Abstract
HemaMax, a recombinant human interleukin-12 (IL-12), is under development to address an unmet medical need for effective treatments against acute radiation syndrome due to radiological terrorism or accident when administered at least 24 hours after radiation exposure. This study investigated pharmacokinetics, pharmacodynamics, and efficacy of m-HemaMax (recombinant murine IL-12), and HemaMax to increase survival after total body irradiation (TBI) in mice and rhesus monkeys, respectively, with no supportive care. In mice, m-HemaMax at an optimal 20 ng/mouse dose significantly increased percent survival and survival time when administered 24 hours after TBI between 8–9 Gy (p<0.05 Pearson's chi-square test). This survival benefit was accompanied by increases in plasma interferon-γ (IFN-γ) and erythropoietin levels, recovery of femoral bone hematopoiesis characterized with the presence of IL-12 receptor β2 subunit–expressing myeloid progenitors, megakaryocytes, and osteoblasts. Mitigation of jejunal radiation damage was also examined. At allometrically equivalent doses, HemaMax showed similar pharmacokinetics in rhesus monkeys compared to m-HemaMax in mice, but more robustly increased plasma IFN-γ levels. HemaMax also increased plasma erythropoietin, IL-15, IL-18, and neopterin levels. At non-human primate doses pharmacologically equivalent to murine doses, HemaMax (100 ng/Kg and 250 ng/Kg) administered at 24 hours after TBI (6.7 Gy/LD50/30) significantly increased percent survival of HemaMax groups compared to vehicle (p<0.05 Pearson's chi-square test). This survival benefit was accompanied by a significantly higher leukocyte (neutrophils and lymphocytes), thrombocyte, and reticulocyte counts during nadir (days 12–14) and significantly less weight loss at day 12 compared to vehicle. These findings indicate successful interspecies dose conversion and provide proof of concept that HemaMax increases survival in irradiated rhesus monkeys by promoting hematopoiesis and recovery of immune functions and possibly gastrointestinal functions, likely through a network of interactions involving dendritic cells, osteoblasts, and soluble factors such as IL-12, IFN-γ, and cytoprotectant erythropoietin.
Highlights
Use of ionizing radiation or nuclear devices as weapons of terrorism is recognized as a major public health threat
We found that m-HemaMax was able to dramatically increase survival in mice following exposure to lethal doses of total body irradiation (TBI) when it was administered at a single, low dose, either 24 hours before or within 1 hour after radiation exposure [13,14]
Since we previously found that m-HemaMax was highly effective when administered shortly after TBI, we attempted to utilize a more stringent model of radiation exposure to investigate the ability of m-HemaMax and HemaMax to increase survival when administered at protracted time points post radiation in mice and non-human primates (NHP), respectively
Summary
Use of ionizing radiation or nuclear devices as weapons of terrorism is recognized as a major public health threat. The majority of deaths that occur from exposures of 2–10 Gy will result from the combined effects of immune, hematopoietic, and gastrointestinal (GI) failure, as these are the most radiosensitive tissues [1,2,3]. There are no FDA approved therapeutic agents capable of increasing the chance for survival by simultaneously promoting or accelerating the recovery of the immune, hematopoietic and gastrointestinal compartments following radiation injury. In the event of a radiation disaster or act of terrorism affecting a large civilian population, the goal would be to provide a potent frontline therapy that increases the chance for survival of the exposed, or potentially exposed, individuals. One of the challenges in such events is that medical care and treatments will not be available immediately following radiation exposure. It is envisioned that it will take 24 hours or more to mobilize medical teams and necessary life-saving drugs and equipment to the scene of a radiation disaster [4]
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