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

Haematologica
Rajeswaran ManiNatarajan Muthusamy

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 no...Continue Reading

Citations

Aug 30, 2019·Expert Review of Clinical Pharmacology·Minas P EconomidesNaveen Pemmaraju
Dec 10, 2019·Leukemia & Lymphoma·Namrata S ChandhokThomas Prebet
Dec 6, 2019·Expert Opinion on Biological Therapy·Mansour AlfayezNaveen Pemmaraju
Mar 13, 2019·Drugs·Yahiya Y Syed
Jul 20, 2019·Therapeutic Advances in Hematology·Eric S Winer, Richard M Stone
Apr 28, 2020·Hematology/oncology Clinics of North America·Mayumi Sugita, Monica L Guzman
Mar 7, 2021·International Journal of Molecular Sciences·Vincenzo NasilloTommaso Trenti
May 28, 2021·Frontiers in Oncology·Alessandro IsidoriAntonio Curti
Aug 23, 2021·Paediatric Drugs·LaQuita M JonesTodd Cooper

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Methods Mentioned

BETA
MDS
xenograft
flow cytometry
xenografts

Software Mentioned

Kaluza

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