Session Title: Systemic Lupus Erythematosus – Animal Models Poster
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: The proteasome inhibitor bortezomib has been used successfully to treat patients with SLE. The immunoproteasome is a distinct class of proteasome found predominantly in immune effector cells. Here we describe KZR-616, an analog of ONX 0914 (Nature Medicine 2009 15;781-788), that selectively targets the LMP7 and LMP2 subunits of the immunoproteasome and examine its potential as a novel therapeutic for the treatment of SLE and lupus nephritis (LN).
Methods: Cytokine release was measured in human PBMCs stimulated with endotoxin and in CD4+ T-cells stimulated with antibodies to CD3 and CD28. Human peripheral blood B-cells were stimulated with IL-21 and antibodies to CD40 and IgM to induce plasmablast differentiation. Cytokines and IgG were measured by mesoscale detection. Immunoproteasome inhibition was measured in human PBMCs and in mice following administration of KZR-616 by measuring proteasome active site occupancy. The therapeutic effect of KZR-616 treatment alone or in combination with mycophenylate mofetil (MMF) was evaluated in the NZB/W F1 model of SLE. Nephritis was monitored by proteinuria. Kidneys were harvested and stained with H&E and anti-IgG. Serum anti-dsDNA were measured by ELISA. Spleen and bone marrow cells were analyzed by flow cytometry. T-dependent antibody responses (TDAR) were measured in mice and monkeys following 1, 4, or 13 weekly administrations.
Results: At a concentration resulting in inhibition of LMP7 and LMP2 by 89% and 59%, respectively, KZR-616 induced a decrease in pro-inflammatory cytokine production in human PBMCs, including TNF-α, GM-CSF, IL-6, and IL12/IL-23 p40. In lymphocytes, KZR-616 blocked T-cell production of IFN-γ, TNF-α and GM-CSF, and the differentiation of B-cells to plasmablasts. KZR-616 administration to mice resulted in selective inhibition of LMP7 and LMP2 similar to levels in vitro. KZR-616 treatment in diseased mice resulted in a complete resolution of proteinuria and significant reductions in autoantibody production and renal IgG deposition. The halt in disease progression was durable as proteinuria levels did not significantly increase 8 weeks after treatment discontinuation. Histologic analysis following 12 weeks of treatment revealed a complete prevention in glomerular nephritis and sclerosis. Administration of KZR-616 in combination with MMF resulted in significantly greater disease inhibition and prolonged survival compared to either treatment alone. Levels of activated T-cells, B-cells and plasma cells were effectively depleted in diseased animals following KZR-616 treatment. KZR-616 had no significant effect on TDAR in mice or monkeys and did not affect the number of circulating lymphocytes in monkeys.
Conclusion: KZR-616 is a novel and selective covalent inhibitor of the immunoproteasome that potently blocks inflammatory cytokine production in vitro and disease progression in mouse models of SLE. Durable disease remission in animals was achieved at well tolerated doses without affecting normal T-cell dependent immune responses. KZR-616 is currently being developed for the treatment of LN and Phase 1 safety and pharmacokinetics results are presented elsewhere at this meeting.
To cite this abstract in AMA style:Muchamuel T, Anderl J, Fan RA, Johnson HWB, Kirk CJ, Lowe E. KZR-616, a Selective Inhibitor of the Immunoproteasome, Blocks the Disease Progression in Multiple Models of Systemic Lupus Erythematosus (SLE) [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/kzr-616-a-selective-inhibitor-of-the-immunoproteasome-blocks-the-disease-progression-in-multiple-models-of-systemic-lupus-erythematosus-sle/. Accessed September 28, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/kzr-616-a-selective-inhibitor-of-the-immunoproteasome-blocks-the-disease-progression-in-multiple-models-of-systemic-lupus-erythematosus-sle/