Background/Purpose: The immunoproteasome is a distinct class of proteasome found predominantly in immune effector cells and has been shown to play a distinct role in the regulation of the immune cell function. We have previously demonstrated that selective inhibition of the LMP7 and LMP2 subunit of the immunoproteasome with KZR-616 effectively blocks the progression of lupus in the NZB/W mouse model of lupus nephritis (LN), including reducing serum levels of anti-dsDNA antibodies. Here we describe changes to global gene expression in the spleens and kidneys of diseased mice following KZR-616 treatment.

Methods: The therapeutic effect of KZR-616 was examined in the NZB/W model of SLE. The degree of proteinuria (0 – 4 scale) was used to evaluate the severity of nephritis. Kidneys were harvested and stained with hematoxylin and eosin and anti-immunoglobulin G (IgG). RNA was extracted from spleens and kidneys of NZB/W mice after 11 weeks of subcutaneous KZR-616 treatment and evaluated by RNA sequencing analysis. Canonical pathways were analyzed using Ingenuity Pathway Analysis software.

Results: KZR-616 administration to mice resulted in selective inhibition of LMP7 and LMP2 by 91% and 71%, respectively, similar to levels of inhibition seen in vitro and previously reported data in humans at doses ≥ 30 mg (Lickliter et al. ACR 2017). KZR-616 treatment of diseased mice resulted in complete resolution of proteinuria and an absence of renal IgG deposition compared to vehicle treated animals. Consistent with these findings, we noted decreased gene expression associated with inflammation, the T helper (Th) 1 pathway, Th17 activation, interferon signaling, generation of antibody secreting cells, and plasma cell (PC) differentiation in the spleen. In the kidney, immunoproteasome inhibition abrogated transcripts associated with inflammation, cell and myeloid trafficking into the glomerulus as well as expression of renal ortholog genes previously identified to be differentially expressed in the glomerular and tubulointerstitial compartments in LN patients.

Conclusion: KZR-616 effectively blocks disease progression in a mouse model of SLE by regulating expression of genes that are involved in immune response and effector cell function, PC differentiation and antibody secretion, and glomerular and tubulointerstitial renal pathology. These experimental data support the ongoing clinical evaluation of KZR-616 in patients with LN.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/selective-inhibition-of-the-immunoproteasome-with-kzr-616-blocks-multiple-cell-signaling-pathways-plasma-cell-signatures-and-myeloid-cell-associated-damage-in-the-nzb-w-lupus-nephritis-model/