Advancements in Non-Toxic HSCT: Targeting cKIT and CD47 in NHPs

The abstract describes a breakthrough in the field of hematopoietic stem cell transplantation (HSCT), addressing the long-standing challenges of chemotherapy and radiation-based treatments. A new approach using a non-toxic monoclonal antibody regimen has been developed, targeting cKIT-CD47 antibodies to selectively remove host HSCs without causing off-target toxicities. This method significantly reduces the morbidity and mortality associated with traditional HSCT, broadening its applicability to a wider range of disorders.

A novel monoclonal antibody, FSI-174, has been created with an active Fc region, designed to work synergistically with magrolimab, a CD47 antibody that blocks the "don't eat me" signal. The aim is to translate these promising preclinical findings into clinical trials, offering a safer and less toxic alternative for bone marrow conditioning in HSCT.

In vitro studies have shown that FSI-174 can inhibit stem cell factor signaling, reduce the proliferation of hematopoietic stem and progenitor cells (HSPCs), and enhance the phagocytosis of cKIT-positive cells. Importantly, FSI-174 does not induce mast cell degranulation. In non-human primate (NHP) studies, FSI-174 achieved complete cKIT receptor occupancy at all tested doses, with the duration of occupancy correlating with the dose administered.

When administered alone, FSI-174 did not reduce the frequency of bone marrow HSCs or affect peripheral blood cell counts. However, when combined with magrolimab, the treatment significantly reduced the frequency of bone marrow HSCs, with no recovery observed over an 85-day period. Notably, there were no changes in peripheral blood cell counts or incidence of cytopenias throughout the study.

The conclusion highlights the development of FSI-174, which exhibits the desired properties of blocking stem cell factor, promoting phagocytosis, and avoiding mast cell degranulation. The NHP studies confirm the potential of the chemo- and radiation-free cKIT-CD47 antibody-based conditioning approach. The absence of cytopenias with both monotherapy and combination therapy underscores the specificity, efficacy, and safety of the FSI-174/magrolimab combination. With magrolimab's favorable safety profile demonstrated in several clinical studies, these results are setting the stage for the first-in-human trials of this innovative conditioning method for HSCT.