FRI0380 HM71224, A Selective Bruton's Tyrosine Kinase Inhibitor, Ameliorates Murine Lupus Development
Authors: Y.Y. Kim, K.T. Park, K.H. Lee, S.Y. Jang, T.H. Song, Y.-M. Lee, Y.H. Kim, K.H. Suh
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> 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. <h3>Objectives</h3> We evaluated ameliorative effects of BTK inhibition by HM71224 on the development of SLE in MRL/<i>lpr</i> and NZB/W F1 mice lupus models. <h3>Methods</h3> 8 weeks old MRL/<i>lpr</i> 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/<i>lpr</i> 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<sup>+</sup>GL7<sup>+</sup>), activated (B220<sup>+</sup>CD69<sup>+</sup>) or plasma (B220<sup>+</sup>CD138<sup>+</sup>) 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&amp;E and PAS stain. Survival rate estimates were calculated with the Kaplan-Meier. <h3>Results</h3> HM71224 treatment dose-dependently ameliorated the severity of disease in both MRL/<i>lpr</i> and NZB/W F1 mice. Compared to vehicle control, 30 mg/kg treatment of HM71224 in MRL/<i>lpr</i> mice effectively decreased splenomegaly (<i>p</i>&lt;0.001), lymph node enlargement (<i>p</i>&lt;0.01), proportions of activated (<i>p</i>&lt;0.01) and germinal center (23%) B cells in spleen, anti-dsDNA IgG (47%), skin lesions (<i>p</i>&lt;0.001), AUC of urine protein (<i>p</i>&lt;0.01), BUN (<i>p</i>&lt;0.05), nephromegaly (<i>p</i>&lt;0.001), GN score (<i>p</i>&lt;0.01) and IN score (40%). Likewise, compared to vehicle control, 30 mg/kg treatment of HM71224 in NZB/W F1 mice showed the effects of significantly decreasing splenomegaly (<i>p</i>&lt;0.01), proportions of activated (<i>p</i>&lt;0.01) and plasma (<i>p</i>&lt;0.001) B cells in spleen, proteinuria (<i>p</i>&lt;0.05), BUN (77%), creatinine (29%), IN score (<i>p</i>&lt;0.01), VI score (<i>p</i>&lt;0.01), and GN score (28%). Furthermore, there was no mortality in HM71224 treatment group (<i>vs.</i> 67% survival rate of vehicle).These therapeutic effects of HM71224 were more efficacious than MMF at the same dose level. <h3>Conclusions</h3> 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. <h3>References</h3> 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 <h3>Disclosure of Interest</h3> None declared