SL‐401 and SL‐501, targeted therapeutics directed at the interleukin‐3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia

• Published in: British journal of haematology 2014-09, Vol.166 (6), p.862-874
• Main Authors: Frolova, Olga, Benito, Juliana, Brooks, Chris, Wang, Rui‐Yu, Korchin, Borys, Rowinsky, Eric K., Cortes, Jorge, Kantarjian, Hagop, Andreeff, Michael, Frankel, Arthur E., Konopleva, Marina
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Benzamides - pharmacology; Biological and medical sciences; Cell Proliferation - drug effects; chronic myeloid leukaemia; Drug Resistance, Neoplasm - drug effects; Hematologic and hematopoietic diseases; Humans; Imatinib Mesylate; Interleukin-3 Receptor alpha Subunit - metabolism; interleukin‐3 receptor; leukaemic stem cells; Leukemia, Myeloid, Chronic-Phase - drug therapy; Leukemia, Myeloid, Chronic-Phase - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Piperazines - pharmacology; Pyrimidines - pharmacology; Receptors, Interleukin-3 - drug effects; Recombinant Fusion Proteins - pharmacology; SL‐401; SL‐501; Transplantation, Heterologous; Tumor Cells, Cultured; Tumors
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/bjh.12978

Summary While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that interleukin‐3 receptor (IL3R, CD123) is highly expressed on CD34+/CD38− BCR‐ABL1+ CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)‐IL3 fusion proteins SL‐401 (DT388‐IL3) and SL‐501 (DT388‐IL3[K116W]) could eradicate these stem cells. SL‐401 and SL‐501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI‐resistant KBM5‐STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL‐401 and SL‐501 decreased the absolute numbers of viable CD34+/CD38−/CD123+ CML progenitor cells by inducing apoptosis. IL3‐targeting agents reduced clonogenic growth and diminished the fraction of primitive long‐term culture‐initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI‐resistant CML blast crisis. These data suggest that the DT‐IL3 fusion proteins, SL‐401 and SL‐501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk.