PMID- 24720569
OWN - NLM
STAT- MEDLINE
DCOM- 20141110
LR  - 20211021
IS  - 2159-3345 (Electronic)
IS  - 2159-3337 (Print)
IS  - 2159-3337 (Linking)
VI  - 24
IP  - 4
DP  - 2014 Aug
TI  - Non-clinical safety studies of IMT504, a unique non-CpG oligonucleotide.
PG  - 267-82
LID - 10.1089/nat.2013.0479 [doi]
AB  - IMT504 is a non-CpG 24-mer oligodeoxynucleotide (ODN) with immunomodulatory as 
      well as tissue repair activity. IMT504 has been previously proven to be effective 
      in animal models of vaccine potency, chronic lymphocytic leukemia, tissue 
      regeneration, and sepsis. Here, we assessed the safety, including 
      pharmacokinetics and toxicity studies in rats and monkeys, of IMT504 in a single- 
      or repeated-dose administration by the subcutaneous (SC) or intravenous (IV) 
      routes. In rats, the maximum tolerated dose was determined to be 50 mg/kg when 
      administered SC. Adverse effects at 50 mg/kg were mild and reversible liver 
      injury, revealed as lobular inflammation, focal necrosis, and small changes in 
      the transaminase profile. Dose-dependent splenomegaly and lymphoid hyperplasia, 
      most probably associated with immune stimulation, were commonly observed. Rats 
      and monkeys were also IV injected with a single dose of 10 or 3.5 mg/kg, and no 
      adverse effects were observed. Rats injected IV with 10 mg/kg showed a transient 
      increase in spleen weight, together with a slight increase in the marginal zone 
      of the white pulp and in leukocyte count 2 days post-administration. In monkeys, 
      this dosage caused slight changes in total serum complement and leukocyte count 
      on day 14. No adverse effects were observed at 3.5 mg/kg IV in rats or monkeys. 
      Therefore, this dose was defined as the "no observed adverse effect level" for 
      this route. Furthermore, repeated-dose toxicity studies were performed in these 
      species using 3.5 or 0.35 mg/kg/day IV for 6 weeks. A transient increase in the 
      spleen and liver weight was observed at 3.5 mg/kg/day only in female rats. No 
      changes in clotting time and activation of the alternative complement pathway 
      were observed. The toxicity profile of IMT504 herein reported suggests a dose 
      range in which IMT504 can be used safely in clinical trials.
FAU - Franco, Raul
AU  - Franco R
AD  - 1 Immunotech S.A. , Ciudad de Buenos Aires, Argentina .
FAU - Rodriguez, Juan M
AU  - Rodriguez JM
FAU - Elias, Fernanda
AU  - Elias F
FAU - Hernando-Insua, Andres
AU  - Hernando-Insua A
FAU - Flo, Juan
AU  - Flo J
FAU - Lopez, Ricardo
AU  - Lopez R
FAU - Nagle, Carlos
AU  - Nagle C
FAU - Lago, Nestor
AU  - Lago N
FAU - Zorzopulos, Jorge
AU  - Zorzopulos J
FAU - Horn, David L
AU  - Horn DL
FAU - Montaner, Alejandro D
AU  - Montaner AD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140410
PL  - United States
TA  - Nucleic Acid Ther
JT  - Nucleic acid therapeutics
JID - 101562758
RN  - 0 (IMT504)
RN  - 0 (Immunologic Factors)
RN  - 0 (Oligodeoxyribonucleotides)
SB  - IM
MH  - Animals
MH  - Cebus
MH  - Chemical and Drug Induced Liver Injury/etiology/pathology
MH  - Dose-Response Relationship, Drug
MH  - Drug Administration Schedule
MH  - Drug Evaluation, Preclinical
MH  - Female
MH  - Immunologic Factors/pharmacokinetics/*toxicity
MH  - Inflammation/chemically induced/pathology
MH  - Injections, Intravenous
MH  - Injections, Subcutaneous
MH  - Male
MH  - Oligodeoxyribonucleotides/pharmacokinetics/*toxicity
MH  - Rats
MH  - Sex Factors
MH  - Splenomegaly/chemically induced/pathology
PMC - PMC4106379
EDAT- 2014/04/12 06:00
MHDA- 2014/11/11 06:00
PMCR- 2015/08/01
CRDT- 2014/04/12 06:00
PHST- 2014/04/12 06:00 [entrez]
PHST- 2014/04/12 06:00 [pubmed]
PHST- 2014/11/11 06:00 [medline]
PHST- 2015/08/01 00:00 [pmc-release]
AID - 10.1089/nat.2013.0479 [pii]
AID - 10.1089/nat.2013.0479 [doi]
PST - ppublish
SO  - Nucleic Acid Ther. 2014 Aug;24(4):267-82. doi: 10.1089/nat.2013.0479. Epub 2014 
      Apr 10.