FRI0380 HM71224, A Selective Bruton's Tyrosine Kinase Inhibitor, Ameliorates Murine Lupus Development

BackgroundThe 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 Bruton's tyrosine kinase (BTK) as crucial parts of the B-cell activation and BCR signaling pathway has been considered as therapeutic target for SLE.ObjectivesWe evaluated ameliorative effects of BTK inhibition by HM71224 on the development of SLE in MRL/lpr and NZB/W F1 mice lupus models.Methods8 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.ResultsHM71224 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