Long-Acting G-CSF analogs for treating acute radiation syndrome

描述(由申请人提供)： 开发治疗急性辐射综合征(ARS)的放射/核医学对策是NIAID的一个高度优先的研究领域。骨髓是对辐射损伤最敏感的组织之一，而造血功能受损是过度辐射暴露的首批临床迹象之一，通常会导致死亡。粒细胞集落刺激因子(G-CSF)是一种19 kDa的蛋白质，能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化疗相关的中性粒细胞减少症，最近的研究表明，它可以提高ARS动物模型的总存活率。G-CSF在人类体内的半衰期很短，这需要每天服用，而且可能不会优化这种蛋白质对患者的治疗效果。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著的治疗优势，在这种情况下，医护人员的时间将非常宝贵，患者的日常剂量可能被证明是困难的。我们开发了合理设计的长效G-CSF类似物，通过用聚乙二醇(PEG)对蛋白质进行定点化学修饰。我们的长效PEG-G-CSF类似物比未经修饰的G-CSF有更长的半衰期，并且在促进化疗大鼠中性粒细胞恢复方面明显比G-CSF有效。我们的位点特异性的聚乙二醇化的G-CSF类似物在中性粒细胞减少的大鼠中比领先的商用聚乙二醇化的G-CSF产品更有效。这项第一阶段SBIR赠款的主要目标是证明使用我们的新型、长效G-CSF类似物来加速中性粒细胞恢复和改善ARS小鼠模型的存活率的可行性。此外，我们将在GLP(良好实验室实践)条件下优化蛋白质的制造工艺，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概况和药代动力学特性，这是FDA在人体上测试化合物之前所要求的。我们新的G-CSF类似物的改进特性可能为医生提供一种更有效、更方便的治疗ARS造血并发症的方法，与现有的治疗方法相比，可以提高ARS患者的总体存活率。公共卫生相关性：制定治疗急性辐射综合征(ARS)的放射/核医学对策是NIAID的高度优先研究领域。这一第一阶段SBIR赠款的主要目标是证明使用一种新的、长效的G-CSF类似物来提高ARS小鼠模型的存活率的可行性。此外，我们将优化在GLP(良好实验室实践)条件下生产蛋白质的工艺，并在对化合物进行人体试验之前执行食品和药物管理局要求的许多GLP动物安全和毒理学研究。我们的长效G-CSF类似物可能被证明有助于提高因辐射/核灾难而暴露于否则致命剂量的辐射的人的存活率。

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 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.