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.
BACKGROUND
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Zoya
Z
Gluzman-Poltorak
Sarita R
SR
Mendonca
Vladimir
V
Vainstein
Hue
H
Kha
Neumedicines Inc,, 133 North Altadena Drive, Suite 310, 91107 Pasadena, CA, USA. basile@neumedicines.com.
Lena A
LA
Basile
D000818:Animals; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D011833:Radiation Injuries, Experimental / Q000097:blood* / Q000188:drug therapy*; D011897:Random Allocation; D011994:Recombinant Proteins / Q000494:pharmacology; D015996:Survival Rate; D014916:Whole-Body Irradiation
D011994:Recombinant Proteins; D018664:Interleukin-12