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FRI0296 Kzr-616, a selective inhibitor of the immunoproteasome, blocks the disease progression in multiple models of systemic lupus erythematosus (SLE)
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  1. T. Muchamuel1,
  2. J.L. Anderl2,
  3. R.A. Fan2,
  4. H.W.B. Johnson3,
  5. C.J. Kirk4,
  6. E. Lowe2
  1. 1Pharmacology
  2. 2Biology
  3. 3Chemistry
  4. 4Research, Kezar Life Sciences, South San Francisco, USA

Abstract

Background 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.

Objectives To examine the therapeutic potential of KZR-616 in preclinical models of SLE and lupus nephritis (LN).

Methods 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.

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- 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.

Conclusions 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.

Reference [1] Muchamuel T, et al. Nat. Med. 2009;15:781.

Disclosure of Interest 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

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