Novel drug combinations for improving survival from acute radiation syndrome when administered 48 hours post- irradiation

放射后 48 小时给药可提高急性放射综合征生存率的新型药物组合

• 批准号: 10604184
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-12 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604184
• 关键词: Acceleration; Acute; Acute-Phase Proteins; Age; Agonist; Anemia; Angiotensin-Converting Enzyme Inhibitors; Animals; Applications Grants; Awareness; Biological Assay; Biological Markers; Blood Cells; Blood Platelets; Bone Marrow; C57BL/6 Mouse; CSF3 gene; Cause of Death; Cell Count; Childhood; Clinical Trials; Dose; Drug Combinations; Drug Kinetics; Drug usage; Emergency Situation; Exposure to; FDA approved; Filgrastim; Future; GMP lots; Government; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic; Hematopoietic Cell Growth Factors; Hematopoietic stem cells; Hemorrhage; Hour; Human; Inbreeding; Individual; Infection; Inflammatory; Interleukin-1; Interleukin-11; Knowledge; Life; Lisinopril; Lymphopenia; Medical; Miniature Swine; Modeling; Mouse Strains; Mus; Neutropenia; Nuclear; Nuclear Radiology; Nuclear Warfare; Patients; Pegfilgrastim; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Plasma; Proteins; Radiation; Radiation Accidents; Radiation Dose Unit; Radiation Tolerance; Radiation Toxicity; Radiation exposure; Radiology Specialty; Recovery; Safety; Sampling; Sterility; Survival Rate; Testing; Therapeutic; Thrombocytopenia; Time; Tissues; Toxicology; Whole-Body Irradiation; chemokine; cytokine; drinking water; drug development; emergency settings; improved; irradiation; manufacture; neutrophil; nonhuman primate; novel; novel drug combination; novel therapeutics; patient population; protein structure; radiation mitigator; safety testing; sargramostim; sex; stem; stem cells; young adult

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. We demonstrated that a novel drug (PEG IL-11) and 3 drug combination including PEG IL-11 significantly improve 30d and 180d survival of LD70/30 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 in mice. When dosed once 24h or 48h post-TBI, the 3 proteins interact positively with each other to increase survival more than the individual proteins, most evident at high TBI doses. The 3 protein combination and PEG IL-11 show sex-specific survival effects, up to 100% survival at LD95/30 TBI doses, when combined with a 4th radiation mitigator, an angiotensin converting enzyme inhibitor (ACEI), an unprecedented survival rate. Most H-ARS studies to date have used inbred young adult mice. Since mouse strains and different age mice show different radiation sensitivities, the Phase 2 grant will evaluate whether these exciting findings extend to pediatric mice and outbred mice to determine whether the survival efficacy and sex-specific effects of the proteins (+/- ACEI) are universal or mouse strain / age specific. We will evaluate whether (1) PEG IL-11 and the 3 protein combination (+/- the ACEI) increase survival of pediatric and outbred mice exposed to LD70/30 radiation doses when the proteins are administered 24 and 48h post-TBI; (2) whether increased 30d survival correlates with accelerated peripheral blood cell recovery (neutrophils, platelets) and more rapid increases in hematopoietic stem and progenitor cell numbers early after irradiation; and (3) whether drug treatment and increased survival correlate with specific plasma biomarker changes. We will evaluate safety of different doses of PEG IL-1 in a mouse GLP toxicology study to identify safe doses of the drug for use in humans, and manufacture a GMP lot of the protein, both of which are required for filing an IND to begin testing the protein in humans. PEG IL-11 and TC are potential life-saving treatment options 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， 全身照射（TBI）剂量> 2戈伊会导致严重的中性粒细胞减少、血小板减少、贫血和淋巴细胞减少 在暴露后的几天到几周内，经常死于感染（由于缺乏中性粒细胞）和不受控制的 出血（血小板不足）（称为造血急性辐射综合征，或H-ARS）。为数不多 已获得FDA批准的治疗H-ARS的药物在24小时内给药可增加生存率。 辐射暴露，但在稍后时间（如辐射后48小时）给药时不会增加存活率 在动物H-ARS模型中。在辐射/核紧急情况下，数十万人可能会 暴露于> 2戈伊的辐射，并且在最初的24小时内，他们都不太可能得到治疗 辐射暴露。因此，对于能够增加存活率的药物存在关键的未满足的医疗需求 在辐照后48小时或之后给药时，来自H-ARS。我们证明了一种新型药物（PEG IL-11） PEG IL-11和3种药物联合应用可显著提高LD_（70/30）照射后30天和180天的存活率 TBI后48小时给药一次。这是我们所知道的唯一能够 当给药延迟至小鼠TBI后48小时时增加存活率。TBI后24小时或48小时给药一次， 这3种蛋白质相互作用积极，以增加生存超过个别蛋白质，大多数 在高TBI剂量下明显。3种蛋白组合和PEG IL-11显示出性别特异性存活效应， LD 95/30 TBI剂量下，当与第4种辐射缓解剂（血管紧张素转换酶）组合时，100%存活 酶抑制剂（ACEI），前所未有的生存率。迄今为止，大多数H-ARS研究都使用近交系幼仔 成年老鼠由于小鼠品系和不同年龄的小鼠表现出不同的辐射敏感性， 将评估这些令人兴奋的发现是否延伸到儿科小鼠和远系小鼠，以确定是否 蛋白质（+/- ACEI）的生存功效和性别特异性效应是普遍的或小鼠品系/年龄 特定.我们将评估（1）PEG IL-11和3种蛋白质组合（+/-ACEI）是否增加 当给予蛋白质时暴露于LD 70/30辐射剂量的儿科和远系繁殖小鼠的存活率 （2）TBI后30天生存率的增加是否与外周血细胞加速增殖有关 恢复（中性粒细胞，血小板）和造血干细胞和祖细胞数量的更快增加 照射后早期;（3）药物治疗和生存率增加是否与特定的血浆 生物标志物变化。我们将在小鼠GLP毒理学研究中评价不同剂量PEG IL-1的安全性， 确定用于人类的药物的安全剂量，并生产GMP批次的蛋白质，两者都是 申请IND以开始在人体中测试该蛋白质所需的时间。PEG IL-11和TC可能挽救生命 迄今为止无法治疗的H-ARS人群的治疗选择-直到48小时才能治疗的患者，或 在TBI之后。