Long-Acting G-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，造血功能受损是过度辐射照射的最初临床症状之一，通常导致死亡。粒细胞集落刺激因子（G-CSF）是一种19 kDa的蛋白质，可刺激骨髓细胞分裂和分化为中性粒细胞。重组人G-CSF被广泛用于治疗癌症患者的化疗相关中性粒细胞减少症，最近的研究表明，它提高了ARS动物模型的总生存率。G-CSF在人体内的半衰期较短，需要每日给药，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G-CSF类似物可以在核紧急情况下提供显着的治疗优势，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很困难。我们通过用聚乙二醇（PEG）对蛋白质进行位点特异性化学修饰，开发了合理设计的长效G-CSF类似物。我们的长效PEG-G-CSF类似物比未修饰的G-CSF具有更长的半衰期，并且在加速化疗治疗的大鼠中的中性粒细胞恢复方面比G-CSF显著更有效。我们的位点特异性聚乙二醇化G-CSF类似物在血小板减少大鼠中比领先的商业聚乙二醇化G-CSF产品更有效。这项I期SBIR资助的主要目标是证明使用我们的新型长效G-CSF类似物加速中性粒细胞恢复并提高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IND启用、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在人体测试化合物之前所要求的。我们的新型G-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，与现有疗法相比，提高ARS患者的总生存率。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。这项SBIR资助的主要目标是证明使用新型长效G-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G-CSF类似物可能被证明可用于改善因辐射/核灾难而暴露于致命剂量辐射的人的生存。

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 hematopoiesis is one of the first clinical signs of excessive radiation exposure, often resulting in death. Granulocyte colony-stimulating factor (G-CSF) is a 19 kDa protein that stimulates bone marrow cells to divide and differentiate into neutrophils. Recombinant human G-CSF is widely used to treat chemotherapy-related neutropenia in cancer patients, and recent studies indicate that it improves overall survival in animal models of ARS. G- 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 G-CSF analogs that do not require frequent dosing could provide significant treatment advantages in a nuclear emergency setting, where healthcare worker time will be at a premium and daily dosing of patients may prove difficult. We developed rationally designed, long-acting G-CSF analogs through site-specific chemical modification of the protein with polyethylene glycol (PEG). Our long-acting PEG-G-CSF analog has a longer half-life than unmodified G-CSF and is significantly more effective than G-CSF at accelerating neutrophil recovery in chemotherapy-treated rats. Our site-specific PEGylated G-CSF analog was more potent than the leading commercial PEGylated G-CSF product in neutropenic rats. The primary goal of this Phase I SBIR grant is to demonstrate the feasibility of using our novel, long-acting G-CSF analog to accelerate neutrophil recovery and 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 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 novel G-CSF analog may provide physicians with a more effective and more convenient therapy for the treatment of the hematopoietic complications of ARS, an improve overall survival in ARS patients compared to existing therapies. 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 G-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 G-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.