Longitudinal Serum Proteomic Profiling of Nonhuman Primates Exposed to Total-body Gamma Radiation and Treated with BBT-059

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.