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

基本信息

批准号：
8049571
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
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-22 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8049571
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 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 radiation effect response

项目摘要

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（申请人提供）：开发用于治疗急性辐射综合征（ARS）的放射/核医学对策是NIAID的高优先研究领域。骨髓是辐射损伤最敏感的组织之一，造血受损是过度辐射暴露的第一个临床迹象之一，通常导致死亡。白介素11（IL-11）是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对包括肠细胞在内的多种其他组织作用，在该组织中充当生存因子。重组人IL-11是FDA目前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，并改善ARS动物模型中的总体存活率。 IL-11在人类中的半衰期短，需要每天给药，并且可能不会优化患者蛋白质的治疗益处。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，在核紧急情况下，医疗保健工作者的时间将保持溢价，并且患者的每日剂量可能很困难。我们通过用聚乙烯甘氨酸（PEG）对蛋白质的位点特异性化学修饰（PEG）开发了合理设计的长效IL-11类似物。我们的长效IL-11类似物的半衰期比未修饰的IL-11具有更长的半衰期，并且在大鼠刺激血小板形成时IL-11的强大程度要高得多。该阶段I SBIR赠款的主要目标是证明使用我们的新型长效IL-11类似物来加速血小板恢复并改善ARS小鼠模型中的生存的可行性。此外，我们将优化在GLP（良好的实验室实践）条件下生产蛋白质的过程，并测量蛋白质在辅助，GLP动物药理学和毒理学研究中的安全性和药代动力学特性，这是FDA在FDA之前所要求的测试人类中的化合物。我们新颖的IL-11类似物的提高特征可能会为医生提供更有效，更方便的治疗方法，以治疗ARS的造血和胃肠道并发症，并改善与现有疗法相比，ARS患者的总体存活率。公共卫生相关性：开发用于治疗急性辐射综合征（ARS）的放射/核医学对策是NIAID的高优先研究领域。该阶段I SBIR赠款的主要目标是证明使用新型的长效IL-11类似物来改善ARS小鼠模型中的生存的可行性。此外，我们将优化在GLP（良好的实验室实践）条件下生产蛋白质的过程，并在对人类的化合物进行测试之前，进行食品和药物管理局所需的许多GLP动物安全和毒理学研究。我们的长效IL-11模拟可能被证明可用于改善因放射线/核灾难而受到致命剂量辐射的人的生存。