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

Yuko Ariza,Yoshiko Ueda,Toshio Yoshizawa,Masayuki Murata

doi:10.36648/2248-9215.9.1.79

Abstract

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.

Highlights

Systemic Lupus Erythematosus (SLE) is an autoimmune disease that is characterized by autoantibody production and tissue damage caused by immune complex [1,2]
Since the levels of anti-dsDNA antibodies correlate with disease activity in systemic lupus erythematosus, the mice were randomized into 3 groups to receive control chow, 0.0037% and 0.012% tirabrutinib-formulated chow at 28 wk of age
Tirabrutinib (0.012%) significantly prevented further increases in anti-dsDNA antibody levels, while control mice showed a two-fold increase at 31 wk, the levels were slowly starting to decrease until the end of the study at 38 wk (Figure 1b)

Summary

Introduction

Systemic Lupus Erythematosus (SLE) is an autoimmune disease that is characterized by autoantibody production and tissue damage caused by immune complex [1,2]. Preclinical and clinical data suggest that pathogenic B-cells contribute to SLE pathogenesis by autoantibody production, antigen presentation, and cytokine generation. Pathogenic autoantibodies have been shown to play a central role in the manifestations of SLE and the titres of anti-dsDNA antibodies rise during flares of SLE disease activity, lupus nephritis. Lupus nephritis is a severe manifestation of SLE with significant morbidity and mortality

Methods

Results

Conclusion