Randomized comparison of single dose of recombinant human IL-12 versus placebo for restoration of hematopoiesis and improved survival in rhesus monkeys exposed to lethal radiation

Abstract

BackgroundThe hematopoietic syndrome of the acute radiation syndrome (HSARS) is a life-threatening condition in humans exposed to total body irradiation (TBI); no drugs are approved for treating this condition. Recombinant human interleukin-12 (rHuIL-12) is being developed for HSARS mitigation under the FDA Animal Rule, where efficacy is proven in an appropriate animal model and safety is demonstrated in humans.MethodsIn this blinded study, rhesus monkeys (9 animals/sex/dose group) were randomized to receive a single subcutaneous injection of placebo (group 1) or rHuIL-12 at doses of 50, 100, 250, or 500 ng/kg (groups 2–5, respectively), without antibiotics, fluids or blood transfusions, 24–25 hours after TBI (700 cGy).ResultsSurvival rates at Day 60 were 11%, 33%, 39%, 39%, and 50% for groups 1–5, respectively (log rank p < 0.05 for each dose vs. control). rHuIL-12 also significantly reduced the incidences of severe neutropenia, severe thrombocytopenia, and sepsis (positive hemoculture). Additionally, bone marrow regeneration following TBI was significantly greater in monkeys treated with rHuIL-12 than in controls.ConclusionsData from this study demonstrate that a single injection of rHuIL-12 delivered one day after TBI can significantly increase survival and reduce radiation-induced hematopoietic toxicity and infections. These data significantly advance development of rHuIL-12 toward approval under the Animal Rule as an effective stand-alone medical countermeasure against the lethal effects of radiation exposure.

Recombinant interleukin‐12, but not granulocyte‐colony stimulating factor, improves survival in lethally irradiated nonhuman primates in the absence of supportive care: Evidence for the development of a frontline radiation medical countermeasure

“…The consistent survival benefit we have demonstrated in three randomized vehicle-controlled studies of rHuIL-12 in NHP without the use of fluids, antibiotics, or blood products supports the potential for this agent as a viable radiation medical countermeasure in the mass casualty scenario. It should be noted that the finding of numerical, but not statistical, significance for rHuIL-12 when compared to control in the prespecified log rank and two-tailed chi-square analyses in this study appears to be owing to the higher than expected survival rate in the control group (36%) at 700 cGy, compared to 11% of survival for controls in our previous NHP study that used the same radiation dose as was used in this study and which showed statistically significant survival benefit of rHuIL-12 relative to control at doses of 50, 100, 250, and 500 ng/kg [7]. Nevertheless, the totality of the data in this study demonstrates a numerical survival benefit of rHuIL-12 over both the vehicle control and a statistically significant benefit over the G-CSF control, the latter being numerically worse and statistically not different from the vehicle control.…”

“…In conclusion, the results from this randomized vehicle-controlled blinded Phase 2-equivalent study in NHP build upon the results from our proof-of-concept study [6] and a dose-escalation study of rHuIL-12 in lethally irradiated rhesus monkeys [7] by demonstrating, in a large cohort of male and female monkeys, that a single dose of rHuIL-12 alone, without antibiotics, fluids, blood products, or other growth factors, increases survival compared with a regimen of 18 consecutive days of treatment with G-CSF, the currently recommended treatment for radiation victims. These findings support the further development of rHuIL-12 under the FDA Animal Rule as a single agent to counteract the effects of HSARS in humans.…”

“…Our previous studies suggest that rHuIL-12's effect in animals exposed to TBI is mediated by an early induction of bone marrow regeneration as evidence by the presence of immature megakaryocytes and myeloid progenitors as early as 12 days after bone marrow ablation by TBI and the expression of IL-12 b2 receptors on these cells [6]. Furthermore, we have observed that both the number and the size of bone marrow regeneration islands were significantly higher in animals treated with rHuIL-12 than in controls [7]. In this study, earlier recovery of reticulocytes in rHuIL-12-treated group compared to control and G-CSF-treated groups further supports that rHuIL-12 promotes regeneration of the bone marrow.…”

“…A subsequent randomized, blinded, placebo-controlled Phase 2-equivalent study in NHP demonstrated a statistically significant survival benefit for a single subcutaneous injection of rHuIL-12 when administered 24-25 hr after lethal TBI (700cGy; LD 90/60 ) without the use of other growth factors, antibiotics, fluids, or blood products [7]. Here, we report the results from a Phase 2-level randomized, blinded, controlled study in NHPs that demonstrate significantly improved efficacy for rHuIL-12 relative to that of G-CSF, the currently recommended drug for the treatment of HSARS in victims of a radiation disaster.…”

Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34 + Human Progenitor Cells

“…We initially focused our examination on the expression of IL-12 and transforming growth factor ␤ (TGF-␤) transcripts. IL-12, a T cell-stimulating factor involved in the differentiation of naive T cells into Th1 cells, has been shown to promote hematopoiesis and stem cell engraftment after ionizing radiation (69,70). TGF-␤ is also involved in stem cell differentiation and T cell regulation/differentiation and suppresses general hema-FIG 5 HCMV-induced EGFR signaling enhances IE1 expression in primary monocytes.…”