The interleukin-3 receptor CD123 targeted SL-401 mediates potent cytotoxic activity against CD34⁺CD123⁺ cells from acute myeloid leukemia/myelodysplastic syndrome patients and healthy donors

Abstract

Diseases with clonal hematopoiesis such as myelodysplastic syndrome and acute myeloid leukemia have high rates of relapse. Only a small subset of acute myeloid leukemia patients are cured with chemotherapy alone. Relapse in these diseases occurs at least in part due to the failure to eradicate leukemic stem cells or hematopoietic stem cells in myelodysplastic syndrome. CD123, the alpha chain of the interleukin-3 receptor heterodimer, is expressed on the majority of leukemic stem cells and myelodysplastic syndrome hematopoietic stem cells and in 80% of acute myeloid leukemia. Here, we report indiscriminate killing of CD123+ normal and acute myeloid leukemia / myelodysplastic syndrome cells by SL-401, a diphtheria toxin interleukin-3 fusion protein. SL-401 induced cytotoxicity of CD123+ primary cells/blasts from acute myeloid leukemia and myelodysplastic syndrome patients but not CD123− lymphoid cells. Importantly, SL-401 was highly active even in cells expressing low levels of CD123, with minimal effect on modulation of the CD123 target in acute myeloid leukemia. SL-401 significantly prolonged survival of leukemic mice in acute myeloid leukemia patient-derived xenograft mouse models. In addition to primary samples, studies on normal cord blood and healthy marrow show that SL-401 has activity against normal hematopoietic progenitors. These findings indicate potential use of SL-401 as a “bridge-to-transplant” before allogeneic hematopoietic cell transplantation in acute myeloid leukemia / myelodysplastic syndrome patients.

CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

“…In addition to the above-mentioned studies, additional more recent observations support the rationale of using SL-401 as an IL-3Rα targeting agent in AML patients. Thus, tagraxofusp induced potent cytotoxic activity against CD123-positive AMLs and myelodysplastic syndrome blast cells; furthermore, it exerted also some cytotoxic activity against normal hemopoietic progenitor cells [100]. Thus, this drug was active against hemopoietic cells expressing high or low CD123 levels.…”

Novel therapy in Acute myeloid leukemia (AML): moving toward targeted approaches

“…SL-401 (Tagraxofusp) is a recombinant fusion protein combining human IL-3, the CD123 ligand, with a truncated diphtheria toxin that has demonstrated activity against CD34+CD123+ AML and MDS cells. 104 It is highly effective in blastic plasmacytoid dendritic cell neoplasm (BPDCN), 104 and has modest single-agent activity in AML. 105 Current studies are ongoing with combination therapy with azacitidine (ClinicalTrials.gov identifier: NCT03113643) and also as a single-agent consolidation for eradication of minimal residual disease (ClinicalTrials.gov identifier: NCT02270463).…”

Advances in Acute Myeloid Leukemia: Recently Approved Therapies and Drugs in Development

“…Tagraxofusp or SL401 (Stemline Therapeutics, New York, NY, USA) is an immunotoxin composed of a recombinant protein made of diphtheria toxin fused to human IL-3. Although initially approved by the FDA for adult and pediatric blastic plasmacytoid dendritic cell neoplasm (BPDCN), in December 2018 this agent showed promising cytotoxic activity against CD123-positive AML blast cells in animal models [88]. Clinical data on tagraxofusp remain limited.…”