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- W2397301093 abstract "Background The B-cell targeted therapy against systemic lupus erythematosus (SLE) has generated great interest due to the multiple pathogenic roles carried out by B cells, and Bruton9s tyrosine kinase (BTK) as crucial parts of the B-cell activation and BCR signaling pathway has been considered as therapeutic target for SLE. Objectives We evaluated ameliorative effects of BTK inhibition by HM71224 on the development of SLE in MRL/lpr and NZB/W F1 mice lupus models. Methods 8 weeks old MRL/lpr mice and 18 weeks old NZB/W F1 mice were orally treated daily with vehicle, 3, 10 and 30 mg/kg of HM71224 for 20 and 22 weeks, respectively. 50 mg/kg of Cyclophosphamide (CPA) and 30 mg/kg of Mycophenolate mofetil (MMF) were intraperitoneally treated weekly and daily in MRL/lpr and NZB/W F1 mice, respectively. The measurements of urine protein with urine strips, BUN and creatinine with chemical analyzer, serum anti-dsDNA IgG with ELISA, and organ weight of spleen, cervical lymph nodes and kidney were conducted. Phenotypes of germinal center (B220+GL7+), activated (B220+CD69+) or plasma (B220+CD138+) B cells were performed by flow cytometry. Renal histopathology was analyzed as membranous glomerulonephritis (GN) score, renal interstitial inflammation/fibrosis (IN) score and vessel inflammation (VI) score in H&E and PAS stain. Survival rate estimates were calculated with the Kaplan-Meier. Results HM71224 treatment dose-dependently ameliorated the severity of disease in both MRL/lpr and NZB/W F1 mice. Compared to vehicle control, 30 mg/kg treatment of HM71224 in MRL/lpr mice effectively decreased splenomegaly (p Conclusions BTK inhibition by HM71224 effectively dampened B cells and significantly ameliorated the lupus nephropathy in rodent SLE models. Therefore, these findings support that the inhibition of B cells by HM71224 may be an effective therapeutic approach for human lupus. References Matthew M. Seavey et al. Animal Models of Systemic Lupus Erythematosus (SLE) and Ex Vivo Assay Designs for Drug Discovery. Curr. Protoc. Pharmacol. 2011; 5.:5.60.1-5.60.40 Harvey PR, et al. B-cell targeted therapies in systemic lupus erythematosus: successes and challenges. BioDrugs. 2013; 27(2):85-95 Disclosure of Interest None declared" @default.
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- W2397301093 date "2015-06-01" @default.
- W2397301093 modified "2023-09-23" @default.
- W2397301093 title "FRI0380 HM71224, A Selective Bruton's Tyrosine Kinase Inhibitor, Ameliorates Murine Lupus Development" @default.
- W2397301093 doi "https://doi.org/10.1136/annrheumdis-2015-eular.4364" @default.
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