Background Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by simultaneous 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. Selective Inhibitor of Nuclear Export (SINE) compounds such as verdinexor (KPT-335) are potent, orally available XPO1 inhibitors. SINE compounds inhibit the nuclear export of over 220 cargoes, and this pleiotropic effect on multiple signaling pathways exerts apoptotic and anti-inflammatory effects, particularly in dampening NF-B transcriptional activity. Based on previous studies with SINE compounds, we sought to define the minimal amount and frequency of verdinexor treatment necessary to maintain disease inhibition.

Methods To evaluate the minimal efficacious dose of verdinexor in SLE, cohorts of mice with established disease were dosed orally twice weekly with 7.5 mg/kg verdinexor or vehicle for eight weeks. Thereafter, various administration schedules of verdinexor (7.5 mg/kg) plus or minus bortezomib (0.75 mg/kg) a proteasome inhibitor (PI) known to eliminate autoreactive antibody-secreting cells (ASC) were administered for 4 weeks to examine their ability to control recurrent disease. We used flow cytometry and ELISPOT to enumerate ASC in the spleen and bone marrow (BM) and immunofluorescence to visualize germinal centers (GC) in spleen.

Results Therapy with verdinexor twice weekly significantly inhibited disease progression (GC: Control=622499.06 338011.04 vs KPT-335=100952.44 62652.09, p=0.0033. plasmablasts: Control=263790.82 148146.57 vs KPT-335=20967.31 19009.25, p=0.0027. plasma cells: Control=62078.36 22539.49 vs KPT-335=21277.82 13909.45, p=0.0056). Thus, we observed significantly decreased levels of GC B cells, plasma cells and plasmablasts in the BM and the spleen with 4 weeks of induction therapy. The potent effect of SINE compound monotherapy on GC and auto-reactive ASC was further highlighted by the pronounced elimination of GCs histologically and reduction in auto-reactive ASC achieved after 4 weeks of maintenance therapy administered once weekly. In a concurrent study, when combined with bortezomib, 1 week verdinexor plus PI treatment resulted in a synergistic effect, significantly reducing in the number of auto-reactive ASC, particularly in the BM.

Conclusions Verdinexor has demonstrated efficacy by reducing generation and survival of auto-reactive immune cells. Additional experiments are underway to examine if inhibition of the canonical NFB pathway underlies verdinexors inhibitory effect. Together, our findings suggest the potential of SINE compounds to have a significant impact on SLE disease progression alone or in combination with currently utilized PIs.

Funding Source(s): NIH R44 AI124949-03