Zetomipzomib (KZR-616) attenuates lupus in mice via modulation of innate and adaptive immune responses.
Front Immunol
; 14: 1043680, 2023.
Article
in En
| MEDLINE
| ID: mdl-36969170
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Lupus Nephritis
/
Leukocytes, Mononuclear
Limits:
Animals
/
Humans
Language:
En
Journal:
Front Immunol
Year:
2023
Document type:
Article
Affiliation country:
Estados Unidos