Non-Clinical Safety Studies of IMT504, a Unique Non-CpG Oligonucleotide

Abstract

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.

Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes

“…Furthermore, in preclinical toxicity studies, we demonstrated that IMT504 is a very safe drug (17,23). We are presently validating the effects of IMT504 in NOD mice, a spontaneous model of T1D.…”

“…of doses : 20). Glycemia was measured in tail blood samples in nonfasted conditions on days 1,6,11,17,21,26,29,32,36,41,46,53, and 66 at 11-12 AM (last IMT504 injection on day 40). Intraperitoneal glucose tolerance tests (IPGTT) were performed on day 60.…”

The Novel Immunotherapeutic Oligodeoxynucleotide IMT504 Protects Neutropenic Animals from Fatal Pseudomonas aeruginosa Bacteremia and Sepsis

“…IL-6 has long been known to serve as a predictor of outcome in experimental and human sepsis (26). The capacity to promote granulocyte-macrophage colony-stimulating factor (GM-CSF) expression by IMT504 in the presence of IL-2 might also be involved in the protection of animals from neutropenic sepsis (17). Expression of GM-CSF likely leads to increased production of granulocytes and macrophages.…”

“…Moreover, IMT504 activates CD4 and CD8 T cells and natural killer cells (NK cells and NKT cells) to promote cellular immune functions with activities against specific forms of cancer and virusinfected cells (15). In addition, preclinical studies indicate an excellent safety profile (16)(17)(18).…”

Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy

“…In addition, formulations of IMT504 are not problematic because IMT504 is highly soluble. Additionally, once injected using different routes, IMT504 has a rapid and broad distribution[364]. Moreover, because IMT504 has good thermal stability, extreme conditions of transport and storage are not necessary.…”