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

用于治疗急性放射综合征的长效 G-CSF 类似物

基本信息

批准号：
7748113
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：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7748113
关键词：
Acute Adopted Amines Anemia Animal Model Animals Applications Grants Area Biological Assay Blood Cells Bone Marrow Bone Marrow Cells Bone Marrow Transplantation 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 Feedback Filgrastim Goals Government Grant Granulocyte Colony-Stimulating Factor Guidelines Half-Life Health Personnel Hematopoiesis Hematopoietic Heterogeneity High Pressure Liquid Chromatography Human In Vitro Injection of therapeutic agent Interleukin-3 Investigational New Drug Application Lead Leukocytes Liquid substance Lymphopenia Measures Medical Modeling Molecular Conformation Morbidity - disease rate Mus National Institute of Allergy and Infectious Disease Neutropenia Nuclear Organ Pancytopenia Patients Pegfilgrastim Persons Pharmacodynamics Pharmacology and Toxicology Phase Physicians Polyethylene Glycols Post-Translational Protein Processing Procedures Process Production Property Proteins Protocols documentation Radiation Radiation Syndromes Rattus Recombinant Granulocyte Colony Stimulating Factor Recombinants Recovery 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 Treatment Protocols United States Food and Drug Administration analog analytical method animal efficacy animal rule base cell type chemotherapy comparative efficacy design efficacy trial flasks good laboratory practice granulocyte improved in vivo manufacturing process meetings mouse model neutrophil nonhuman primate novel pre-clinical public health relevance radiation effect

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. 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.

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。粒细胞集落刺激因子 (G-CSF) 是一种 19 kDa 的蛋白质，可刺激骨髓细胞分裂并分化为中性粒细胞。重组人 G-CSF 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 动物模型的总体生存率。 G-CSF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 G-CSF 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，开发了设计合理的长效 G-CSF 类似物。我们的长效 PEG-G-CSF 类似物比未修饰的 G-CSF 具有更长的半衰期，并且在加速化疗大鼠中性粒细胞恢复方面比 G-CSF 更有效。我们的位点特异性聚乙二醇化 G-CSF 类似物在中性粒细胞减少大鼠中比领先的商业聚乙二醇化 G-CSF 产品更有效。 I 期 SBIR 资助的主要目标是证明使用我们的新型长效 G-CSF 类似物加速中性粒细胞恢复并提高 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 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 造血并发症的疗法，与现有疗法相比，可以提高 ARS 患者的总体生存率。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 G-CSF 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 G-CSF 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。