title: Auger electron-emitting (111)In-DTPA-NLS-CSL360 radioimmunoconjugates are cytotoxic to human acute myeloid leukemia (AML) cells displaying the CD123(+)/CD131(-) phenotype of leukemia stem cells.
abstract: Chimeric IgG1 monoclonal antibody CSL360 recognizes the CD123(+)/CD131(-) phenotype expressed by leukemic stem cells (LSC). Auger electron-emitting (111)In-DTPA-NLS-CSL360 radioimmunoconjugates incorporating nuclear translocation sequence (NLS) peptides bound specifically to Raji cells transfected with CD123 and exhibited a KD of 11nmols/L in a competition receptor-binding assay using CD123-transfected CHO cells. (111)In-DTPA-NLS-CSL360 was bound, internalized and transported to the nucleus of human AML-5 myeloid leukemia cells. The clonogenic survival of AML-5 cells was reduced by (111)In-DTPA-NLS-CSL360 up to 3.7-fold. Isotype control (111)In-DTPA-chIgG1 was 2-fold less cytotoxic, and unlabeled CSL360, DTPA-NLS-CSL360 or free (111)In acetate did not decrease cell survival. These results are promising for further evaluation of (111)In-DTPA-NLS-CSL360 for Auger electron radioimmunotherapy of AML targeting the critical LSC subpopulation.
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Ontario, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Gao
authors.affiliation: Département de médecine nucléaire et de radiobiologie, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Leyton
authors.affiliation: Department of Hematology/Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.affiliation: Department of Hematology/Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Minden
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Ontario, Canada; Department of Medical Imaging, University of Toronto, Ontario, Canada; Toronto General Research Institute and Joint Department of Medical Imaging, University Health Network, Toronto, Ontario, Canada. Electronic address: raymond.reilly@utoronto.ca.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Reilly
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D045744:Cell Line, Tumor; D053648:Cytokine Receptor Common beta Subunit / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D007205:Indium Radioisotopes / Q000627:therapeutic use; D053650:Interleukin-3 Receptor alpha Subunit / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000532:radiotherapy*; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000528:radiation effects; D004369:Pentetic Acid / Q000627:therapeutic use; D016499:Radioimmunotherapy; D019275:Radiopharmaceuticals; D014410:Tumor Stem Cell Assay
chemical_list: D000911:Antibodies, Monoclonal; C115876:CSF2RB protein, human; C000606072:CSL360; D053648:Cytokine Receptor Common beta Subunit; C115022:IL3RA protein, human; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D053650:Interleukin-3 Receptor alpha Subunit; D019275:Radiopharmaceuticals; D004369:Pentetic Acid
keywords: Acute myeloid leukemia (AML); Auger electrons; CD123; Indium-111; Nuclear translocation sequences (NLS); Radioimmunotherapy