Mgta-145 in Combination with Plerixafor Rapidly Mobilizes High Numbers of Hematopoietic Stem Cells and Graft-Versus-Host Disease Inhibiting Myeloid-Derived Suppressor Cells in Non-Human Primates

Abstract Background. The majority of bone marrow transplants (BMTs) are performed with granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood (mPB) as the source of hematopoietic stem cells (HSCs) for patients. Up to 80% of mPB allogeneic recipients, however, will experience graft-versus-host disease (GvHD). Despite higher levels of CD3+ T cells in mPB grafts compared to BM, the level of acute GvHD observed following transplant of HLA-matched mPB is comparable to HLA-matched BM. One explanation is that G-CSF mobilized grafts contain myeloid-derived suppressor cells (MDSCs) possessing potent immunosuppressive properties capable of inhibiting T cell proliferation in vitro. The percentage of MDSCs is variable in grafts mobilized with G-CSF and clinical data suggest that patients transplanted with mPB grafts that contain higher numbers of MDSCs may have better outcomes including lower rates of acute GvHD (Vendramin et al., BBMT 2014). Identification of a mobilizing regimen that consistently produces high numbers of HSCs and MDSCs may be preferred. We recently reported that MGTA-145 (GroβT), a CXCR2 agonist, when combined with the CXCR4 inhibitor, plerixafor, robustly mobilizes HSCs (Blood 2017 130:1920). In this study, non-human primates (NHPs) were mobilized with a single dose of MGTA-145, plerixafor, or MGTA-145/plerixafor versus a multi-dose regimen of G-CSF, and mPB was harvested to allow detailed immune profiling at 0 through 24 hours. We observed a significant and rapid increase in number of HSCs and CD34dim monocytes with potent in vitro and in vivo immunosuppressive properties. Results. MGTA-145/plerixafor consistently produced a 16-fold increase in number of CD34+CD90+CD45RA- HSCs within four hours of dosing (p=0.0003, n=11). Profiling of graft subsets from these primates also showed a 10-fold increase over baseline in the number of CD34dim monocytes at 4 hours post treatment (p To assess whether these immunosuppressive monocytes may prevent GvHD, we developed a xenograft GvHD model in NSG mice. MGTA-145/plerixafor mPB (6 x 106 PBMCs) containing a high percentage of CD34dim monocytes were injected into sublethally irradiated NSG mice. This was compared to unmobilized primate PBMCs (6 x 106 PBMCs) containing relatively low numbers of CD34dim cells. At day 20, all mice (8/8) transplanted with unmobilized PBMCs had died of acute GvHD compared to none of the mice transplanted with MGTA-145/plerixafor mPB. Mice transplanted with unmobilized PBMCs also demonstrated 3-fold higher numbers of T-cells and increased T-cell activation compared to mice transplanted with MGTA-145/plerixafor mobilized PBMCs (p Conclusions. Co-administration of MGTA-145/plerixafor in NHPs results in both rapid and efficacious mobilization of highly enriched HSCs and a CD34dim monocyte population with potent immunosuppressive activity compared to cells mobilized with plerixafor alone or with the current standard of care, G-CSF. The increased number of these immunosuppressive monocytes compared to G-CSF has the potential to reduce GvHD in the allogenic transplant setting. Thus, MGTA-145/plerixafor may offer an advantageous graft in the allogeneic setting where the risk of GvHD remains a significant clinical problem. IND-enabling studies of MGTA-145 are in progress to assess this regimen for mPB collection and transplant. Download : Download high-res image (658KB) Download : Download full-size image Disclosures Goncalves: Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Falahee: Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Hyzy: Magenta Therapeutics: Employment, Equity Ownership. Li: Magenta Therapeutics: Employment, Equity Ownership. Boitano: Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow: Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke: Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties.