Novel drugs combinations for improving survival from Acute Radiation Syndrome when administered 48h postirradiation

放射后 48 小时给药可提高急性放射综合症生存率的新型药物组合

基本信息

批准号：
9976446
负责人：
George Norbert Cox
金额：
$ 29.35万
依托单位：
BOLDER BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-12 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976446
关键词：
Acute Anemia Angiotensin-Converting Enzyme Inhibitors Animals Applications Grants Awareness Blood Cells Blood Platelets Bone Marrow Bone Marrow Stem Cell CSF3 gene Cause of Death Cell Count Cells Development Dose Drug Combinations Drug Kinetics Emergency Situation Exposure to FDA approved Filgrastim Formulation Future Government Grant Granulocyte-Macrophage Colony-Stimulating Factor Growth Factor Hematopoietic Hematopoietic Cell Growth Factors Hematopoietic stem cells Hemorrhage Hour Individual Infection Interleukin-11 Life Lisinopril Lymphopenia Measures Medical Modeling Mus National Institute of Allergy and Infectious Disease Neutropenia Nuclear Radiology Nuclear Warfare Patients Pegfilgrastim Pharmaceutical Preparations Pharmacotherapy Phase Pilot Projects Plasma Polypharmacy Positioning Attribute Program Development Proteins Radiation Radiation Accidents Radiation Dose Unit Radiation Toxicity Radiation exposure Recovery Running Savings Signal Pathway Signal Transduction Small Business Innovation Research Grant Survival Rate Therapeutic Thrombocytopenia Time Tissues Toxicology Treatment Protocols Whole-Body Irradiation cell type drinking water drug development emergency settings improved innovation irradiation liquid formulation manufacturing process medical countermeasure neutrophil novel novel drug combination patient population phase 2 study product development radiation mitigator response sargramostim stem cells

项目摘要

Abstract. Bone marrow is one of the most radiation-sensitive tissues, and patients acutely exposed to total body irradiation (TBI) doses > 2 Gy develop severe neutropenia, thrombocytopenia, anemia, and lymphopenia within days to weeks of exposure, often dying from infections (due to a lack of neutrophils) and uncontrolled bleeding (insufficient platelets) (referred to as the hematopoietic acute radiation syndrome, or H-ARS). The few drugs that have received FDA approval to treat H-ARS increase survival when administered within 24h of radiation exposure, but do not increase survival when administered at later times such as 48h post-irradiation in animal H-ARS models. In a radiological/nuclear emergency, hundreds of thousands of people potentially will be exposed to > 2 Gy radiation and it is extremely unlikely that they all can be treated within the first 24 hours of radiation exposure. Thus, there is a critical unmet medical need for drugs capable of increasing survival from H-ARS when administered 48h or later post-irradiation. In a pilot study we identified a novel combination of 3 long-acting hematopoietic growth factor proteins that significantly improves 30-day survival of LD40/30 irradiated mice when administered once 48h post-TBI. This is the only drug/drug combination we are aware of capable of increasing survival when dosing is delayed until 48h post-TBI. When dosed once 24h post-TBI, the 3 proteins interact positively with each other to increase survival more than the individual proteins, most evident at high TBI doses (> 9 Gy). By combining the 3 proteins with a 4th radiation mitigator, an angiotensin converting enzyme inhibitor (ACEI), it is possible to obtain 100% 30-d survival of LD95/30 TBI mice, an unprecedented survival rate. This SBIR grant will build upon these exciting findings by (1) determining if the 3 protein combination (+/- the ACEI) can increase survival of mice exposed to higher LD70/30 and LD90/30 radiation doses when the proteins are administered 48h post-TBI; (2) determine whether all 3 proteins or only a subset of the proteins are required for increasing 30-d survival when dosed 48h post-TBI; (3) determine whether the 3 drug combination (+/- ACEI) can improve 30-d survival when administered at even later times post-TBI, e.g., 72h; and (4) perform a pharmacokinetic and mechanistic study of the 3 proteins and the ACEI in TBI mice to measure effective plasma levels of the 3 proteins and the ACEI over time, and to determine if increased 30d survival correlates with a more rapid increase in hematopoietic progenitor cell numbers early after irradiation in the mice. Additional mechanistic studies include performing complete blood cell analyses at various times post-TBI to determine if increased 30-d survival correlates with accelerated recovery of neutrophils, platelets, and other peripheral blood cell types. In addition, we will finalize GMP manufacturing processes and identify stable liquid formulations of the 3 proteins for use in future IND-enabling studies. These studies will lead to the development of a life-saving treatment option for a heretofore untreatable H-ARS population – patients who cannot be treated until 48h or later post-TBI.

