GM-CSF analogs for treating acute radiation syndrome

用于治疗急性放射综合征的 GM-CSF 类似物

• 批准号: 7748130
• 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: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7748130
• 关键词: Acute; Adopted; Amines; Anemia; Animal Model; Animals; Applications Grants; Area; Biological Assay; Blood; Blood Cells; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cancer Patient; Canis familiaris; Cells; Cessation of life; Characteristics; Clinical; Clinical Trials; Colony-Stimulating Factors; Data; Dendritic Cells; Development; Disasters; Dose; Drug Kinetics; Effectiveness; Emergency Situation; Feedback; Goals; Government; Grant; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Guidelines; Half-Life; Health Personnel; Hematopoiesis; Hematopoietic; Heterogeneity; Human; Injection of therapeutic agent; Interleukin-3; Investigational New Drug Application; Lead; Leukocytes; Lymphopenia; Measures; Medical; Modeling; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Neutropenia; Nuclear; Organ; Pancytopenia; Patients; Personal Communication; Persons; Pharmacodynamics; Pharmacology and Toxicology; Phase; Physicians; Process; Production; Property; Proteins; Protocols documentation; Radiation; Radiation Syndromes; Rattus; Reagent; Recombinants; Recovery; Relative (related person); Research Priority; Rodent; Safety; Site; Small Business Innovation Research Grant; Solutions; Staging; Stem cell transplant; Stem cells; Technology; Testing; Therapeutic; Thrombocytopenia; Time; Tissues; Toxicology; Transplantation; Treatment Protocols; United States Food and Drug Administration; analog; animal efficacy; animal rule; base; cell type; chemotherapy; cytokine; design; efficacy testing; efficacy trial; eosinophil; flasks; good laboratory practice; improved; in vivo; irradiation; macrophage; manufacturing process; meetings; monocyte; mouse model; neutrophil; nonhuman primate; novel; patient population; pre-clinical; public health relevance; radiation effect

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 bone marrow hematopoiesis is one of the first clinical signs of excessive radiation exposure, often leading to death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a 14 kDa cytokine that stimulates bone marrow cells to divide and differentiate into neutrophils and macrophages. Recombinant human GM-CSF is used to treat chemotherapy- induced neutropenia in cancer patients and accelerate bone marrow recovery following transplantation. Recent studies suggest that hematopoietic factors such as GM-CSF can accelerate white blood cell recovery and improves survival in animal models of ARS. GM-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 GM-CSF analogs that do not require frequent dosing could provide significant treatment advantages in a nuclear emergency scenario, where healthcare worker time will be at a premium and daily dosing of patients may prove difficult. We developed a long-acting human GM-CSF analog using site-specific PEGylation technology. We also developed a murine GM-CSF analog of our lead human GM-CSF analog for testing efficacy of the protein in rodents (human GM-CSF is inactive in rodents). Our long-acting PEG-GM-CSF analog has a longer half-life than GM-CSF in rats and is significantly more effective than GM-CSF at accelerating neutrophil recovery in chemotherapy-treated rats. The primary goal of this Phase I SBIR grant is to demonstrate the feasibility of using this novel, long-acting GM-CSF analog to accelerate white blood cell recovery and improve survival in a mouse model of ARS. The murine PEG GM-CSF protein will be used for these studies. In addition we will optimize processes for manufacture of the human PEG-GM-CSF 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 long-acting GM-CSF analog may provide physicians with a more effective and more convenient therapy for the treatment of the hematopoietic complications of ARS, and improve overall survival in this patient population. 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 GM-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 GM-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，骨髓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。粒细胞巨噬细胞刺激因子（GM-CSF）是14 kDa细胞因子，可刺激骨髓细胞分裂并分化为中性粒细胞和巨噬细胞。重组人GM-CSF用于治疗癌症患者化学疗法诱导的中性粒细胞减少症，并在移植后加速骨髓恢复。最近的研究表明，造血因素（例如GM-CSF）可以加速白细胞恢复并改善ARS动物模型的生存。 GM-CSF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GM-CSF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，医护人员的时间将保持溢价，并且患者的每日给药可能很困难。我们使用特定于现场的Pegylation技术开发了长效的人GM-CSF模拟。我们还开发了一种鼠类GM-CSF类似物的鼠类GM-CSF类似物，以测试蛋白质在啮齿动物中的功效（人GM-CSF在啮齿动物中无活性）。我们的长效PEG-GM-CSF类似物的半衰期比GM-CSF在大鼠中的半衰期更长，并且在化学疗法治疗的大鼠中加速中性粒细胞恢复时，比GM-CSF有效得多。该阶段I SBIR赠款的主要目标是证明使用这种新型的，长效的GM-CSF类似物来加速白细胞恢复并改善ARS小鼠模型中的生存​​率。鼠PEG GM-CSF蛋白将用于这些研究。此外，我们还将优化在GLP（良好的实验室实践）条件下生产人PEG-GM-CSF蛋白的过程，并测量该蛋白在促进，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在对人类中进行测试之前的FDA所需的。我们长效的GM-CSF类似物的改进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的造血并发症，并改善该患者人群的总体生存率。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GM-CSF类似物来提高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GM-CSF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。