Abstract
Despite the heterogeneity of acute myeloid leukemia (AML), overexpression of the interleukin-3 receptor-α (CD123) on both the more differentiated leukemic blast and leukemic stem cells (LSCs) provides a therapeutic target for antibody treatment. Here we present data on the potential clinical activity of the monoclonal antibody CSL362, which binds to CD123 with high affinity. We first validated the expression of CD123 by 100% (52/52) of patient samples and the correlation of NPM1 and FLT3-ITD mutations with the high frequency of CD123 in AML. In vitro studies demonstrated that CSL362 potently induced antibody-dependent cell cytotoxicity (ADCC) of AML blasts including CD34+CD38−CD123+ LSCs by natural killer cells (NKs). Importantly, compared with healthy donor (HD) NKs, NKs drawn from AML patients in remission had a comparable ADCC activity against leukemic cells; of note, during remission, immature NKs were five times higher in AML patients than that in HDs. Significantly, we report a case where leukemic cells were resistant to autologous ADCC; however, the blasts were effectively lysed by CSL362 together with donor-derived NKs after allogeneic hematopoietic stem cell transplantation. These studies highlight CSL362 as a promising therapeutic option following chemotherapy and transplant so as to improve the outcome of AML patients.
Highlights
In the past 40 years, the standard treatment of acute myeloid leukemia (AML) has relied on cytotoxic chemotherapy combinations; despite changes in the drugs being used, there has been little improvement in outcomes
As one of the aims of this study was to determine the degree of CSL362-enhanced natural killer cells (NKs) cell killing of AML cells as it relates to the cell surface expression of CD123, we focused on the mean expression value/intensity as well as the proportion of cells above a certain threshold
In keeping with other studies,13,28 and in contrast to a report by Jordan et al.,6,32 we did not observe that CD123 expression was higher on the leukemic stem cells (LSCs) containing CD34+ CD38 − blasts than bulk leukemia cells
Summary
In the past 40 years, the standard treatment of acute myeloid leukemia (AML) has relied on cytotoxic chemotherapy combinations; despite changes in the drugs being used, there has been little improvement in outcomes. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered definitive consolidation therapy in first or later CR, albeit at the expense of high morbidity and mortality due to infections and graft versus host disease; the predominant benefit of allo-HSCT is considered to be the effect of the immunemediated graft versus leukemia that occurs post transplant. Among the various potential antigen targets for antibody-based AML therapy, CD123 (interleukin-3 receptor-α, an important growth and differentiation receptor for early hematopoietic cells and the myeloid lineage) has attracted much attention because of its high expression in AML and in particular on leukemic stem cell (LSCs).. LSCs have an inherent resistance to traditional chemotherapeutics associated with their stem cell nature; their persistence following chemotherapy is responsible for disease relapse.. It has previously been reported that antibodies against CD123 can mediate cytolysis of AML cells and in particular of LSCs.. A secondgeneration anti-CD123 antibody (CSL362) has been developed
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