Non-clinical safety studies of IMT504, a unique non-CpG oligonucleotide.
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.
1 Immunotech S.A. , Ciudad de Buenos Aires, Argentina .
Raúl
R
Franco
Juan M
JM
Rodriguez
Fernanda
F
Elías
Andrés
A
Hernando-Insúa
Juan
J
Fló
Ricardo
R
López
Carlos
C
Nagle
Néstor
N
Lago
Jorge
J
Zorzopulos
David L
DL
Horn
Alejandro D
AD
Montaner
D000818:Animals; D002428:Cebus; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005260:Female; D007155:Immunologic Factors / Q000493:pharmacokinetics / Q000633:toxicity*; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D009838:Oligodeoxyribonucleotides / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D012737:Sex Factors; D013163:Splenomegaly / Q000139:chemically induced / Q000473:pathology
C514285:IMT504; D007155:Immunologic Factors; D009838:Oligodeoxyribonucleotides