Background/Purpose: We have found that the expression level of BAFF receptor (BR3) is abnormally enhanced in peripheral monocytes of patients with pSS, and BAFF robustly increases IL-6 production in vitro by pSS monocytes. In addition, the proportion of BR3-positive monocytes to total monocytes was positively and significantly correlated with the serum IgG level of pSS patients. These data collectively suggest that the elevated expression of BR3 on monocytes is involved in the pathogenesis of pSS which is often accompanied with hypergammaglobulinemia (HgG). Our findings suggest that BR3 is a therapeutic target to treat pSS. In our previous study, we have successfully discovered two pyrrolopryimidine derivatives, BIK12 and BIK13, which inhibit binding of BAFF to BR3, by our original high-throughput screening (HTS) system. In this study, we investigated inhibitory effects of these compounds on BAFF signaling pathways. To this end, we measured not only IL-6 production by monocytes, but also IgG production by B cells co-cultured with BAFF-stimulated monocytes. In addition, we analyzed the effects of the compounds on serum level of an anti-dsDNA antibody in autoimmune disease model mice received these compounds.

Methods: Peripheral monocytes were stimulated with soluble BAFF (sBAFF) and cultured in vitro with or without peripheral B cells in the presence of BIK-12 or BIK-13. IL-6 production by monocytes and IgG production by B cells were measured by ELISA. For examination of the effects of these compounds in vivo, MRL/lpr and NZBWF1 mice were treated with these compounds three times a week at a dose of 1 mg/kg or 0.2 mg/kg for 6 months. The titer of an anti-ds DNA antibody was measured by ELISA.

Results: sBAFF-induced IL-6 production by peripheral monocytes was significantly suppressed by BIK12 and BIK13 in a dose dependent manner. Similarly, IgG production by B cells cultured with sBAFF-stimulated peripheral monocytes was significantly suppressed by these compounds, while sBAFF itself did not increase IgG production by B cells. These data suggest that inhibition of BAFF binding to BR3 on monocytes suppressed IgG production by co-cultured B cells. Interestingly, the titer of an anti-dsDNA antibody in both MRL/lpr and NZBWF1 mice received BIK13 was lower as compared to control mice after 16 weeks of treatment, indicating that the compound was also efficacious in vivo.

Conclusion: We discovered pyrrolopyrimidine derivatives by HTS which inhibited BAFF signaling, and found that the compounds suppressed IgG production by B cells through affecting monocytes. Our findings strongly suggest that BR3 is a therapeutic target to treat autoimmune diseases which accompany HgG, such as pSS. Moreover, these compounds may provide novel tools to explore the pathological mechanism of the development of autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pyrrolopyrimidine-derivatives-that-inhibit-baff-binding-to-its-receptor-br3-decrease-igg-production-by-b-cells-in-vitro-and-in-vivo-model-of-autoimmune-diseases/