using site-specific PEGylation technology. We also developed a murine GM-CSF analog of our lead human GM-CSF analog for testing efficacy of the protein in rodents (human GM-CSF is inactive in rodents). Our long-acting PEG-GM-CSF analog has a longer half-life than GM-CSF in rats and is significantly more effective than GM-CSF at accelerating neutrophil recovery in chemotherapy-treated rats. The primary goal of this Phase I SBIR grant is to demonstrate the feasibility of using this novel, long-acting GM-CSF analog to accelerate white blood cell recovery and improve survival in a mouse model of ARS. The murine PEG GM-CSF protein will be used for these studies. In addition we will optimize processes for manufacture of the human PEG-GM-CSF protein under GLP (Good Laboratory Practices) conditions and measure the safety profile and pharmacokinetic properties of the protein in IND- enabling, GLP animal pharmacology and toxicology studies, which are required by the FDA prior to testing the compound in humans. The improved characteristics of our long-acting GM-CSF analog may provide physicians with a more effective and more convenient therapy for the treatment of the hematopoietic complications of ARS, and improve overall survival in this patient population. PUBLIC HEALTH RELEVANCE: Development of radiological/nuclear medical countermeasures to treat Acute Radiation Syndrome (ARS) is a high priority research area for NIAID. The primary goal of this Phase I SBIR grant is to demonstrate the feasibility of using a novel, long-acting GM-CSF analog to improve survival in a mouse model of ARS. In addition we will optimize processes for manufacture of the protein under GLP (Good Laboratory Practices) conditions and perform many of the GLP animal safety and toxicology studies required by the Food and Drug Administration prior to testing the compound in humans. Our long-acting GM-CSF analog may prove useful for improving survival in people exposed to an otherwise lethal dose of radiation as a result of a radiological/nuclear disaster.