PDM-608

Widespread uses of nuclear materials increase the risk of accidental or intentional radiation exposure, which can result in acute radiation syndrome (ARS). Hematopoietic ARS (H-ARS) occurs at relatively low doses and is potentially lethal without intervention. While several FDA-approved cytokine-based radiomitigators exist, many require repeated dosing, complicating deployment in mass-casualty scenarios. This study evaluated a novel long-acting, murine-reactive granulocyte–macrophage colony-stimulating factor (LA-GM-CSF; mPDM608) as a prophylactic and mitigative countermeasure for H-ARS. Male and female C57BL/6 mice were exposed to lethal or sublethal total body irradiation (TBI) and treated with LA-GM-CSF using single- or multi-dose regimens administered before or after TBI. Safety, 30-day survival, hematologic recovery, bone marrow cellularity, serum GM-CSF pharmacokinetics, endothelial injury markers, and cytokine profiles were assessed using standard hematology, histopathology, ELISA, and multiplex assays. LA-GM-CSF was well tolerated at doses up to 30 mg/kg. Single or limited dosing conferred significant survival benefits compared with vehicle controls, with optimal efficacy observed at lower doses (3 mg/kg). Post-TBI administration as a single dose 24 h after exposure markedly improved survival in both sexes, with stronger hematopoietic recovery in males. LA-GM-CSF accelerated recovery of neutrophils, red blood cells, platelets, hematocrit, and sternal megakaryocytes, prolonged circulating GM-CSF levels, and favorably modulated endothelial injury markers and select cytokines. LA-GM-CSF demonstrates strong potential as a next-generation radiation countermeasure, providing robust survival benefit and hematopoietic recovery with minimal dosing. The results shown here support further development for H-ARS management under the FDA Animal Rule.