Proteomic Studies in Rhesus Nonhuman Primates Administered a Promising Radiation Medical Countermeasure under Development, BBT-059.

BBT-059 is a long-acting PEGylated interleukin-11 (IL-11) analog that is believed to have hematopoietic-promoting and anti-apoptotic properties, making it an ideal candidate for further development as a potential radiation medical countermeasure (MCM) for the hematopoietic acute radiation syndrome (H-ARS). The efficacy of BBT-059 has been previously established in an H-ARS murine model and in a nonhuman primate (NHP) model through pharmacokinetic and pharmacodynamic (PK/PD) studies. In the current study, a total of 12 naïve NHPs (rhesus macaques) were administered a single 37.5 µg/kg, 75 µg/kg, or 150 µg/kg dose of BBT-059 (n = 4 animals per group) subcutaneously and monitored for 21 days post-administration. To further evaluate the safety profile of BBT-059 and better understand its mechanism of action, proteomic analyses were performed to assess the impact of BBT-059 on proteins, pathways, and any dose-dependent differences. Blood samples were collected and serum was isolated and analyzed using trapped ion mobility time-of-flight mass spectrometry (timsTOF-MS). Statistically significant time-dependent changes were present in all dose groups when comparing pre-administration to post-administration samples, peaking around 3 days post-administration and reverting to near-normal levels by the end of the study period. Any dose of BBT-059 triggered a robust, acute-phase proteomic response characterized by an increase in platelet and neutrophil counts, elevated IL-6 expression, and an activation of the neutrophil degranulation and platelet activation, signaling and aggregation pathways. Taken together, these observations suggest that BBT-059 has a good safety profile for further development as a radiation MCM.