Evaluating BBT-059 as a medical countermeasure to protect against hematopoietic acute radiation syndrome

Due to the increasing threat of a terrorist nuclear attack or radiation accident, development of drugs to prevent death and morbidity resulting from radiation exposure has become a high government priority. Bone marrow is one of the most radiation sensitive tissues, and subjects acutely exposed to radiation doses greater than 2 Gray develop severe neutropenia, thrombocytopenia, anemia, and lymphopenia within days to weeks of exposure (referred to as the hematopoietic acute radiation syndrome or H-ARS). Many subjects die within 30 to 60 days of radiation exposure as a result of infection (due to insufficient neutrophils) or uncontrolled bleeding (due to insufficient platelets). Currently there are no drugs approved as radiation protectants, putting military personnel and other first responders who may have to enter a radioactive emergency zone at significant risk of developing severe radiation injuries and perhaps death. BBT-059, a long-acting IL-11 analog, has proven very effective at improving survival from H-ARS when administered either prior to or following radiation exposure using a mouse H-ARS model. Improved survival correlate’s with the ability of BBT-059 to accelerate neutrophil and platelet recovery, reducing the time the animals are at risk of developing infections or bleeding episodes. BBT-059 requires only a single administration for efficacy, eliminating the need for frequent dosing and greatly simplifying its use in an emergency situation. To improve ease of use and storage, a new proprietary formulation of BBT-059 is being investigated that should be amenable to lyophilization and provide superior long term stability over a broad temperature range. This property is specifically relevant for deployed military and first responders. The two main goals of this research are to: (1) determine whether the new BBT-059 formulation is as efficacious as the original BBT-059 formulation as a radiation protectant in the mouse H-ARS model; and (2) determine whether BBT-059 is able to improve survival and/or rescue human primary bone marrow (hBM) cells from irradiation in vitro. For the mouse H-ARS efficacy study, the two BBT-059 formulations and a control solution will be administered once to mice 24h prior to LD70/30 radiation exposure and 30 day survival measured. For the in vitro hBM studies, isolated primary hBM cells will be treated with the two BBT-059 formulations and a control solution for 24 hr prior to irradiation and cell survival measured 24h post-irradiation. The ability of surviving BM cells to differentiate into different hematopoietic progenitor cell populations will be assessed using selective media. Mechanistic studies will be performed to determine the effects of BBT-059 on hBM cells at the cellular, protein, and transcript levels. These studies will lead to a novel radioprotectant that military personnel can use to protect themselves against acute radiation exposure in case of a nuclear emergency.