IMO-8400, a novel TLR7, TLR8 and TLR9 antagonist, inhibits disease development in lupus-prone NZBW/F1 mice (119.12)

Abstract Several studies have implicated Toll-like receptors (TLRs) 7, 8 and 9 in the development and progression of lupus. We have developed IMO-8400, a synthetic DNA-based antagonist that has shown potent inhibition of TLR7-, TLR8-, and TLR9-mediated immune responses in cell-based assays and in non-human primates. To assess the therapeutic potency of IMO-8400, we have tested this compound in lupus-prone NZBW/F1 mice. Mice were injected subcutaneously with IMO-8400 at 1.9, 3.8 or 7.5 mg/kg once a week or 7.5 mg/kg once every two weeks from the age of week 21 to 33, and sacrificed at week 34. NZBW/F1 mice treated with IMO-8400 at the weekly dose of 3.8 or 7.5 mg/kg or 7.5 mg/kg every two weeks showed a significant reduction in urine protein and blood urea nitrogen levels in compression to that of untreated mice. Additionally, anti-DNA, anti-RNP and anti-SM IgG levels were also lower in treated mice than untreated controls. No treatment-related side-effects were observed. Histological examination of kidney sections revealed improvement in nephritis (reduced glomerular sclerosis and decreased interstitial inflammation), accompanied by decreased glomerular deposits of IgG immune complex in mice treated with IMO-8400. These results indicate that IMO-8400 suppressed autoimmune antibody production and improved renal function by inhibiting immune responses in lupus-prone NZBW/F1 mice. Thus, IMO-8400 has the potential for the treatment of lupus and other autoimmune diseases.