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: Jeffrey V Leyton, Brent Williams, Catherine Gao, Armand Keating, Mark Minden, Raymond M Reilly
• Journal: Leukemia research (Leuk Res) Vol. 38 Issue 11 Pg. 1367-73 (Nov 2014) ISSN: 1873-5835 [Electronic] England
• PMID: 25278187 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• CSF2RB protein, human
• Cytokine Receptor Common beta Subunit
• IL3RA protein, human
• Immunoconjugates
• Indium Radioisotopes
• Interleukin-3 Receptor alpha Subunit

Topics

• Animals
• Bone Marrow (pathology)
• Cell Line, Tumor
• Cytokine Receptor Common beta Subunit (immunology)
• Humans
• Immunoconjugates (pharmacokinetics)
• Indium Radioisotopes
• Interleukin-3 Receptor alpha Subunit (immunology)
• Leukemia, Myeloid, Acute (pathology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Multimodal Imaging
• Neoplastic Stem Cells (immunology)
• Spleen (pathology)
• Tissue Distribution
• Tomography, Emission-Computed, Single-Photon