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：
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
项目类别：
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

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（由申请人提供）：开发治疗急性辐射综合症（ARS）的放射/核医学对策是 NIAID 的高度优先研究领域。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暴露的首要临床症状之一，通常会导致死亡。白介素 11 (IL-11) 是一种 19 kDa 的非糖基化蛋白质，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，包括作为生存因子的肠细胞。重组人IL-11是目前FDA批准用于治疗癌症患者化疗相关血小板减少症的唯一药物。最近的研究表明，IL-11 可以减轻辐射暴露引起的一些造血和胃肠道并发症，并提高 ARS 动物模型的总体生存率。 IL-11 在人体中的半衰期较短，因此需要每天给药，并且可能无法优化该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，因为在这种情况下，医护人员的时间非常宝贵，而且患者的每日给药可能会很困难。我们通过聚乙二醇 (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 更有效。该 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，我们将在 GLP（良好实验室规范）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性和药代动力学特性，这是 FDA 之前要求的。在人体中测试该化合物。我们的新型IL-11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患者的总生存期。公共健康相关性：开发治疗急性辐射综合症 (ARS) 的放射/核医学对策是 NIAID 的高度优先研究领域。 I 期 SBIR 资助的主要目标是证明使用新型长效 IL-11 类似物提高 ARS 小鼠模型存活率的可行性。此外，我们将在 GLP（良好实验室规范）条件下优化该蛋白质的制造工艺，并在人体测试该化合物之前进行美国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 IL-11 类似物可能有助于改善因放射/核灾难而暴露于致命剂量辐射的人们的生存率。