New Therapeutic Approaches in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) remains the most common acute leukemia in adults and is associated with poor outcome. Leukemia stem cells (LSCs) play a major role in AML initiation, growth, and relapse. Current therapeutic strategies do not effectively target LSCs, as evident by high relapse rates of patients with this disease. Among patients with AML, those who carry FLT3-ITD mutations, have a higher incidence of relapse and a shorter survival. The FLT3-ITD mutation alters the structure of the juxtamembrane domain of the FLT3 receptor, which leads to constitutive kinase activity and continued proliferation of AML cells. Targeted therapies against FLT3-ITD have long been investigated and two FLT3 inhibitors (midostaurin and gilteritinib) are currently approved for treating FLT3-ITD+ AML. Still half of treated patients die of their disease within 4 years. Thus, the need to develop better therapeutic approaches in AML is high.
Our recent efforts in the search for target genes that are differentially overexpressed in AML compared with health hematopoietic cells led to the discovery of CD99 as a potential target in this disease. We have shown that CD99, a cell surface protein, is upregulated in AML, particularly in CD34+ cells, which marks LSCs enriched population. Using anti-CD99 monoclonal antibody (α-CD99mAb), a previous study reported that CD99 is a viable therapeutic target for LSCs in myeloid malignancies. We demonstrated that targeting CD99 via a knockdown approach or α-CD99mAb reduced cell viability and induced apoptotic cell death in AML cell lines and patient primary leukemia blasts. We also found that CD99 is expressed at higher levels in FLT3-ITD+ than in FLT3-WT cells and that targeting CD99 leads to upregulation of the FLT3 surface expression on FLT3-ITD positive cells. In collaboration with Dr. Mackay at USC school of pharmacy, we recently developed nanoparticle-based antibodies against CD99 (α-CD99scFv-ELP) and FLT3 (α-FLT3scFv-ELP) and established their antileukemia activity both in AML cells and in xenograft mouse models. We observed a superior activity when the two fusion proteins were combined or co-assembled. These data along with new directions of targeting CD99 in FLT3-ITD+ AML will be covered.