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FRI0380 HM71224, A Selective Bruton's Tyrosine Kinase Inhibitor, Ameliorates Murine Lupus Development
  1. Y.Y. Kim1,
  2. K.T. Park1,
  3. K.H. Lee1,
  4. S.Y. Jang2,
  5. T.H. Song3,
  6. Y.-M. Lee3,
  7. Y.H. Kim1,
  8. K.H. Suh2
  1. 1Toxicology Team
  2. 2NCE Team
  3. 3Pharmacology Team, Research Center, Hanmi Pharma. Co.Ltd., Hwaseong-si, Korea, Republic Of

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 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.

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<0.001), lymph node enlargement (p<0.01), proportions of activated (p<0.01) and germinal center (23%) B cells in spleen, anti-dsDNA IgG (47%), skin lesions (p<0.001), AUC of urine protein (p<0.01), BUN (p<0.05), nephromegaly (p<0.001), GN score (p<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 (p<0.01), proportions of activated (p<0.01) and plasma (p<0.001) B cells in spleen, proteinuria (p<0.05), BUN (77%), creatinine (29%), IN score (p<0.01), VI score (p<0.01), and GN score (28%). Furthermore, there was no mortality in HM71224 treatment group (vs. 67% survival rate of vehicle).These therapeutic effects of HM71224 were more efficacious than MMF at the same dose level.

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

  1. 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

  2. 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

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