THU0047 IA-14069, A NOVEL SMALL-MOLECULE INHIBITOR DIRECT-TARGETING TUMOR NECROSIS FACTOR-α, ATTENUATES COLLAGEN INDUCED ARTHRITIS

Background:

Rheumatoid arthritis (RA) is systemic autoimmune disease that is characterized by autoreactive immune cells and various cytokines-mediated inflammation in multiple joints, leading to cartilage degradation, bone erosion and finally irreversible joint destruction¹. The inflammatory cytokine tumor necrosis factor-α (TNF-α) is known to play a central role in several chronic immune-mediated inflammatory disorders².

Objectives:

Despite the great success of anti-TNF-α biological drugs in the treatment of RA, no chemical drug targeting TNF-α is available. Here we report that IA-14069, a novel small molecule inhibitor, binds directly to TNF-α and inhibits TNF-α activities both in vitro and in vivo.

Methods:

IA-14069 was screened and identified by competitive binding assay using TNF-α and TNF receptor. In vitro neutralization activity of IA-14069 against TNF-α was determined using MTT assay. The direct binding IA-14069 to TNF-α was demonstrated by surface plasmon resonance and bead pull-down assays. The inhibition of TNF-α-TNFR interactions by direct binding of IA-14069 to TNF-α was analyzed by flow cytometry. Levels of phosphorylated IκBα (p-IκBα) and NF-κB p65 were analyzed by western blot. IA-14069 was orally administrated to TNF-α-transgenic (TNF-α-TG) RA mice at 3.3 or 33 mg/kg twice per week or at 25, 50 or 100 mg/kg 3 times per week for preventive or therapeutic effect, respectively. In vivo therapeutic efficacy of IA-14069 or methotrexate was evaluated in collagen-induced arthritis (CIA) mice immunized with bovine type II collagen (CII) emulsified in complete Freund's adjuvant, and boosted with CII emulsified in incomplete Freund's adjuvant.

Results:

IA-14069 potently inhibits both TNF-α-induced cytotoxicity (IC₅₀ < 0.7 μM) which directly binds to TNF-α and TNF-α-triggered signaling (p-IκBα and NF-κB p65) activities. The therapeutic as well as preventive anti-RA effects of IA-14069 were demonstrated in TNF-α-TG and CIA models. IA-14069 and MTX had synergistic effects in the CIA therapeutic model. According to pharmacokinetic analysis, IA-14069 showed significant bioavailability. In addition, no in vivo toxicity was observed even under treatment of excessive amount of IA-14069.

Conclusion:

The data indicate that IA-14069 can be a novel and potential TNF-α inhibitor for the treatment of RA and other inflammatory diseases.

References:

[1] Choy EH, et al. N Engl J Med. 2001;344:907-16. [2] Wong M, et al. Clin Immunol. 2008;126:121-36.

Disclosure of Interests:

Sung-Dong Park Employee of: MOGAM Institute for Biomedical Research, Hyung Gun Maeng: None declared, Yeon-Hwa Park: None declared, Kye-Jung Shin: None declared, Tae-Hwe Heo: None declared