Long-Acting G-CSF Analog for Treating ARS

用于治疗 ARS 的长效 G-CSF 类似物

基本信息

批准号：
8634011
负责人：
George Norbert Cox
金额：
$ 100万
依托单位：
BOLDER BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-08 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8634011
关键词：
Acute Adopted Affect Anemia Animal Model Animals Antibodies Applications Grants Area Biological Assay Blood Cells Blood Platelets Bone Marrow Bone Marrow Cells CSF3 gene Cancer Patient Canis familiaris Cell Proliferation Cells Cessation of life Charge Chemicals Clinical Clinical Trials Collaborations Development Disasters Disease Dose Drug Exposure Drug Formulations Drug Kinetics Effectiveness Emergency Situation Endotoxins Enzyme-Linked Immunosorbent Assay Erythrocytes Escherichia coli Escherichia coli Proteins FDA approved Fermentation Goals Gold Government Grant Granulocyte Colony-Stimulating Factor Half-Life Health Personnel Healthcare Hematopoiesis Hematopoietic High Pressure Liquid Chromatography Human Hydrophobicity In Vitro Indiana Injection of therapeutic agent Laboratories Lethal Dose 50 Lymphopenia Macaca mulatta Measures Medical Minor Modeling Morbidity - disease rate Mus NIH Program Announcements National Institute of Allergy and Infectious Disease Neutropenia Nuclear Organ Pancytopenia Patients Persons Pharmaceutical Preparations Pharmacodynamics Pharmacology and Toxicology Phase Physicians Pilot Projects Placebos Plasma Polyethylene Glycols Post-Translational Protein Processing Process Property Proteins Publishing Radiation Radiation Syndromes Rattus Recombinants Recovery Research Priority Resources Safety Sampling Site Small Business Innovation Research Grant Solutions Subcutaneous Injections Suggestion Testing Therapeutic Thrombocytopenia Time Tissues Toxicology Universities Work analog cell bank cell type chemotherapy design drug testing immunogenicity improved irradiation medical schools meetings mortality neutrophil nonhuman primate novel phase 1 study product development programs public health relevance safety study scale up

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 i 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, although the drug requires daily administration, which may not be possible following a radiological/nuclear disaster. G-CSF has a short half-life in humans, which necessitates daily dosing for two weeks or more, 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 provider time will be at a premium and daily dosing of patients may not be possible. We developed a rationally designed, long-acting G-CSF analog through site-specific chemical modification of the protein with polyethylene glycol (PEG). Our long-acting PEG-G-CSF analog has a 10-fold half-life than unmodified G-CSF and is significantly more effective than G-CSF at accelerating neutrophil recovery in chemotherapy-treated rats. Studies performed during the Phase I SBIR grant demonstrated the utility of this novel, long-acting G-CSF analog for improving survival in a well characterized mouse ARS model. In contrast to G-CSF, our long-acting G-CSF analog required only a single administration to be effective. Notably, 100% (20/20 mice) of lethally irradiated mice treated 24h post-irradiation with a single administration of this long-acting G-CSF analog survived 30 days compared to a mortality rate of 50 % (10/20 mice) for vehicle-treated mice. Our long-acting G-CSF analog also improved survival compared to placebo following multiple injections into irradiated mice. Irradiated mice treated with our long-acting G-CSF analog showed accelerated recovery of neutrophils, red blood cells and platelets compared to vehicle-treated mice, indicating that the protein positively affected recovery of multiple blood cell types. The Phase II grant has three major goals. First, we will perform additional studies in irradiated mice to determine how long after irradiation the drug can be administered and still improve survival. Second, we will determine whether the protein improves survival of lethally-irradiated non-human primates, which is the gold standard ARS model adopted by the FDA. Third, we will measure the safety profile and pharmacokinetic properties of the protein in IND-enabling, GLP animal pharmacology and toxicology studies in order to identify safe doses of the drug for testing in humans. Our novel G- CSF analog will provide physicians with an effective and convenient therapy for the treatment of all of the major hematopoietic complications of ARS, and improve survival of subjects exposed to high radiation doses as a result of a radiological/nuclear disaster. The fact that the drug requires only a single administration for effectiveness represents a significance advance in the treatment of ARS and will optimize healthcare provider time in a radiological/nuclear emergency setting, where patient numbers are expected to overwhelm available healthcare resources. The drug should prove useful for treating other diseases for which G-CSF is used as a therapy, such as neutropenia resulting from chemotherapy use in cancer patients.

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I死亡。粒细胞刺激因子（G-CSF）是一种19 kDa蛋白，可刺激骨髓细胞分裂并分化为中性粒细胞。重组人G-CSF被广泛用于治疗癌症患者的化学疗法相关性中性粒细胞减少症，最近的研究表明，尽管该药物需要日常给药，但它可以提高ARS动物模型的总体生存，这在放射学/核灾难之后可能是不可能的。 G-CSF在人类中的半衰期短，需要每天给药两周或更长时间，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G-CSF类似物可以在核紧急情况下提供显着的治疗优势，在核急诊室中，医疗保健提供者时间将保持溢价，并且可能无法每天服用患者。我们通过聚乙烯甘氨酸（PEG）对蛋白质的位点特异性化学修饰进行了合理设计的长效G-CSF类似物。我们的长效PEG-G-CSF类似物的半衰期比未修饰的G-CSF具有10倍的半衰期，并且在加速化疗治疗的大鼠中嗜中性粒细胞恢复时比G-CSF有效得多。在第一阶段进行的研究证明了这种新颖的长效G-CSF类似物的实用性，以改善特征良好的小鼠ARS模型中的生存。与G-CSF相反，我们的长效G-CSF类似物仅需要一个单一的管理才能有效。值得注意的是，100％（20/20小鼠）致命的辐照小鼠辐照后24小时治疗了这种长效的G-CSF模拟，而对车辆处理的小鼠的死亡率为50％（10/20小鼠），而死亡率为50％（10/20小鼠）。与安慰剂相比，我们的长效G-CSF类似物在对辐照小鼠进行多次注射后也提高了生存率。与媒介物处理的小鼠相比，用我们的长效G-CSF类似物治疗的辐照小鼠表明，与媒介物处理的小鼠相比，中性粒细胞，红细胞和血小板的恢复加速了，表明该蛋白质会对多种血细胞类型的恢复产生积极影响。第二阶段赠款有三个主要目标。首先，我们将在辐照小鼠中进行其他研究，以确定可以施用药物后多长时间，并仍能提高生存率。其次，我们将确定蛋白质是否改善了致命的非人类非人类灵长类动物的存活，这是FDA采用的金标准ARS模型。第三，我们将测量蛋白质的安全性和药代动力学特性，以鉴定在人类中进行测试的安全剂量，以确定该药物的安全剂量。我们的新型G-CSF模拟将为医生提供有效且方便的疗法，以治疗ARS的所有主要造血并发症，并改善因放射学/核灾难而暴露于高辐射剂量的受试者的生存。该药物仅需要一个事实有效性管理代表了ARS治疗方面的重要性，并将在放射线/核紧急情况下优化医疗保健提供者时间，预计患者人数会淹没可用的医疗保健资源。该药物应被证明可用于治疗其他G-CSF用作治疗的其他疾病，例如癌症患者化学疗法引起的中性粒细胞减少症。