Anti-CD117 antibody depletes normal and myelodysplastic syndrome human hematopoietic stem cells in xenografted mice

Abstract

The myelodysplastic syndromes (MDS) represent a group of clonal disorders that result in ineffective hematopoiesis and are associated with an increased risk of transformation into acute leukemia. MDS arises from hematopoietic stem cells (HSCs); therefore, successful elimination of MDS HSCs is an important part of any curative therapy. However, current treatment options, including allogeneic hematopoietic cell transplantation (HCT), often fail to ablate disease-initiating MDS HSCs, and thus have low curative potential and high relapse rates. Here, we demonstrate that human HSCs can be targeted and eliminated by monoclonal antibodies (mAbs) that bind cell-surface CD117 (c-Kit). We show that an anti-human CD117 mAb, SR-1, inhibits normal cord blood and bone marrow HSCs in vitro. Furthermore, SR-1 and clinical-grade humanized anti-human CD117 mAb, AMG 191, deplete normal and MDS HSCs in vivo in xenograft mouse models. Anti-CD117 mAbs also facilitate the engraftment of normal donor human HSCs in MDS xenograft mouse models, restoring normal human hematopoiesis and eradicating aggressive pathologic MDS cells. This study is the first to demonstrate that anti-human CD117 mAbs have potential as novel therapeutics to eradicate MDS HSCs and augment the curative effect of allogeneic HCT for this disease. Moreover, we establish the foundation for use of these antibody agents not only in the treatment of MDS but also for the multitude of other HSC-driven blood and immune disorders for which transplant can be disease-altering.

Different Human Immune Lineage Compositions Are Generated in Non-Conditioned NBSGW Mice Depending on HSPC Source

“…Indeed, recognition of the adverse impact of pre-transplant conditioning has led to increasing interest in the use of reduced intensity conditioning or alternative protocols for clinical HSCT. For example, it has recently been shown that depleting endogenous murine HSPCs by administering an antibody-bead conjugate against CD117, allows for the survival and differentiation of human HSPCs in non-conditioned NSG mice (35,36). With this approach now entering phase-I clinical trials, murine models that provide an HSPC-deficient host environment will likely become increasingly useful tools for further research.…”

Nonmyeloablative TLI-ATG conditioning for allogeneic transplantation: mature follow-up from a large single-center cohort

“…[42][43][44] Finally, our group recently showed that an anti-CD117 (c-KIT) antibody can deplete MDS hematopoietic stem cells and restore normal donor hematopoiesis in xenografted mice. 45 Combining this c-KIT antibody with TLI-ATG conditioning for patients with MDS and AML may deplete stem cell niches, thereby improving donor cell engraftment and chimerism.…”

Targeting CD300f to enhance hematopoietic stem cell transplantation in acute myeloid leukemia

“…Recent advances in antibody-based therapeutics have presented the possibility of targeted conditioning agents. 13,48 Clinical trials have begun with unconjugated antibodies as conditioning agents (NCT02963064). The potent effect demonstrated by DCR-2-PBD against healthy HSPCs suggests that therapeutic derivatives targeting CD300f may be incorporated into conditioning for nonmalignant disorders of erythropoiesis or immunodeficiency either as part of an allo-HSCT or a gene-modified autologous HSCT.…”