Wesolowski Radoslaw, Fish Brian L, Eibl Michael, Bähr Stella, Munjal Mehta Srishti, Czajkowski Maciej T, Gasperetti Tracy, Orschell Christie M, Asang Corinna, Singh Nikita, Himburg Heather A, Pleimes Dirk
Myelo Therapeutics GmbH, Berlin, Germany.
Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
Int J Radiat Biol. 2025;101(1):1-14. doi: 10.1080/09553002.2024.2425312. Epub 2024 Nov 12.
Repurposing therapeutic agents with existing clinical data is a common strategy for developing radiation countermeasures. IEPA (imidazolyl ethanamide pentandioic acid) is an orally bioavailable small molecule pseudopeptide with myeloprotective properties, a good clinical safety profile, and stable chemical characteristics facilitating stockpiling. Here, we evaluated IEPA's radiomitigative efficacy in the hematopoietic subsyndrome of acute radiation syndrome (H-ARS) using total-body irradiation (TBI) models in C57BL/6J mice and WAG/RijCmcr rats, applying various posology schemes and introducing syringe feeding of the IEPA formulation in the pudding. Additionally, we assessed IEPA in the delayed effects of acute radiation exposure (DEARE) model after partial-body irradiation (PBI) in WAG/RijCmcr rats. Endpoints included survival, body weight, hematology, and pulmonary parameters, depending on the model. Results from mouse and rat TBI models demonstrated survival improvements with repeated IEPA dosing at 10 mg/kg, with the largest benefits observed in the bi-daily (BID) treatment over the 30-day ARS phase in female rats. Survival across PBI-DEARE subsyndromes was comparable between IEPA and vehicle groups, though IEPA improved pulmonary parameters in female rats during the lung-DEARE phase. Sex-related differences in response to irradiation and IEPA were noted, with females showing a survival advantage. IEPA treatment is compatible with Neulasta® (Pegfilgrastim; PEG-G-CSF); adequately powered studies are needed to confirm the trend toward improved survival over standard care alone. IEPA is a promising development candidate as a medical countermeasure against the effects of acute radiation syndrome. Further confirmatory studies in small and large animal models should validate the robustness and translatability of preliminary rodent data on IEPA's radiomitigative efficacy.
将具有现有临床数据的治疗药物重新用于开发辐射防护对策是一种常见策略。IEPA（咪唑基乙酰胺戊二酸）是一种口服生物可利用的小分子假肽，具有骨髓保护特性、良好的临床安全性以及便于储存的稳定化学特性。在此，我们使用C57BL/6J小鼠和WAG/RijCmcr大鼠的全身照射（TBI）模型，应用各种给药方案并在布丁中引入IEPA制剂的灌胃给药，评估了IEPA在急性放射综合征造血亚综合征（H-ARS）中的辐射缓解效果。此外，我们在WAG/RijCmcr大鼠的局部照射（PBI）后的急性辐射暴露延迟效应（DEARE）模型中评估了IEPA。根据模型不同，终点指标包括存活率、体重、血液学指标和肺部参数。小鼠和大鼠TBI模型的结果表明，以10mg/kg重复给予IEPA可提高存活率，在雌性大鼠30天的ARS阶段，每日两次（BID）治疗的益处最大。在PBI-DEARE亚综合征中，IEPA组和赋形剂组的存活率相当，不过在肺部DEARE阶段，IEPA改善了雌性大鼠的肺部参数。注意到辐射和IEPA反应存在性别相关差异，雌性具有生存优势。IEPA治疗与Neulasta®（聚乙二醇化重组人粒细胞刺激因子；PEG-G-CSF）兼容；需要进行充分有力的研究来证实与单独标准治疗相比生存率提高的趋势。IEPA作为对抗急性放射综合征影响的医学对策是一个有前景的开发候选药物。在小型和大型动物模型中进行的进一步验证性研究应验证关于IEPA辐射缓解效果的初步啮齿动物数据的稳健性和可转化性。
