Ixazomib, an Oral Proteasome Inhibitor, Induces Rapid Mobilization of Hematopoietic Stem Cells in Mice

Introduction: Granulocyte colony-stimulating factor (G-CSF) is the most commonly used drug for stem cell mobilization. Unfortunately, 5-30% of patients fail to collect sufficient hematopoietic stem/progenitor cells (HSPCs) to proceed to transplant. New strategies are needed to increase HSPCs collection in these patients. We previously reported that bortezomib directly and rapidly mobilizes HSPCs in mice by modulating the VLA-4/VCAM-1 axis (Ghobadi A et al. Blood 2014, 124: 2742-2753). Ixazomib (MLN9708) is a next-generation small-molecule proteasome inhibitor that has several potential advantages over bortezomib including oral route of administration. Here we study the effect of ixazomib on stem cell mobilization in mice.

Methods: DBA mice were treated with: (1) ixazomib via oral gavage (o.g., 8 mg/kg), (2) a single intravenous (iv) dose of bortezomib (0.8 mg/kg), (3) AMD3100 (5 mg/kg) SC, and (4) control diluent for ixazomib (2-hydroxypropyl-β-cyclodextrin [HPBCD]). Blood was harvested at baseline and 12, 15, and 24 hours (h) after ixazomib and bortezomib administration and at 3 hours and 12 hours after AMD3100 administration. Harvested peripheral blood (PB) was plated on MethoCult media (Stem Cell Technologies) for colony forming unit-cells (CFU-C) enumeration.

Results: Compared to vehicle (ixazomib diluent, 2-hydroxypropyl-β-cyclodextrin [HPBCD]), ixazomib mobilized significantly more peripheral blood colony forming unit-cells (CFU-C) at 12 - 15 h after administration (mean peak CFU-C: 105/ml vs. 870/ml respectively, i.e., a 0.6 vs. 5-fold increase in CFU-C , P < 0.02; Figure 1A). The majority of CFU-Cs mobilized by ixazomib were CFU-GM (CFU-granulocyte and monocyte, Figure 1B). The magnitude and kinetics of HSPC mobilization in the single ixazomib oral gavage group was identical to a single dose of IV bortezomib (Figure 1C, mean peak of 870/ml vs. 975/ml respectively, P > 0.66). There was no statistically significant difference in peak HSPC mobilization between the ixazomib (12 h after ixazomib administration) and AMD3100 groups (3 h after AMD3100 administration) (mean peak of 870/ml vs. 1240/ml respectively, P = 0.36) suggesting that ixazomib is a potent HSPC mobilizing agent (Figure 1D) with intermediate mobilization kinetics compared to AMD3100 (2-3 hours) and G-CSF (5-6 days) and with identical kinetics to IV bortezomib (12-15 hours).

Conclusion: Ixazomib is a potent and modestly rapid HSPC mobilizer agent in mice. Kinetics and magnitude of HSPC mobilization by ixazomib is identical to bortezomib. Trials to assess proteasome inhibitors as mobilizing agents are currently underway at Washington University.

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