Arthritis & Rheumatism 58: 1433 - 1444
An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus
Frances Rena Bahjat 1, Polly R. Pine 1, Andrea Reitsma 1, Gail Cassafer 2 3, Muhammad Baluom 1, Sunny Grillo 1, Betty Chang 1, Fei Fei Zhao 1, Donald G. Payan 1, Elliott B. Grossbard 1, David I. Daikh 2 3 *
1Rigel Pharmaceuticals, South San Francisco, California
2University of California, San Francisco, California
3San Francisco VA Medical Center, San Francisco, California
*Correspondence to David I. Daikh, University of California, San Francisco, and San Francisco VA Medical Center, 4150 Clement Street, Immunology/Arthritis 111R, San Francisco, CA 94121
Abstract
Objective
To assess whether R788, an orally bioavailable small molecule inhibitor of spleen tyrosine kinase (Syk)-dependent signaling, could modulate disease in lupus-prone (NZB × NZW)F1 (NZB/NZW) mice via inhibition of Fc receptor (FcR) and B cell receptor signaling.
Methods
R788 was administered to NZB/NZW mice before and after disease onset. Proteinuria, blood urea nitrogen levels, and autoantibody titers were examined periodically, and overall survival and renal pathologic features were assessed following long-term treatment (24-34 weeks). The distribution and immunophenotype of various splenic T cell and B cell subpopulations were evaluated at the time of study termination. Arthus responses in NZB/NZW mice pretreated with R788 or Fc-blocking antibody (anti-CD16/32) were also examined.
Results
When R788 was administered prior to or after disease onset, it delayed the onset of proteinuria and azotemia, reduced renal pathology and kidney infiltrates, and significantly prolonged survival of lupus-prone NZB/NZW mice; autoantibody titers were minimally affected throughout the study. Dose-dependent reductions in the numbers of CD4+ activated T cells expressing high levels of CD44 or CD69 were apparent in spleens from R788-treated mice. Minimal effects on the numbers of naive T cells expressing CD62 ligand and total CD8+ T cells per spleen were observed following long-term drug treatment. R788 pretreatment resulted in reduced Arthus responses in NZB/NZW mice, similar to results obtained in mice pretreated with FcR-blocking antibody.
Conclusion
We demonstrate that a novel Syk-selective inhibitor prevents the development of renal disease and treats established murine lupus nephritis. These data suggest that Syk inhibitors may be of therapeutic benefit in human lupus and related disorders. |
