The online version of this article (doi:10.1186/1756-8722-7-31) contains supplementary material, which is available to authorized users.
All authors are employees of and own equity of $10,000 or more in Neumedicines, Inc. The authors declare that they have no competing interests.
ZGP designed research, performed research, collected data, analyzed and interpreted data, performed statistical analysis, and wrote the manuscript. SRM performed research, collected, analyzed and interpreted data, and wrote the manuscript. VV analyzed and interpreted data, performed statistical analysis, and wrote the manuscript. HK collected and analyzed data. LAB designed research, analyzed and interpreted data, and wrote the manuscript. All authors read and approved the final manuscript.
The 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.
In 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).
Survival 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.
Data 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.
Additional file 1: Table 1: Percentage of animals presenting with selected early clinical signs on one or more days following TBI. Figure 1. Decrease in physical activity. Figure 2. Decrease in appetite score. Figure 3. Body weight over time. Figure 4. Blood counts over time in surviving vs. non-surviving rhesus monkeys exposed to lethal TBI and treated 24 hours after TBI with either vehicle or rHuIL-12 (Average ± SEM). (DOCX 665 KB)13045_2014_383_MOESM1_ESM.docx
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- 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
Sarita R Mendonca
Lena A Basile
- BioMed Central
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