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

用于治疗急性放射综合症的长效 IL-11 类似物

• 批准号: 7910657
• 负责人: George Norbert Cox
• 金额: $ 30万
• 依托单位: BOLDER BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-22 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7910657
• 关键词: Acute; Adopted; Amines; Anemia; Animal Model; Animals; Applications Grants; Area; Biological Assay; Blood Cells; Blood Platelets; Bone Marrow; Bone Marrow Cells; Cancer Patient; Canis familiaris; Cell Proliferation; Cells; Cessation of life; Characteristics; Chemicals; Clinical; Clinical Trials; DNA; Data; Development; Disasters; Dose; Drug Formulations; Drug Kinetics; Effectiveness; Emergency Situation; Endotoxins; Enzyme-Linked Immunosorbent Assay; Escherichia coli; FDA approved; Feedback; Goals; Government; Grant; Guidelines; Half-Life; Health Personnel; Hematopoiesis; Hematopoietic; Heterogeneity; High Pressure Liquid Chromatography; Human; In Vitro; Injection of therapeutic agent; Interleukin-11; Interleukin-3; Intestines; Investigational New Drug Application; Lead; Leukocytes; Liquid substance; Lymphopenia; Measures; Medical; Megakaryocytes; Modeling; Molecular Conformation; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Neutropenia; Nuclear; Oprelvekin; Organ; Pancytopenia; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology and Toxicology; Phase; Physicians; Polyethylene Glycols; Post-Translational Protein Processing; Procedures; Process; Production; Property; Proteins; Protocols documentation; Radiation; Radiation Syndromes; Rattus; Recovery; Regimen; Relative (related person); Research Priority; Rodent; Safety; Schedule; Site; Small Business Innovation Research Grant; Solutions; Staging; Stem cells; Subcutaneous Injections; Technology; Testing; Therapeutic; Thrombocytopenia; Time; Tissues; Toxicology; United States Food and Drug Administration; Yang; analog; analytical method; animal efficacy; animal rule; base; cell type; chemotherapy; comparative efficacy; design; efficacy trial; flasks; gastrointestinal; good laboratory practice; improved; in vivo; manufacturing process; meetings; mouse model; neutrophil; nonhuman primate; novel; pre-clinical; public health relevance; radiation effect; response

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.

描述（由申请人提供）：开发放射/核医学对策以治疗急性辐射综合征（ARS）是NIAID的一个高度优先研究领域。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照射的最初临床症状之一，通常导致死亡。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和分化为血小板。IL-11对多种其他组织发挥作用，包括肠细胞，在那里它作为一种生存因子。重组人IL-11是目前FDA批准的唯一一种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在人体中的半衰期较短，需要每天给药，并且可能无法优化蛋白质对患者的治疗益处。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，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比IL-11显著更有效。这项I期SBIR资助的主要目标是证明使用我们的新型长效IL-11类似物加速血小板恢复并提高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IL-11类似物的改进特性可以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疗法，并与现有疗法相比提高ARS患者的总生存率。 公共卫生关系：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IL-11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IL-11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率。