title: Antileukemia Efficacy and Mechanisms of Action of SL-101, a Novel Anti-CD123 Antibody Conjugate, in Acute Myeloid Leukemia.
abstract: Purpose:The persistence of leukemia stem cells (LSC)-containing cells after induction therapy may contribute to minimal residual disease (MRD) and relapse in acute myeloid leukemia (AML). We investigated the clinical relevance of CD34+CD123+LSC-containing cells and antileukemia potency of a novel antibody conjugate SL-101 in targeting CD123+LSCs.Experimental Methods and Results:In a retrospective study on 86 newly diagnosed AML patients, we demonstrated that a higher proportion of CD34+CD123+LSC-containing cells in remission was associated with persistent MRD and predicted shorter relapse-free survival in patients with poor-risk cytogenetics. Using flow cytometry, we explored the potential benefit of therapeutic targeting of CD34+CD38-CD123+cells by SL-101, a novel antibody conjugate comprising an anti-CD123 single-chain Fv fused toPseudomonas exotoxin AThe antileukemia potency of SL-101 was determined by the expression levels of CD123 antigen in a panel of AML cell lines. Colony-forming assay established that SL-101 strongly and selectively suppressed the function of leukemic progenitors while sparing normal counterparts. The internalization, protein synthesis inhibition, and flow cytometry assays revealed the mechanisms underlying the cytotoxic activities of SL-101 involved rapid and efficient internalization of antibody, sustained inhibition of protein synthesis, induction of apoptosis, and blockade of IL3-induced p-STAT5 and p-AKT signaling pathways. In a patient-derived xenograft model using NSG mice, the repopulating capacity of LSCs pretreated with SL-101in vitrowas significantly impaired.Conclusions:Our data define the mechanisms by which SL-101 targets AML and warrant further investigation of the clinical application of SL-101 and other CD123-targeting strategies in AML.Clin Cancer Res; 23(13); 3385-95. ©2017 AACR.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Jorgensen
authors.affiliation: Stemline Therapeutics, Inc., New York, New York.
authors.forename: Chris
authors.initials: C
authors.lastname: Brooks
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Ce
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Graciela M
authors.initials: GM
authors.lastname: Nogueras González
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cavazos
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rongqing
authors.initials: R
authors.lastname: Pan
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hong
authors.initials: H
authors.lastname: Mu
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Sa A
authors.initials: SA
authors.lastname: Wang
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gheath
authors.initials: G
authors.lastname: Ai-Atrash
authors.affiliation: Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Ciurea
authors.affiliation: Bone Marrow Transplantation and Leukemia Program, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Mike
authors.initials: M
authors.lastname: Rettig
authors.affiliation: Bone Marrow Transplantation and Leukemia Program, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xuelin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. mkonople@mdanderson.org.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000276:immunology; D053650:Interleukin-3 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D014411:Neoplastic Stem Cells; D015398:Signal Transduction / Q000276:immunology; D057127:Single-Chain Antibodies / Q000008:administration & dosage* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D018796:Immunoconjugates; D053650:Interleukin-3 Receptor alpha Subunit; D057127:Single-Chain Antibodies