Characterization of theIn VitroandIn VivoActivity of Monoclonal Antibodies to Human IL-18

Abstract

IL-18 is a cytokine with potent IFN-gamma inducing activities as well as an important mediator of Th1 polarized immune responses. In this study we demonstrated that IL-18 induces the concentration-dependent production of the proinflammatory mediators IFN-gamma, IL-6, and GM-CSF, but not the anti-inflammatory cytokine, IL-10 from peripheral blood lymphocytes in the presence of mitogen. Three neutralizing IL-18 monoclonal antibodies (MAbs) were investigated, one of which (2C10) inhibited IL-18 bioactivity with an IC50 of 0.1 nM and had a K(D) of 3.9 x 10(-11) M. A NOD/SCID mouse model engrafted with human peripheral blood lymphocytes was developed to test the in vivo efficacy of this MAb. The IFN-gamma production induced by LPS administration was inhibited approximately 90% by prior dosing of MAb 2C10. The therapeutic utility of a high-affinity IL-18 MAb may be of benefit in Th1-driven autoimmune diseases such as rheumatoid arthritis and Crohn's Disease, where elevated levels of IL-18 have been observed.

Expression of interleukin-18, IL-18BP, and IL-18R in serum, synovial fluid, and synovial tissue in patients with rheumatoid arthritis

“…Research has shown that a IL-18 mAb, a dissoluble IL-18 receptor (sIL-18R), and IL-18 binding protein (IL-18BP) have been applied in the therapy of some immunological diseases and RA, and can control disease development [16,[30][31][32][33]. Here, we detected the levels of IL-18BP in synovial fluid, serum, and IL-18BP expression in synovial tissue.…”

Inhibitory effect of triptolide on interleukin-18 and its receptor in rheumatoid arthritis synovial fibroblasts

“…TP also maintains the balance of Th1/Th2 in RA. It has been reported that IL-18 monoclonal antibody, dissoluble IL-18 receptor (IL-18R), and IL-18 binding protein (IL-18BP) were applied for RA therapy [30][31][32][33]. In this case, TP cooperates with these IL-18 inhibitors to suppress the expression of IL-18 and IL-18R; this strategy could be applied for clinical therapy of RA.…”

Biologic treatments in Sjögren's syndrome

“…Monoclonal antibodies directed against IL-12 and IL-23 briakinumab (ABT-874) and ustekinumab (CNTO-1275) are being studied in psoriasis, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Anti-IL-18 antibodies may be available in the future [121].…”