Abstract

Abstract 4106

Background:

Therapeutic targeting of the ubiquitin-proteasome pathway is currently used for the treatment of multiple myeloma. The immunoproteasome however, is a distinct class of proteasome found predominantly in monocytes and lymphocytes, and it is known to regulate antigen presentation on class I major histocompatibility complexes (MHC-I). ONX 0914 is a LMP7-selective peptide-epoxyketone proteasome inhibitor that is currently in pre-clinical development for the treatment of inflammatory diseases. In the current study, we evaluated the feasibility of using ONX 0914 in the B10.BR→CBA MHC-matched (H2k), minor histocompatibility antigen (miHA)-disparate bone marrow transplantation (BMT) model to decrease the incidence of GVHD. This well established allogeneic BMT model is relevant to the MHC-matched sibling donor or completely matched unrelated donor clinical situation.

Methods:

To evaluate the effects of ONX 0914 on GVHD, we tested different compound regimens in the model. CBA recipient mice were lethally irradiated (11 Gy, split dose, 4 h apart) and transplanted with 2×106 anti-T cell depleted B10.BR bone marrow cells (ATBM) alone, or in combination with 1×107 enriched B10.BR T cells (GVHD control and ONX 0914 treated groups). ONX 0914 was administrated in full (s.c., once/day at 8 mg/kg) or as a split dose (half dose, twice/day approximately 6 hr apart).

Results:

Treatment with the ONX 0914 compound significantly improved the survival of mice compared to control GVHD recipients when dosing was performed once/day for three consecutive days (0,1,2 post-BMT) [p = 0.02]. Alternating dosage (days 0,2,4) or daily drug treatment (days 0–4) provided comparable amelioration of GVHD in this model.

Conclusion:

Our preclinical findings suggest that the immunoproteasome subunit LMP7 is potentially a novel therapeutic target in GVHD as demonstrated by the improved survival rate of recipient mice treated with ONX 0914 in the B10.BR→CBA BMT murine model.

Disclosures:

Zilberberg:Onyx Pharmaceuticals: Research Funding. Dziopa:Onyx Pharmaceuticals: Research Funding. Korngold:Onyx Pharmaceuticals: Research Funding.

Author notes

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Asterisk with author names denotes non-ASH members.