Background There is great interest in developing new treatment approaches for systemic lupus erythematosus (SLE), but the biologic therapies under investigation have yielded disappointing results. Recently the nuclear export protein XPO1 (Exportin 1/CRM1) has surfaced as an attractive target for the treatment of inflammatory disorders like SLE. Selective Inhibitor of Nuclear Export (SINE) compounds are potent, orally-available, and well-tolerated XPO1 (Exportin 1/CRM1) agonists. In vitro and in vivo, SINE compounds exert apoptotic and anti-inflammatory effects by mediating nuclear retention of important XPO1 cargos like the NFκB pathway regulatory protein, IκB (figure).
Objectives This study evaluated the efficacy of the SINE compound KPT-350 on disease progression, interferon-α (IFN-α) production by plasmacytoid dendritic cells (pDCs) and autoantibody production by plasma cells (PCs) in a murine model of SLE.
Methods Cohorts of nephritic NZB/W F1 lupus-prone female mice, with established disease (elevated anti-dsDNA antibody titer and proteinuria) were treated with low or high dose KPT-350 (5 or 7.5 mg/kg, respectively) or a vehicle control three times per week for 8 weeks (n=8/group). Proteinuria was monitored and kidney histology assessed. Spleen, bone marrow (BM) and kidney cells were harvested and analyzed by flow cytometry. Antibody secreting cells (ASCs) and germinal centers (GCs) were enumerated and measured by ELIspot and immunofluorescent staining. Serum samples and RNA were collected for Luminex assay and qPCR. Effects on pDC production of IFN-α were assessed using in vitro cultures of BM cells stimulated with CpG 2216 10ng/ml for 5 hours.
Results Both high and low doses of KPT-350 prevented nephritis progression with a statistically significant reduction in urine protein levels in treated groups (p<0.05 beginning at 6 weeks). Moreover, nephritis was improved histologically (GN score: 3.3±1.2 vehicle vs. 1.0±-0 SINE; interstitial nephritis: 2±-1.1 vehicle vs. 0±-0 SINE; lipoid infiltrate score: 1.3±-0.6 vehicle vs. 0±-0 SINE). In the spleen, levels of GC B cells (CD19+PNA+CD95+) and IgG and anti-DNA ASCs were dramatically reduced. ASCs were also reduced in the BM and became undetectable in the kidney. Importantly, serum anti-DNA antibodies decreased with treatment but total IgG levels remained intact. KPT-350 inhibited the production of IFN-α by pDCs in a strong, dose-dependent fashion (% of vehicle: 1 uM 88%, 10 uM 66%, 100 um 39%, and 1000 uM 0%). Additionally, IFN-α regulated chemokines in the serum of treated mice were decreased (MCP-1: 250±-90 pg/mL vehicle vs. 54±-26 pg/mL SINE, p=0.049), as were the renal mRNA levels of three PC survival factors: BAFF (38% of vehicle, p<0.05), APRIL (19% of vehicle, p<0.05) and IL6 (40% of vehicle).
Conclusions SINE compounds influence the generation, survival and function of PCs and other immune cells through a multifactorial mechanism involving pDCs, GCs and ASCs. It is likely that a common process, namely inhibition of the canonical NFκB pathway, underlies KPT-350's effect. Collectively, our findings suggest that, by simultaneously modulating IFN-α activation and NFκB signaling, SINE compounds might slow disease progression in SLE.
Disclosure of Interest J. Rangel-Moreno: None declared, W. Wang: None declared, T. Owen: None declared, J. Barnard: None declared, B. Klebanov Employee of: Karyopharm Therapeutics, Inc, Y. Landesman Employee of: Karyopharm Therapeutics, Inc, S. Tamir Employee of: Karyopharm Therapeutics, Inc, S. Shacham Shareholder of: Karyopharm Therapeutics, Inc, Employee of: Karyopharm Therapeutics, Inc, J. Anolik: None declared
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