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

抽象的。骨髓是对辐射最敏感的组织之一，患者对总辐射有强烈的暴露 全身照射(TBI)剂量&gt；2Gy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 在暴露几天到几周内，通常死于感染(由于缺乏中性粒细胞)和不受控制 出血(血小板不足)(称为造血型急性辐射综合征，或称H-ARS)。为数不多的 已获得FDA批准治疗H-ARS的药物在24小时内给药可提高存活率 辐射照射，但在随后的时间给药，如照射后48小时，并不能增加存活率 在动物H-ARS模型中。在辐射/核紧急情况下，数十万人可能会 暴露在2Gy射线下，而且他们都不太可能在最初的24小时内得到治疗 暴露在辐射中。因此，对于能够提高存活率的药物存在着严重的未得到满足的医学需求。 在照射后48小时或更晚的时候给予H-ARS。我们证明了一种新药(聚乙二醇IL-11) PEGIL-11等3种药物联合应用可显著提高LD70/30照射后30d和180d的存活率 脑损伤后48小时给药一次。这是我们知道的唯一一种药物/药物组合 延长小鼠脑损伤后48小时给药后的存活率。当伤后24小时或48小时给药一次时， 这三种蛋白质相互作用比单独的蛋白质更能提高存活率，大多数 在高剂量的TBI中很明显。3种蛋白质组合和聚乙二醇IL-11显示出性别特异性的生存效应，最高可达 在LD95/30 TBI剂量下100%存活，当与第四种放射缓释剂联合使用时，血管紧张素转换 酶抑制剂(ACEI)，前所未有的存活率。到目前为止，大多数H-ARS研究都使用了近亲繁殖的幼崽 成年小鼠。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，第二阶段拨款 将评估这些令人兴奋的发现是否适用于儿科小鼠和远缘繁殖小鼠，以确定 这些蛋白(+/-ACEI)的存活效率和性别特异性效应是普遍存在的，或者是小鼠品系/年龄。 具体的。我们将评估(1)PEGIL-11和3蛋白组合(+/-ACEI)是否增加 给予蛋白质后暴露于LD70/30辐射剂量的儿童和近交系小鼠的存活率 伤后24小时和48小时；(2)30d存活率增加是否与外周血细胞加速相关 恢复(中性粒细胞、血小板)和更快地增加造血干/祖细胞数量 照射后早期；以及(3)药物治疗和延长存活率是否与特定的血浆有关 生物标记物的变化。我们将在小鼠GLP毒理学研究中评估不同剂量的PEGIL-1的安全性 确定用于人类的安全剂量的药物，并生产大量的GMP蛋白质，这两种蛋白质都是 申请IND开始在人类身上测试蛋白质所需的。聚乙二醇IL-11和TC是潜在的救命药物 迄今无法治疗的H-ARS人群的治疗选择--48小时或48小时后才能接受治疗的患者 后来在脑损伤后。

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.