Long-Acting IL-11 Analog for Treating Acute Radiation Syndrome

描述（申请人提供）：发展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，造血功能受损是过度辐射暴露的首要临床症状之一，往往导致死亡。白细胞介素-11 （IL-11）是一种19 kDa的非糖基化蛋白，可刺激骨髓细胞分裂并分化为血小板。IL-11对多种其他组织产生影响，包括肠细胞，在肠细胞中它作为一种生存因子。重组人IL-11是目前唯一被FDA批准用于治疗癌症患者化疗相关血小板减少症的药物。最近的研究表明，IL-11可以减轻辐射暴露的一些造血和胃肠道并发症，并提高ARS动物模型的总生存率。IL-11在人体内的半衰期很短，因此需要每天给药，并且可能无法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IL-11类似物可以在核紧急情况下提供显着的治疗优势，在这种情况下，医护人员的时间将是宝贵的，并且患者的每日给药可能证明是困难的。我们通过聚乙二醇（PEG）对IL-11蛋白进行位点特异性化学修饰，开发出合理设计的长效IL-11类似物。我们的长效IL-11类似物比未修饰的IL-11具有更长的半衰期，并且在刺激大鼠血小板形成方面明显比IL-11更有效。这项I期SBIR拨款的主要目标是证明在ARS小鼠模型中使用我们的新型长效IL-11类似物加速血小板恢复和提高生存率的可行性。此外，我们将在良好实验室规范（GLP）条件下优化蛋白质的生产工艺，并在IND-enabling、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在人体测试该化合物之前所要求的。我们的新型IL-11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的造血和胃肠道并发症的方法，并且与现有疗法相比，提高ARS患者的总生存率。

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 hematopoiesis is one of the first clinical signs of excessive radiation exposure, often resulting in death. Interleukin-11 (IL-11) is a 19 kDa, non-glycosylated protein that stimulates bone marrow cells to divide and differentiate into platelets. IL-11 exerts effects on a variety of additional tissues, including intestinal cells, where it acts as a survival factor. Recombinant human IL-11 is the only drug currently approved by the FDA to treat chemotherapy- related thrombocytopenia in cancer patients. Recent studies indicate that IL-11 can mitigate some of the hematopoietic and gastrointestinal complications of radiation exposure, and improve overall survival in animal models of ARS. IL-11 has a short half-life in humans, which necessitates daily dosing, and may not optimize therapeutic benefits of the protein for patients. Long-acting IL-11 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 IL-11 analogs through site-specific chemical modification of the protein with polyethylene glycol (PEG). Our long-acting IL-11 analog has a longer half-life than unmodified IL-11 and is significantly more potent than IL-11 at stimulating platelet formation in rats. The primary goal of this Phase I SBIR grant is to demonstrate the feasibility of using our novel, long-acting IL-11 analog to accelerate platelet 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 IL-11 analog may provide physicians with a more effective and more convenient therapy for the treatment of the hematopoietic and gastrointestinal complications of ARS, and 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 IL-11 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 IL-11 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.