TO-207 Mitigates Radiation-Induced Hematopoietic Injury in a Murine Model of Lethal Total-Body Irradiation.

INTRODUCTION

Ionizing radiation exposure can cause acute radiation syndrome (ARS) with life-threatening multi-organ damage. Although several hematopoietic growth factors are FDA-approved as radiation countermeasures, alternative strategies that target inflammatory mechanisms remain urgently needed. TO-207, formerly known as JTE-607, is a selective multi-cytokine inhibitor that suppresses pro-inflammatory cytokine secretion in human monocytes and macrophages. TO-207 represents a mechanistically distinct radiation mitigator; however, whether it suppresses the acute post-irradiation cytokine surge in vivo has not yet been directly demonstrated and remains to be confirmed in future studies.

MATERIALS AND

METHODS

Male CD2F1 mice were exposed to lethal total-body irradiation (TBI, 9.0 Gy, LD70/30). Mice received TO-207 (100 mg/kg, s.c.) or vehicle once daily for 3 consecutive days, starting at 24 hours after irradiation. Outcomes included 30-day survival, peripheral blood recovery, bone marrow clonogenic capacity, and serum cytokine profiling.

RESULTS

TO-207 treatment improved survival to 65% compared to 45% in vehicle controls. Hematopoietic recovery was enhanced, with significant increases in colony-forming unit-granulocyte/macrophage (CFU-GM) and higher circulating monocyte counts on day 30. Serum cytokine profiling on day 30 revealed that 3 of 44 cytokines (G-CSF, KC, TNF-α) showed nominally significant differences between groups; however, none remained significant after Benjamini-Hochberg correction for multiple comparisons. These day-30 cytokine observations are exploratory and reflect patterns of altered immune reconstitution rather than direct evidence of acute cytokine suppression.

CONCLUSIONS

TO-207 significantly mitigated hematopoietic injury and improved survival when administered 24 hours after lethal irradiation. These findings highlight TO-207 as a promising candidate for development as a medical countermeasure for ARS. Future studies incorporating early cytokine time points, dose optimization, and both sexes are needed to substantiate the mechanistic hypothesis and maximize translational impact.