PMID- 24725395
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20140418
LR  - 20211021
IS  - 2162-3619 (Print)
IS  - 2162-3619 (Electronic)
IS  - 2162-3619 (Linking)
VI  - 3
IP  - 1
DP  - 2014 Apr 11
TI  - Single low-dose rHuIL-12 safely triggers multilineage hematopoietic and 
      immune-mediated effects.
PG  - 11
LID - 10.1186/2162-3619-3-11 [doi]
AB  - BACKGROUND: Recombinant human interleukin 12 (rHuIL-12) regulates hematopoiesis 
      and cell-mediated immunity. Based on these hematopoietic and immunomodulatory 
      activities, a recombinant human IL-12 (rHuIL-12) is now under development to 
      address the unmet need for a medical countermeasure against the hematopoietic 
      syndrome of the acute radiation syndrome (HSARS) that occurs in individuals 
      exposed to lethal radiation, and also to serve as adjuvant therapy that could 
      provide dual hematopoietic and immunotherapeutic benefits in patients with cancer 
      receiving chemotherapy. We sought to demonstrate in healthy subjects the safety 
      of rHuIL-12 at single, low doses that are appropriate for use as a medical 
      countermeasure for humans exposed to lethal radiation and as an immunomodulatory 
      anti-cancer agent. METHODS: Two placebo-controlled, double-blinded studies 
      assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of 
      rHuIL-12. The first-in-human (FIH) dose-escalation study randomized subjects to 
      single subcutaneous injections of placebo or rHuIL-12 at 2, 5, 10, and 20 mug 
      doses. Due to toxicity, dose was reduced to 15 mug and then to 12 mug. The phase 1b 
      expansion study randomized subjects to the highest safe and well tolerated dose 
      of 12 mug. RESULTS: Thirty-two subjects were enrolled in the FIH study: 4 active 
      and 2 placebo at rHuIL-12 doses of 2, 5, 10, 12, and 15 mug; 1 active and 1 
      placebo at 20 mug. Sixty subjects were enrolled in the expansion study: 48 active 
      and 12 placebo at 12 mug dose of rHuIL-12. In both studies, the most common 
      adverse events (AEs) related to rHuIL-12 were headache, dizziness, and chills. No 
      immunogenicity was observed. Elimination of rHuIL-12 was biphasic, suggesting 
      significant distribution into extravascular spaces. rHuIL-12 triggered transient 
      changes in neutrophils, platelets, reticulocytes, lymphocytes, natural killer 
      cells, and CD34+ hematopoietic progenitor cells, and induced increases in 
      interferon-gamma and C-X-C motif chemokine 10. CONCLUSION: A single low dose of 
      rHuIl-12 administered subcutaneously can elicit hematological and immune-mediated 
      effects without undue toxicity. The safety and the potent multilineage 
      hematopoietic/immunologic effects triggered by low-dose rHuIL-12 support the 
      development of rHuIL-12 both as a radiation medical countermeasure and as 
      adjuvant immunotherapy for cancer. TRIAL REGISTRATION: ClinicalTrials.gov: 
      NCT01742221.
FAU - Gokhale, Mamata S
AU  - Gokhale MS
FAU - Vainstein, Vladimir
AU  - Vainstein V
FAU - Tom, Jamie
AU  - Tom J
FAU - Thomas, Simmy
AU  - Thomas S
FAU - Lawrence, Chris E
AU  - Lawrence CE
FAU - Gluzman-Poltorak, Zoya
AU  - Gluzman-Poltorak Z
FAU - Siebers, Nicholas
AU  - Siebers N
FAU - Basile, Lena A
AU  - Basile LA
AD  - Neumedicines Inc, 133 North Altadena Drive, Suite 310, 91107-7342 Pasadena, CA, 
      USA. basile@neumedicines.com.
LA  - eng
SI  - ClinicalTrials.gov/NCT01742221
PT  - Journal Article
DEP - 20140411
PL  - England
TA  - Exp Hematol Oncol
JT  - Experimental hematology & oncology
JID - 101590676
PMC - PMC3991894
EDAT- 2014/04/15 06:00
MHDA- 2014/04/15 06:01
PMCR- 2014/04/11
CRDT- 2014/04/15 06:00
PHST- 2013/12/26 00:00 [received]
PHST- 2014/04/01 00:00 [accepted]
PHST- 2014/04/15 06:00 [entrez]
PHST- 2014/04/15 06:00 [pubmed]
PHST- 2014/04/15 06:01 [medline]
PHST- 2014/04/11 00:00 [pmc-release]
AID - 2162-3619-3-11 [pii]
AID - 10.1186/2162-3619-3-11 [doi]
PST - epublish
SO  - Exp Hematol Oncol. 2014 Apr 11;3(1):11. doi: 10.1186/2162-3619-3-11.