title: MicroSPECT/CT imaging of primary human AML engrafted into the bone marrow and spleen of NOD/SCID mice using 111In-DTPA-NLS-CSL360 radioimmunoconjugates recognizing the CD123+ / CD131- epitope expressed by leukemia stem cells.
abstract: Engraftment of primary human acute myeloid leukemia (AML) specimens into the bone marrow (BM) of NOD/SCID mice has been used to study leukemia biology and new treatments for the disease. CSL360 is a chimeric IgG1 monoclonal antibody that recognizes CD123 (IL-3 receptor α-subchain) expressed in the absence of CD131 (β-subchain), an epitope that is displayed by leukemia stem cells (LSCs). We are studying CSL360 modified with diethylenetriaminepentaacetic acid (DTPA) for complexing 111In and 13-mer nuclear translocation sequence (NLS) peptides to enable nuclear importation in LSCs for Auger electron radioimmunotherapy (RIT) of AML. We demonstrate that microSPECT/CT imaging using 111In-DTPA-NLS-CSL360 revealed engraftment of primary human AML specimens into the BM and spleen of NOD/SCID mice. Our results suggest that microSPECT/CT imaging is a powerful tool which enables non-invasive assessment of the engraftment of AML into NOD/SCID mice and in the current study specifically probes an epitope displayed by the LSC subpopulation. The targeting of 111In-DTPA-NLS-CSL360 to sites of AML engraftment in the NOD/SCID mouse model is encouraging for future RIT studies. Ultimately, SPECT imaging could be applied in AML patients to assess the delivery of 111In-DTPA-NLS-CSL360 to sites of leukemia and be combined with Auger electron RIT using the same agent targeting the LSC population as a "theranostic" pair.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Leyton
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, ON, Canada; The Hospital for Sick Children, Toronto, ON, Canada; Cell Therapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Brent
authors.initials: B
authors.lastname: Williams
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Gao
authors.affiliation: Cell Therapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Hematology/Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Armand
authors.initials: A
authors.lastname: Keating
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, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada; Department of Medical Imaging, University of Toronto, Toronto, ON, Canada; Toronto General Research Institute, University Health Network, Toronto, ON, Canada. Electronic address: raymond.reilly@utoronto.ca.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Reilly
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D045744:Cell Line, Tumor; D053648:Cytokine Receptor Common beta Subunit / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics; D007205:Indium Radioisotopes; D053650:Interleukin-3 Receptor alpha Subunit / Q000276:immunology; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D064847:Multimodal Imaging; D014411:Neoplastic Stem Cells / Q000276:immunology*; D013154:Spleen / Q000473:pathology*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C115876:CSF2RB protein, human; D053648:Cytokine Receptor Common beta Subunit; C115022:IL3RA protein, human; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D053650:Interleukin-3 Receptor alpha Subunit
keywords: CD123; Leukemia stem cells; MicroSPECT/CT; NOD/SCID mouse; Radioimmunotherapy