CD117 Antibody-Based HCT Conditioning for Myeloid Malignancies

ABSTRACT PROJECT 4 Allogeneic hematopoietic cell transplantation (HCT) is the only proven cure for myelodysplastic syndrome (MDS) and certain forms of acute myeloid leukemia (AML). Although powerful, the field of HCT has relied for decades on non-specific, genotoxic agents to achieve hematopoietic stem and progenitor cell (HSPC) eradication (also termed myeloablation) and the death of malignant clones. This project has developed a first-of-its kind antibody (Ab) that binds CD117 resulting in the targeted depletion of HSPC. CD117, also known as c-Kit, is a receptor tyrosine kinase present on HSPC. Interaction of CD117 with its ligand, stem cell factor (SCF), is critical for HSPC survival, self-renewal, differentiation, and proliferation. CD117 is also a proto-oncogene and mutations of CD117 are known to drive the pathogenesis of different cancers. However, its role in MDS and AML is not fully characterized. We showed that CD117 is also expressed on disease-initiating MDS and AML cells, and further, that the -CD117 Abs can deplete these malignant myeloid clones. In the prior funding period, we determined that -CD117 treatment combined with standard therapies, including the hypomethylating agent, 5-Azacytidine, or low dose radiation, increases the cytotoxic effect of these modalities. Based on those findings we conducted a clinical trial combining -CD117 Ab plus low dose radiation as conditioning for older patients with MDS/AML. Results of the study showed the Ab to be safe and the emerging efficacy results are promising. Here we will build on our expertise of targeting CD117. We aim to advance our understanding of the role of CD117 expressed on malignant myeloid cells and use this knowledge to optimize the treatment of MDS/AML by CD117 antibody- targeted agents. We will develop next-generation of -CD117 Ab constructs that recruit and activate immune effector cells to kill CD117-expressing MDS/AML HSPC and blasts. Ab constructs that target CD117 and other leukemia antigens will also be made. We will use multiomics to study CD117’s role in leukemogenesis and predict susceptibility to CD117 targeted agents. In parallel with the preclinical studies, we will conduct a clinical HCT trial that builds upon our discoveries made in the prior funding period, of ways to potentiate the efficacy of existing - CD117 Abs. If successful, the potential impact of our work is broad, with implications to transform the field of HCT to improve outcomes for all patients.