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- W4313373418 abstract "Abstract Systemic lupus erythematous (SLE) is a complex autoimmune disease affecting multiple organs. Anti-nuclear antibody (Ab) producing plasma cells (PCs) play a critical role in the disease pathogenesis and are an important target for developing therapies against SLE. Karyopharm Therapeutics (KPTI) is an oncology-focused pharmaceutical company dedicated to the discovery, development, and commercialization of novel first-in-class drugs for the treatment of cancer and other major diseases. KPTI’s lead compound, XPOVIO™ (selinexor), received accelerated approval from the FDA in combination with dexamethasone as a treatment for patients with heavily pretreated multiple myeloma. KPTI’s selective inhibitors of nuclear export (SINE, verdinexor) are effective in reducing nephritis in the NZBW/F1 mouse model, and dramatically reduced autoreactive PCs. To further define whether SINEs directly decrease PC survival and/or generation, we studied PCs in human lupus ex vivo. Peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) from healthy (n=3) and SLE donors (n=3) were treated with verdinexor and PC survival was determined by IgG ELISPOT and apoptosis assay. Verdinexor treatment significantly reduced the number of Ab secreting cells from healthy and SLE donor PBMCs as well as BMMCs (IC50 =0.1uM). Upon ex vivo verdinexor treatment (0.5uM), the levels of live blood plasmablasts and bone marrow CD19+ PCs were reduced by 30% with increased level of apoptotic cells. In contrast, ex vivo verdinexor treatment had no effect on naïve B cells and T cells from healthy and SLE PBMCs and BMMCs. These results support the hypothesis that SINEs have a direct effect on PC survival and represent a novel treatment approach for SLE." @default.
- W4313373418 created "2023-01-06" @default.
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- W4313373418 date "2020-05-01" @default.
- W4313373418 modified "2023-09-27" @default.
- W4313373418 title "Verdinexor, a selective inhibitor of nuclear export, decreases plasma cell survival in human lupus" @default.
- W4313373418 doi "https://doi.org/10.4049/jimmunol.204.supp.236.1" @default.
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