LA-GM-CSF, a Long-Acting Cytokine Mitigates and Prevents H-ARS Mediated Lethality in Mice Exposed to Total Body Gamma Radiation

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.