Drs. Hilton and Narula own stock or stock options in Hoffmann-La Roche.
Systemic Lupus Erythematosus
Suppression of Glomerulonephritis in Lupus-Prone NZB × NZW Mice by RN486, a Selective Inhibitor of Bruton's Tyrosine Kinase
Article first published online: 26 AUG 2013
Copyright © 2013 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 65, Issue 9, pages 2380–2391, September 2013
How to Cite
Mina-Osorio, P., LaStant, J., Keirstead, N., Whittard, T., Ayala, J., Stefanova, S., Garrido, R., Dimaano, N., Hilton, H., Giron, M., Lau, K.-Y., Hang, J., Postelnek, J., Kim, Y., Min, S., Patel, A., Woods, J., Ramanujam, M., DeMartino, J., Narula, S. and Xu, D. (2013), Suppression of Glomerulonephritis in Lupus-Prone NZB × NZW Mice by RN486, a Selective Inhibitor of Bruton's Tyrosine Kinase. Arthritis & Rheumatism, 65: 2380–2391. doi: 10.1002/art.38047
- Issue published online: 26 AUG 2013
- Article first published online: 26 AUG 2013
- Accepted manuscript online: 10 JUN 2013 09:16AM EST
- Manuscript Accepted: 30 MAY 2013
- Manuscript Received: 9 OCT 2012
Bruton's tyrosine kinase (BTK) plays a critical role in B cell development and function. We recently described a selective BTK inhibitor, RN486, that blocks B cell receptor (BCR) and Fcγ receptor signaling and is efficacious in animal models of arthritis. The aim of this study was to examine the potential efficacy of BTK in systemic lupus erythematosus (SLE), using an NZB × NZW mouse model of spontaneous SLE.
Mice received RN486 or its vehicle (administered in chow) at a final concentration of 30 mg/kg for 8 weeks, starting at 32 weeks of age.
The administration of RN486 completely stopped disease progression, as determined by histologic and functional analyses of glomerular nephritis. The efficacy was associated with striking inhibition of B cell activation, as demonstrated by a significant reduction in CD69 expression in response to BCR crosslinking. RN486 markedly reduced the secretion of IgG anti–double-stranded DNA (anti-dsDNA) secretion, as determined by enzyme-linked immunosorbent and enzyme-linked immunospot assays. Flow cytometric analysis demonstrated depletion of CD138highB220low plasma cells in the spleen. RN486 inhibited secretion of IgG anti-dsDNA but not IgM anti-dsDNA, suggesting that pharmacologic blockade of BTK resembles the reported transgenic expression of low levels of endogenous BTK in B cells. In addition, RN486 may also impact the effector function of autoantibodies, as evidenced by a significant reduction in immune complex–mediated activation of human monocytes in vitro and down-regulation of the expression of macrophage-related and interferon-inducible genes in both the kidneys and spleens of treated mice.
Collectively, our data suggest that BTK inhibitors may simultaneously target autoantibody-producing and effector cells in SLE, thus constituting a promising therapeutic alternative for this disease.