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.
Hematopoietic syndrome of acute radiation syndrome (HSARS) is a life-threatening condition with no approved treatment. We compared recombinant human interleukin-12 (rHuIL-12; 175 ng/kg × 1) with vehicle, granulocyte-colony-stimulating factor (G-CSF; 10 µg/kg/day × 18), or rHuIL-12+G-CSF after lethal irradiation in rhesus monkeys in a Good Laboratory Practice, randomized, blinded, placebo-controlled study. Fluids, antibiotics, and blood products were not used. Survival at day 60 was significantly increased for rHuIL-12 versus G-CSF or vehicle. rHuIL-12/G-CSF combination provided no additional survival benefit over rHuIL-12. Both rHuIL-12 and rHuIL-12+G-CSF increased blood cell nadirs, induced earlier recovery of all hematopoietic lineages, and significantly decreased frequencies of severe cytopenias versus vehicle or G-CSF. In bone marrow, rHuIL-12 alone increased erythroid, myeloid, and megakaryocyte counts relative to vehicle or G-CSF. Thus, a single injection of rHuIL-12, without supportive medical intervention, significantly improved survival and promoted multilineage hematopoietic recovery in a nonhuman primate model of HSARS.
Neumedicines Inc, Pasadena, California.
Zoya
Z
Gluzman-Poltorak
Vladimir
V
Vainstein
Lena A
LA
Basile
D000818:Animals; D016009:Chi-Square Distribution; D004307:Dose-Response Relationship, Radiation; D004359:Drug Therapy, Combination; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000008:administration & dosage / Q000627:therapeutic use*; D008253:Macaca mulatta; D008297:Male; D010166:Palliative Care / Q000379:methods*; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D016019:Survival Analysis; D014916:Whole-Body Irradiation
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D018664:Interleukin-12; D000069585:Filgrastim