摘要：骨髓是对辐射最敏感的组织之一，患者急性暴露于总辐射中。身体照射 (TBI) 剂量 > 2 Gy 会出现严重的中性粒细胞减少症、血小板减少症、贫血和淋巴细胞减少症在接触后数天至数周内，常常因感染（由于缺乏中性粒细胞）而死亡并且不受控制出血（血小板不足）（称为造血急性放射综合征，或 H-ARS）。已获得 FDA 批准治疗 H-ARS 的药物在 24 小时内给药可提高生存率辐射暴露，但在较晚时间（例如辐射后 48 小时）施用不会增加存活率在动物 H-ARS 模型中，在放射/核紧急情况下，数十万人可能会死亡。暴露于 > 2 Gy 的辐射，并且在最初 24 小时内全部接受治疗的可能性极小因此，对于能够提高生存率的药物存在着迫切的未满足的医疗需求。在一项初步研究中，我们发现了一种新的组合，即在照射后 48 小时或更晚进行 H-ARS 治疗。 3 种长效造血生长因子蛋白可显着提高 LD40/30 的 30 天存活率 TBI 后 48 小时给予受照射的小鼠这是我们所知的唯一药物/药物组合。延迟至 TBI 后 48 小时给药时，能够提高生存率。当 TBI 后 24 小时给药一次时， 3 种蛋白质相互积极相互作用，比单个蛋白质更能提高生存率，大多数通过将 3 种蛋白质与第四种辐射缓解剂（血管紧张素）结合，在高 TBI 剂量（> 9 Gy）下效果明显。转换酶抑制剂（ACEI），可以获得 LD95/30 TBI 小鼠 100% 30 天存活率，这项 SBIR 拨款将建立在这些令人兴奋的发现的基础上，通过 (1) 确定是否 3 蛋白质组合（+/- ACEI）可以提高暴露于较高 LD70/30 和 LD90/30 的小鼠的存活率 TBI 后 48 小时施用蛋白质时的辐射剂量 (2) 确定是全部 3 种蛋白质还是仅一种蛋白质； TBI 后 48 小时给药时需要增加 30 天存活率所需的蛋白质子集 (3) 确定；更晚给药时，3 种药物组合 (+/- ACEI) 是否可以提高 30 天生存率 TBI 后，例如 72 小时；以及 (4) 对 3 种蛋白质和 ACEI 进行药代动力学和机制研究 TBI 小鼠随着时间的推移测量 3 种蛋白质和 ACEI 的有效血浆水平，并确定是否 30 天存活率的增加与早期造血祖细胞数量的更快增加相关对小鼠进行辐射后的其他机制研究包括在 TBI 后的不同时间，以确定 30 天生存率的增加是否与加速恢复相关此外，我们将完成中性粒细胞、血小板和其他外周血细胞类型的 GMP 生产。处理并确定 3 种蛋白质的稳定液体配方，用于未来的 IND 支持研究。研究将为迄今为止无法治疗的 H-ARS 开发出挽救生命的治疗方案人群——TBI 后 48 小时或更晚才能接受治疗的患者。