2. Academic Validation
  3. Co-inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity

Co-inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity

  • EMBO Rep. 2018 Dec;19(12):e46512. doi: 10.15252/embr.201846512.
Michael Basler 1 2,  Michelle M Lindstrom 3,  Jacob J LaStant 3,  J Michael Bradshaw 3,  Timothy D Owens 3,  Christian Schmidt 2 4,  Elmer Maurits 5,  Christopher Tsu 6,  Herman S Overkleeft 5,  Christopher J Kirk 7,  Claire L Langrish 3,  Marcus Groettrup 1 2
Affiliations

Affiliations

  • 1 Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland [email protected] [email protected].
  • 2 Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.
  • 3 Principia Biopharma, South San Francisco, CA, USA.
  • 4 Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz, Konstanz, Germany.
  • 5 Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
  • 6 Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
  • 7 Kezar Life Sciences, South San Francisco, CA, USA.
PMID: 30279279 DOI: 10.15252/embr.201846512
Abstract

Cells of hematopoietic origin express high levels of the immunoproteasome, a cytokine-inducible Proteasome variant comprising the proteolytic subunits LMP2 (β1i), MECL-1 (β2i), and LMP7 (β5i). Targeting the immunoproteasome in pre-clinical models of autoimmune diseases with the epoxyketone inhibitor ONX 0914 has proven to be effective. ONX 0914 was previously described as a selective LMP7 inhibitor. Here, we show that PRN1126, developed as an exclusively LMP7-specific inhibitor, has limited effects on IL-6 secretion, experimental colitis, and experimental autoimmune encephalomyelitis (EAE). We demonstrate that prolonged exposure of cells with ONX 0914 leads to inhibition of both LMP7 and LMP2. Co-inhibition of LMP7 and LMP2 with PRN1126 and LMP2 inhibitors LU-001i or ML604440 impairs MHC class I cell surface expression, IL-6 secretion, and differentiation of naïve T helper cells to T helper 17 cells, and strongly ameliorates disease in experimental colitis and EAE. Hence, co-inhibition of LMP2 and LMP7 appears to be synergistic and advantageous for the treatment of autoimmune diseases.

Keywords

autoimmune disease; immunoproteasome; immunoproteasome inhibitor design; proteasome.

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