ACR Meeting Abstracts

ACR Meeting Abstracts

  • Meetings
    • ACR Convergence 2024
    • ACR Convergence 2023
    • 2023 ACR/ARP PRSYM
    • ACR Convergence 2022
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • ACR Meetings

Abstract Number: 85

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

Tony Muchamuel1, Janet Anderl 1, R Andrea Fan 1, Henry Johnson 1, Dustin McMinn 1 and Christopher Kirk 1, 1Kezar Life Sciences, South San Francisco, CA

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Animal models, B cells and lupus nephritis, Mouse model, Systemic lupus erythematosus (SLE)

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print
Session Information

Date: Sunday, November 10, 2019

Title: SLE – Animal Models Poster

Session Type: Poster Session (Sunday)

Session Time: 9:00AM-11:00AM

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.


Disclosure: T. Muchamuel, Kezar Life Sciences, 1, 3; J. Anderl, Kezar Life Sciences, 1, 3; R. Fan, Kezar Life Sciences, 3, 4; H. Johnson, Kezar Life Sciences, 1, 3, 4; D. McMinn, Kezar Life Sciences, 1, 3, 4; C. Kirk, Kezar Life Sciences, 3, 4, 6.

To cite this abstract in AMA style:

Muchamuel T, Anderl J, Fan R, Johnson H, McMinn D, Kirk C. 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 [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). 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/. Accessed .
  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print

« Back to 2019 ACR/ARP Annual Meeting

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/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

All abstracts accepted to ACR Convergence are under media embargo once the ACR has notified presenters of their abstract’s acceptance. They may be presented at other meetings or published as manuscripts after this time but should not be discussed in non-scholarly venues or outlets. The following embargo policies are strictly enforced by the ACR.

Accepted abstracts are made available to the public online in advance of the meeting and are published in a special online supplement of our scientific journal, Arthritis & Rheumatology. Information contained in those abstracts may not be released until the abstracts appear online. In an exception to the media embargo, academic institutions, private organizations, and companies with products whose value may be influenced by information contained in an abstract may issue a press release to coincide with the availability of an ACR abstract on the ACR website. However, the ACR continues to require that information that goes beyond that contained in the abstract (e.g., discussion of the abstract done as part of editorial news coverage) is under media embargo until 10:00 AM ET on November 14, 2024. Journalists with access to embargoed information cannot release articles or editorial news coverage before this time. Editorial news coverage is considered original articles/videos developed by employed journalists to report facts, commentary, and subject matter expert quotes in a narrative form using a variety of sources (e.g., research, announcements, press releases, events, etc.).

Violation of this policy may result in the abstract being withdrawn from the meeting and other measures deemed appropriate. Authors are responsible for notifying colleagues, institutions, communications firms, and all other stakeholders related to the development or promotion of the abstract about this policy. If you have questions about the ACR abstract embargo policy, please contact ACR abstracts staff at [email protected].

Wiley

  • Online Journal
  • Privacy Policy
  • Permissions Policies
  • Cookie Preferences

© Copyright 2025 American College of Rheumatology