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

• 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
• 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

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.

抽象的。骨髓是对辐射最敏感的组织之一，患者急性暴露于总辐射 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）。少数人 已获得 FDA 批准治疗 H-ARS 的药物在 24 小时内服用可提高生存率 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。在放射性/核紧急情况下，数十万人可能会 暴露于 > 2 Gy 的辐射，并且极不可能在最初 24 小时内全部接受治疗 的辐射暴露。因此，对能够提高生存率的药物的医疗需求亟待满足 照射后 48 小时或更晚进行 H-ARS 治疗。在一项试点研究中，我们确定了一种新颖的组合 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 小时给药一次，对受辐射的小鼠进行治疗。这是我们所知的唯一药物/药物组合 当给药延迟至 TBI 后 48 小时时，能够提高生存率。 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 在高 TBI 剂量 (> 9 Gy) 下很明显。通过将 3 种蛋白质与第四种辐射缓解剂（血管紧张素）结合起来 转换酶抑制剂（ACEI），可以获得 LD95/30 TBI 小鼠 100% 30 天存活率， 前所未有的存活率。这笔 SBIR 赠款将建立在这些令人兴奋的发现的基础上，通过 (1) 确定 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 TBI 后 48 小时给药时，需要使用这些蛋白质子集来提高 30 天存活率； (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； (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 对小鼠进行照射后。其他机制研究包括在以下位置进行全血细胞分析： 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 中性粒细胞、血小板和其他外周血细胞类型。此外，我们将完成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 研究。这些 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。