Discovery and Early Clinical Development of Selective Immunoproteasome Inhibitors

Abstract

Inhibitors of the proteolytic activity of the 20S proteasome have transformed the treatment of multiple B-cell malignancies. These agents have also been employed with success in the treatment of patients with autoimmune diseases and immune-mediated disorders. However, new agents are needed to fully unlock the potential of proteasome inhibitors as immunomodulatory drugs. The discovery that selective inhibitors of the immunoproteasome possess broad anti-inflammatory activity in preclinical models has led to the progression of multiple compounds to clinical trials. This review focuses on the anti-inflammatory potential of immunoproteasome inhibition and the early development of KZR-616, the first selective inhibitor of the immunoproteasome to reach clinical testing.

Keywords: KZR-616; autoimmunity; immunomodulatory; immunoproteasome.

Figure 1

Structures of FDA-approved proteasome inhibitors (bortezomib and carfilzomib) and selective inhibitors of the immunoproteasome (ONX 0914 and KZR-616).

Figure 2

Binding modes of KZR-616 (purple) and ONX 0914 (blue) in the LMP7/β6 binding site of the human immunoproteasome. Adapted from [40].

Figure 3

Comparison of Proteasome Subunit Inhibition and Biologic Activity in Preclinical Models to Clinical Pharmacodynamics and Biomarker Activity. Upper panels represent inhibition of selected proteasome subunits following in vitro exposure or single-dose administration to mice or healthy volunteers. Bottom panels represent readouts of cytokine release from endotoxin stimulation of human PBMC in vitro, proteinuria levels in NZB/W F1 mice, and ex vivo stimulation of whole blood and cytokine measurements in healthy volunteers. Data adapted from [40,51,55].

Figure 4

Biomarker Changes in Patients with SLE Treated with KZR-616. A. Flow cytometric analysis of class-switched memory B-cells (CD3⁻CD19⁻IgD⁻CD27⁺) and plasma cells (CD3⁻CD19⁺CD20⁻CD27^hi) from start of treatment (BL) through Week (W) 25. B. Changes in plasma levels of autoantibodies relative to baseline at Weeks 13 (end of treatment) and 25 (end of study). Adapted from [56,57].