FRI0296 Kzr-616, a selective inhibitor of the immunoproteasome, blocks the disease progression in multiple models of systemic lupus erythematosus (SLE)
Authors: T. Muchamuel, J.L. Anderl, R.A. Fan, H.W.B. Johnson, C.J. Kirk, E. Lowe
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> 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. KZR-616 is an analogue of ONX 0914, Nature Medicine 2009) that selectively targets the LMP7 and LMP2 subunits of the immunoproteasome. <h3>Objectives</h3> To examine the therapeutic potential of KZR-616 in preclinical models of SLE and lupus nephritis (LN). <h3>Methods</h3> Cytokines were measured in human PBMCs stimulated with endotoxin and in CD4 +T cells stimulated with antibodies to CD3 and CD28. Human B-cells were stimulated with IL-21 and antibodies to CD40 and IgM to induce plasmablast differentiation. Immunoproteasome inhibition was measured in KZR-616 treated human PBMCs and in mice by measuring proteasome active site occupancy. The therapeutic effect of KZR-616 alone or in combination with mycophenylate mofetil (MMF) was evaluated in the NZB/W F1 model of SLE. T-dependent antibody responses (TDAR) were measured in mice and monkeys following 1, 4, or 13 weekly administrations. <h3>Results</h3> 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 <i>in vitro</i>. 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- and B-cells and short- and long-lived 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. <h3>Conclusions</h3> KZR-616 is a novel and selective covalent inhibitor of the immunoproteasome that potently blocks inflammatory cytokine production <i>in vitro</i> 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. <h3>Reference</h3> [1] Muchamuel T, et al. <i>Nat</i>. Med. 2009;15:781. <h3>Acknowledgements</h3> <h3>Disclosure of Interest</h3> T. Muchamuel Employee of: Kezar Life Sciences, J. Anderl Employee of: Kezar Life Sciences, R. Fan Employee of: Kezar Life Sciences, H. Johnson Employee of: Kezar Life Sciences, C. Kirk Employee of: Kezar Life Sciences, E. Lowe Employee of: Kezar Life Sciences