title: 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.
abstract: 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.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Frolova
authors.forename: Juliana
authors.initials: J
authors.lastname: Benito
authors.forename: Chris
authors.initials: C
authors.lastname: Brooks
authors.forename: Rui-Yu
authors.initials: RY
authors.lastname: Wang
authors.forename: Borys
authors.initials: B
authors.lastname: Korchin
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Frankel
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D053650:Interleukin-3 Receptor alpha Subunit / Q000378:metabolism; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D016185:Receptors, Interleukin-3 / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C115022:IL3RA protein, human; D053650:Interleukin-3 Receptor alpha Subunit; D010879:Piperazines; D011743:Pyrimidines; D016185:Receptors, Interleukin-3; D011993:Recombinant Fusion Proteins; C000592495:diphtheria toxin (1-388)-Trp(116)-interleukin-3 fusion protein; D000068877:Imatinib Mesylate; C000592123:tagraxofusp
keywords: SL-401; SL-501; chronic myeloid leukaemia; interleukin-3 receptor; leukaemic stem cells