Longitudinal Serum Proteomic Profiling of Nonhuman Primates Exposed to Total-body Gamma Radiation and Treated with...

Several radiation medical countermeasures (MCMs) are currently approved by the United States Food and Drug Administration (US FDA) for the mitigation of hematopoietic acute radiation syndrome (H-ARS). Continued development of additional candidates remains a priority to enhance force protection capabilities, combat readiness, and operational preparedness in nuclear/radiological threat environments. One such candidate under development is BBT-059, a long-acting PEGylated interleukin-11 (IL-11) analog with known hematopoietic-promoting and anti-apoptotic properties. BBT-059 is under advanced development as a potential radiation MCM for H-ARS and has been shown to improve survival in lethally irradiated murine models; however, its proteomic responses after irradiation have not been fully characterized in nonhuman primates (NHPs). In this study, NHPs exposed to 4 Gy total-body gamma radiation were subsequently treated with a single subcutaneous dose of either 37.5 or 75 µg/kg of BBT-059 at 24 h postirradiation, and longitudinal serum proteomic profiling was performed using a mass spectrometry (MS)-based approach. Proteomic changes were compared to baseline levels to comprehensively identify time-dependent changes induced by irradiation and BBT-059 administration. These analyses revealed changes in proteins related to inflammation, innate immune activation, and hematological and platelet functions, which peaked at days 2 and 4 and gradually decreased to near baseline levels by the end of the study. Pathway enrichment analysis identified consistent activation of neutrophil degranulation, platelet degranulation, insulin-like growth factor transport, and calcium signaling pathways.