Poster presentations

P140 Verdinexor, a selective inhibitor of nuclear export (SINE), ameliorates cellular and molecular pathogenic immune mechanisms of systemic lupus erythematosus

Abstract

Background SLE is an autoimmune disease characterized by activation of the innate and adaptive arms of the immune system. Recently the nuclear export protein exportin-1 (XPO1) has surfaced as an attractive target for the treatment of SLE. Verdinexor is a potent, orally available and well-tolerated XPO1 inhibitor. Verdinexor inhibits the nuclear export of ∼220 cargoes, and this pleiotropic effect leads to dampening of the NF-κB and IL-6 responses and is linked to its global anti-inflammatory effects. Thus, we examined the ability of verdinexor to alleviate the pathogenic mechanisms underlying SLE.

Methods The minimal efficacious dose of verdinexor was determined in mice with established disease. Mice were dosed with verdinexor for four weeks, followed by treatment cessation for four weeks. Then, escalating doses of verdinexor were tested for their ability to control recurrent disease. We enumerated pathogenic plasma cells (PC), plasmablasts (PB), and T cells in the spleen and bone marrow (BM) and measured systemic inflammatory cytokines and chemokines. Elucidation of the mechanism of PC and PB depletion in human BM from healthy and SLE patients is underway.

Results Verdinexor treatment at 7.5 mg/kg weekly significantly decreased germinal center B cells, PC and PB in the BM and the spleen four weeks after resumption of treatment without affecting normal cells. Furthermore, levels of pro-inflammatory cytokines, chemokines, and B cell survival factors were all significantly decreased. Results from assays in human BM have confirmed these findings.

Conclusions Verdinexor has demonstrated efficacy in a murine model of SLE by reducing generation, survival and function of auto-reactive immune cells without affecting normal cells. It is likely that inhibition of the NF-κB pathway and impaired IL-6 production underlie verdinexor’s efficacy. Taken together with our findings in human BM cells, these data suggest the potential of verdinexor to have a significant impact on disease progression in lupus patients.

Acknowledgements NIH Grant R44 AI124949-03

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