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Abstract

Bruton’s Tyrosine Kinase (Btk) Inhibitor Tirabrutinib Prevents the Development of Murine Lupus

Systemic Lupus Erythematosus (SLE) is a complex and heterogeneous autoimmune disease associated with the over production of high affinity autoantibodies. Overactivity of B-cell responsiveness to immune stimulation and direct activation of circulating FcR bearing cells are sufficient to initiate inflammatory responses, which may be an essential feature of SLE pathogenesis. Here, we examined the potential efficacy of tirabrutinib using NZB/WF1 and MRL/lpr mice in the model of spontaneous SLE. Tirabrutinib inhibited the production of anti-dsDNA in serum, and the onset of proteinuria resulted in markedly lower in both lupus-prone mice. Furthermore, the treatment with tirabrutinib resulted in 100% survival, while 70% survival was observed in untreated mice. Significant reductions in the numbers of total IgG and anti-dsDNAsecreting B-cells were apparent in spleens from tirabrutinib treated mice. Germinal center B-cells and plasma cells were also significantly lower in tirabrutinib treated mice. Our results demonstrate that treatment with tirabrutinib may simultaneously target autoantibody producing and effector cells to prevent the spontaneous disease development in lupus-prone mice. These data suggest that tirabrutinib may provide promising therapeutic benefit in human lupus and related disorders.


Author(s): Yuko Ariza, Masayuki Murata, Yoshiko Ueda and Toshio Yoshizawa*

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