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MicroSPECT/CT imaging of primary human AML engrafted into the bone marrow and spleen of NOD/SCID mice using In-DTPA-NLS-CSL360 radioimmunoconjugates recognizing the CD123/CD131 epitope expressed by leukemia stem cells |
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| Authors: | Jeffrey V. Leyton Brent Williams Catherine Gao Armand Keating Mark Minden Raymond M. Reilly |
| Affiliation: | 1. Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada;2. Institute of Medical Science, University of Toronto, Toronto, ON, Canada;3. The Hospital for Sick Children, Toronto, ON, Canada;4. Cell Therapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada;5. Department of Hematology/Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada;6. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada;g Department of Medical Imaging, University of Toronto, Toronto, ON, Canada;h Toronto General Research Institute, University Health Network, Toronto, ON, Canada |
| 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. |
| Keywords: | CD123 MicroSPECT/CT Leukemia stem cells NOD/SCID mouse Radioimmunotherapy |
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