Background/Purpose:

Systemic Lupus Erythematosus (SLE) is a complex and heterogeneous autoimmune disease associated with the over production of high affinity autoantibodies, mainly raised against nuclear antigens and can be considered a B-cell disease. These autoantibodies mediate tissue injury affecting multiple organs such as skin and joints in mild forms of the disease to Central Nervous System (CNS) and kidney damage in severe forms that can be fatal. SLE is a chronic disease with a relapsing and remitting time-course of unknown etiology and the precise understanding of how these auto-antibodies contribute to the disease is still incomplete. However, over-activity 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. ONO-4059 is a highly potent and dual oral Btk/Tec inhibitor with an IC₅₀ in the sub-nmol/L range. We have previously shown that ONO-4059 strongly suppressed B-cell activation, FcγR-induced TNFα production in monocytes and FcεR-induced TNFα production in mast cells (ACR 2012). Given Btk/Tec play a critical role in B-cell development and function, we examined the potential efficacy of ONO-4059 using female NZB/WF1 mice in a model of spontaneous SLE.

Methods: Mice were randomized to two treatment groups and fed a diet containing 0.012% (equivalent to 20 mg/kg/day) and 0.0037% (6 mg/kg/day) ONO-4059 from 12 to 37 weeks. The mice were weighed weekly and the level of anti-dsDNA antibody was examined on weeks of 28, 32 and 37. The level of proteinuria and overall survival were recorded during the treatment period. A subset of mice was sacrificed at 37 weeks for histopathological analysis of the kidney and ELISpot assays for total Ig-secreting cells and anti-dsDNA-secreting B-cells were evaluated in spleens.

Results:

The treatment with 0.012% and 0.0037% of ONO-4059 resulted in 100% and 90% survival respectively, while 60% survival was observed in untreated mice. The onset of proteinuria was markedly lower in ONO-4059-treated mice (untreated: 6570.2±2520.5 μg/mL vs 0.012% and 0.0037% of ONO-4059 treated: 366.2±19.2 and 358.3±18.4 μg/mL). ONO-4059 dramatically inhibited the production of anti-dsDNA in serum by 76% (P<0.05, 0.0037% diet) and 98.6% (P<0.01, 0.012% diet), compared with untreated mice at week 28. Furthermore, the observed inhibition was much stronger at week 37 (95.5% and 98.9% respectively). Significant reductions in the numbers of total IgG and anti-dsDNA-secreting B-cells were apparent in spleens from ONO-4059-treated mice. Germinal center B-cells and plasma cells were also significantly lower in ONO-4059 treated mice.

Conclusion:

Recent studies indicate that the pathogenesis of SLE is associated with B-cell activation and circulating FcR bearing cells, in which Btk/Tec may play an important role. Our results demonstrate that treatment with ONO-4059 may simultaneously target autoantibody producing and effector cells to prevent the spontaneous disease development in NZB/WF1 mice. These data suggest that ONO-4059 may provide promising therapeutic benefit in human lupus and related disorders.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ono-4059-a-highly-potent-and-dual-oral-inhibitor-of-brutons-tyrosine-kinase-btk-and-tec-kinase-improves-anti-nuclear-antibodies-mediated-sle-in-mice/