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

Catherine Gao; Jeffrey V Leyton; Aaron D Schimmer; Mark Minden; Raymond M Reilly

doi:10.1016/j.apradiso.2015.12.043

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

Appl Radiat Isot. 2016 Apr:110:1-7. doi: 10.1016/j.apradiso.2015.12.043. Epub 2015 Dec 18.

Authors

Catherine Gao¹, Jeffrey V Leyton², Aaron D Schimmer³, Mark Minden³, Raymond M Reilly⁴

Affiliations

¹ Department of Pharmaceutical Sciences, University of Toronto, Ontario, Canada.
² Département de médecine nucléaire et de radiobiologie, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
³ Department of Hematology/Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁴ 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: [email protected].

PMID: 26748017
DOI: 10.1016/j.apradiso.2015.12.043

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.

Keywords: Acute myeloid leukemia (AML); Auger electrons; CD123; Indium-111; Nuclear translocation sequences (NLS); Radioimmunotherapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Monoclonal / therapeutic use
Cell Line, Tumor
Cytokine Receptor Common beta Subunit / metabolism
Humans
Immunoconjugates / therapeutic use
Indium Radioisotopes / therapeutic use
Interleukin-3 Receptor alpha Subunit / metabolism
Leukemia, Myeloid, Acute / immunology
Leukemia, Myeloid, Acute / radiotherapy*
Neoplastic Stem Cells / immunology
Neoplastic Stem Cells / radiation effects
Pentetic Acid / therapeutic use
Radioimmunotherapy
Radiopharmaceuticals
Tumor Stem Cell Assay

Substances

Antibodies, Monoclonal
CSF2RB protein, human
CSL360
Cytokine Receptor Common beta Subunit
IL3RA protein, human
Immunoconjugates
Indium Radioisotopes
Interleukin-3 Receptor alpha Subunit
Radiopharmaceuticals
Pentetic Acid

Grants and funding

MOP111118/Canadian Institutes of Health Research/Canada