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（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中与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，尽管该药物需要每日给药，而这在放射/核检查后可能是不可能的。灾难。 G-CSF 在人体中的半衰期很短，因此需要每天给药两周或更长时间，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，在这种情况下，医疗保健提供者的时间将非常宝贵，并且可能无法每天给患者给药。我们通过聚乙二醇 (PEG) 对蛋白质进行位点特异性化学修饰，开发了一种设计合理、长效的 G-CSF 类似物。我们的长效 PEG-G-CSF 类似物的半衰期是未修饰的 G-CSF 的 10 倍，并且在加速化疗大鼠中性粒细胞恢复方面比 G-CSF 更有效。在 I 期 SBIR 资助期间进行的研究证明了这种新型长效 G-CSF 类似物在改善特征明确的小鼠 ARS 模型中的存活率方面的实用性。与 G-CSF 相比，我们的长效 G-CSF 类似物只需单次给药即可有效。值得注意的是，单次给予这种长效 G-CSF 类似物的致命照射后 24 小时，100%（20/20 小鼠）的致命照射小鼠存活了 30 天，而接受致命照射的小鼠的死亡率为 50%（10/20 小鼠）。媒介物处理的小鼠。与安慰剂相比，我们的长效 G-CSF 类似物在多次注射到受辐射的小鼠体内后也提高了存活率。与用媒介物治疗的小鼠相比，用我们的长效 G-CSF 类似物治疗的受辐射小鼠显示出中性粒细胞、红细胞和血小板的加速恢复，表明该蛋白质对多种血细胞类型的恢复有积极影响。第二阶段拨款有三个主要目标。首先，我们将对受辐射的小鼠进行额外的研究，以确定在辐射后多长时间可以施用药物并仍然提高存活率。其次，我们将确定该蛋白质是否可以提高经过致命辐射的非人类灵长类动物的生存率，这是 FDA 采用的金标准 ARS 模型。第三，我们将在支持 IND 的 GLP 动物药理学和毒理学研究中测量该蛋白质的安全性和药代动力学特性，以确定用于人体测试的药物的安全剂量。我们的新型 G-CSF 类似物将为医生提供一种有效且方便的疗法，用于治疗 ARS 的所有主要造血并发症，并提高因放射/核灾难而暴露于高辐射剂量的受试者的生存率。事实上，该药物只需要一个有效管理代表了 ARS 治疗的重大进步，并将优化医疗保健提供者在放射/核紧急情况下的时间，在这种情况下，患者数量预计会超过现有的医疗资源。该药物应该可用于治疗其他使用 G-CSF 治疗的疾病，例如癌症患者化疗引起的中性粒细胞减少症。