Selective inhibition of NF-kB inducing kinase (NIK) is therapeutically efficacious in IFNα-accelerated lupus nephritis prone mice

Systemic lupus erythematosus (SLE) is often considered a disease driven by autoreactive B cells and anti-nuclear antibodies. However, therapeutic targeting of B cells, for example through BAFF blockade, has been only partially effective in SLE. NF-kB Inducing Kinase (NIK) mediates non-canonical NF-kB signaling downstream of disease relevant TNF family members, such as BAFF, TWEAK, CD40, and OX40. We hypothesized that NIK inhibition might be more efficacious than BAFF blockade in lupus, and therefore generated a highly selective and potent small molecule inhibitor (SMI) of NIK to test this hypothesis. In cellular assays, this molecule inhibits non-canonical NF-kB signaling downstream of multiple TNFRSF family members. In order to differentiate the effects of NIK inhibition and BAFF blockade in vivo , we compared NIK inhibition with BAFF blockade in the context of NZB/W F1 lupus prone mice. As predicted, NIK inhibition recapitulated the pharmacological effects of BAFF blockade. Furthermore, NIK inhibition, but not BAFF blockade, affected T cell parameters in the spleen and pro-inflammatory gene expression in the kidney, the latter of which is partly attributable to TWEAK signaling. Finally, NIK inhibition resulted in improved survival, ameliorated renal pathology, and lower proteinuria scores. Collectively, our data suggest that NIK inhibition affects multiple disease-relevant pathways and may therefore have superior efficacy compared to BAFF inhibition in SLE.