THU0241 LUPUS PROGRESSION IS PREVENTED BY TREATMENT WITH VERDINEXOR, AN INHIBITOR OF THE NUCLEAR EXPORT PROTEIN EXPORTIN-1, BY LIMITING GERMINAL CENTER FORMATION AND DEVELOPMENT OF AUTOREACTIVE ANTIBODY SECRETING CELLS
Authors: Javier Rangel-Moreno, Nida Meednu, Douglas Widman, Savanna Gornisiewicz, Sharon Tamir, Jennifer H. Anolik
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> 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 and other autoimmune disorders. Selective Inhibitor of Nuclear Export (SINE) compounds are potent, orally available and well-tolerated 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 the NF-κB response. Based on previous studies with different SINE compounds, we decided to define the minimal amount and frequency of verdinexor treatment necessary to maintain disease inhibition after induction therapy. <h3>Objectives</h3> The primary objective of this study was to examine the ability of verdinexor to control the formation of germinal centers and limit the numbers of autoreactive antibody secreting cells (ASC) in a NZB/NZW F1 murine model of SLE. <h3>Methods</h3> To evaluate the minimal efficacious dose of SINE compounds in a preclinical recovery model of SLE, cohorts of lupus-prone mice with established disease (elevated anti-dsDNA antibody titer and proteinuria) were dosed with SINE compound or vehicle for eight weeks, at which time treatment groups were stratified, and escalating administration schedules (both dose and frequency) of verdinexor were examined for their ability to control recurrent disease. We used flow cytometry to enumerate dsDNA antibody-secreting cells (ASC) in the spleen and bone marrow and immunofluorescence to visualize germinal centers (GC) in spleen. <h3>Results</h3> We found that following induction therapy, treatment with verdinexor significantly maintained disease inhibition effectively at 7.5mg/kg administered weekly. Concomitantly, we observed significantly decreased levels of GC B cells, plasma cells and plasmablast levels in the bone marrow and the spleen 4 weeks after treatment groups were stratified. The potent effect of SINE compound monotherapy on GC and auto-reactive ASC showed that a pronounced elimination of GC and auto-reactive ASC is achieved after 4 weeks of maintenance therapy administered once weekly. When combined with a proteasome inhibitor (PI), short-term verdinexor plus PI treatment resulted in a synergistic effect, resulting in a significant reduction in the number of auto-reactive antibody secreting cells (ASC). <h3>Conclusion</h3> Verdinexor has demonstrated efficacy in a murine induction/disease inhibition model of SLE by reducing generation, survival and function of auto-reactive immune cells. It is likely that inhibition of the canonical NF-κB pathway underlies verdinexor's inhibitory effect. The reversible impact of SINE compounds on SLE (symptoms return when therapy is removed) provides a potential window of time for immunization of lupus patients. Together, our findings suggest the potential of SINE compounds to have a significant impact on disease progression in SLE. <h3>Disclosure of Interests</h3> Javier Rangel-Moreno: None declared, Nida Meednu: None declared, Douglas Widman Shareholder of: Karyopharm Therapeutics, Employee of: Karyopharm Therapeutics, Savanna Gornisiewicz Shareholder of: Karyopharm Therapeutics, Employee of: Karyopharm Therapeutics, Sharon Tamir Shareholder of: Karyopharm Therapeutics, Employee of: Karyopharm Therapeutics, Jennifer H. Anolik: None declared