Advertisement

 

 

HM71224, a selective Bruton’s tyrosine kinase inhibitor, attenuates the development of murine lupus.

HM71224, a selective Bruton’s tyrosine kinase inhibitor, attenuates the development of murine lupus.
Author Information (click to view)

Kim YY, Park KT, Jang SY, Lee KH, Byun JY, Suh KH, Lee YM, Kim YH, Hwang KW,


Kim YY, Park KT, Jang SY, Lee KH, Byun JY, Suh KH, Lee YM, Kim YH, Hwang KW, (click to view)

Kim YY, Park KT, Jang SY, Lee KH, Byun JY, Suh KH, Lee YM, Kim YH, Hwang KW,

Advertisement
Share on FacebookTweet about this on TwitterShare on LinkedIn

Arthritis research & therapy 2017 09 2619(1) 211 doi 10.1186/s13075-017-1402-1
Abstract
BACKGROUND
Systemic lupus erythematosus (SLE) is associated with B cell hyperactivity, and lupus nephritis (LN), in particular, is promoted by the production of autoantibodies and immune complex deposition. Bruton’s tyrosine kinase (BTK) plays critical roles in B cell receptor-related and Fc receptor-related signaling. We aimed to investigate the impact of therapeutic intervention with HM71224 (LY3337641), a selective BTK inhibitor, on the development of murine SLE-like disease features.

METHODS
We examined the therapeutic effects of HM71224 on SLE-like disease features in MRL/lpr and NZB/W F1 mice. The disease-related skin lesion was macroscopically observed in MRL/lpr mice, and the impact on splenomegaly and lymphadenopathy was determined by the weight of the spleen and cervical lymph node. The renal function was evaluated by measuring blood urea nitrogen, serum creatinine, and urine protein, and the renal damage was assessed by histopathological grading. Survival rate was observed during the administration period. The impact of B cell inhibition was investigated in splenocytes from both mice using flow cytometry. Autoantibody was measured in serum by ELISA.

RESULTS
HM71224 effectively suppressed splenic B220(+)GL7(+), B220(+)CD138(+), and B220(+)CD69(+) B cell counts, and anti-dsDNA IgG and reduced splenomegaly and lymph node enlargement. The compound also prevented skin lesions caused by lupus development, ameliorated renal inflammation and damage with increased blood urea nitrogen and creatinine, and decreased proteinuria. Furthermore, HM71224 also decreased mortality from lupus development in both mouse models.

CONCLUSION
Our results indicate that inhibition of BTK by HM71224 effectively reduced B cell hyperactivity and significantly attenuated the development of SLE and LN in rodent SLE models.

Submit a Comment

Your email address will not be published. Required fields are marked *

five × five =

[ HIDE/SHOW ]