Efficacious Mobilization of HSCs and GvHD-Inhibiting MDSCs by MGTA-145 and Plerixafor in NHPs

The primary focus of this study is on the use of granulocyte-colony stimulating factor (G-CSF) for mobilizing hematopoietic stem cells (HSCs) from peripheral blood for bone marrow transplants. However, GvHD is a common complication affecting up to 80% of recipients. Interestingly, the presence of myeloid-derived suppressor cells (MDSCs) in G-CSF mobilized grafts may mitigate GvHD due to their immunosuppressive capabilities. A recent finding suggests that higher MDSC content in mPB grafts correlates with better patient outcomes and lower GvHD rates.

In an attempt to enhance HSC and MDSC mobilization, the study introduces MGTA-145 (GroβT), a CXCR2 agonist, combined with the CXCR4 inhibitor plerixafor. This combination was found to effectively mobilize HSCs in non-human primates (NHPs). The single dose of this combination resulted in a rapid and significant increase in HSCs and CD34dim monocytes, which exhibited strong immunosuppressive properties both in vitro and in vivo.

The study's results indicate that the MGTA-145/plerixafor combination led to a 16-fold increase in CD34+CD90+CD45RA- HSCs within four hours. Furthermore, a 10-fold increase in CD34dim monocytes was observed, which was significantly higher compared to G-CSF or plerixafor alone. These monocytes were found to suppress T cell proliferation effectively.

To evaluate the impact on GvHD, a xenograft model was developed using NSG mice. The results showed that mice receiving mPB containing a high percentage of CD34dim monocytes mobilized by MGTA-145/plerixafor had a significantly lower incidence of GvHD and higher survival rates compared to those receiving unmobilized PBMCs.

The study concludes that the co-administration of MGTA-145/plerixafor in NHPs not only rapidly mobilizes a highly enriched population of HSCs but also a CD34dim monocyte population with potent immunosuppressive activity. This approach may offer a significant advantage in reducing GvHD in allogeneic transplants, a major clinical challenge. Ongoing studies are aimed at assessing the potential of MGTA-145 for mPB collection and transplant in a clinical setting.