Frontiers in Immunology (Mar 2023)

Zetomipzomib (KZR-616) attenuates lupus in mice via modulation of innate and adaptive immune responses

  • Tony Muchamuel,
  • R. Andrea Fan,
  • Janet L. Anderl,
  • Darrin J. Bomba,
  • Henry W. B. Johnson,
  • Eric Lowe,
  • Brian B. Tuch,
  • Dustin L. McMinn,
  • Beatriz Millare,
  • Christopher J. Kirk

DOI
https://doi.org/10.3389/fimmu.2023.1043680
Journal volume & issue
Vol. 14

Abstract

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Zetomipzomib (KZR-616) is a selective inhibitor of the immunoproteasome currently undergoing clinical investigation in autoimmune disorders. Here, we characterized KZR-616 in vitro and in vivo using multiplexed cytokine analysis, lymphocyte activation and differentiation, and differential gene expression analysis. KZR-616 blocked production of >30 pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs), polarization of T helper (Th) cells, and formation of plasmablasts. In the NZB/W F1 mouse model of lupus nephritis (LN), KZR-616 treatment resulted in complete resolution of proteinuria that was maintained at least 8 weeks after the cessation of dosing and was mediated in part by alterations in T and B cell activation, including reduced numbers of short and long-lived plasma cells. Gene expression analysis of human PBMCs and tissues from diseased mice revealed a consistent and broad response focused on inhibition of T, B, and plasma cell function and the Type I interferon pathway and promotion of hematopoietic cell lineages and tissue remodeling. In healthy volunteers, KZR-616 administration resulted in selective inhibition of the immunoproteasome and blockade of cytokine production following ex vivo stimulation. These data support the ongoing development of KZR-616 in autoimmune disorders such as systemic lupus erythematosus (SLE)/LN.

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