+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Auger electron radioimmunotherapeutic agent specific for the CD123+/CD131- phenotype of the leukemia stem cell population

Auger electron radioimmunotherapeutic agent specific for the CD123+/CD131- phenotype of the leukemia stem cell population

Journal of Nuclear Medicine 52(9): 1465-1473

Our aim was to construct and characterize (111)In-nuclear translocation sequence (NLS)-7G3, an Auger electron-emitting radioimmunotherapeutic agent that preferentially recognizes the expression of CD123 (interleukin-3 receptor [IL-3R] α-subchain) in the absence of CD131 (IL-3R β-subchain) displayed by leukemia stem cells. Monoclonal antibody 7G3 was modified with 13-mer peptides [CGYGPKKKRKVGG] harboring the NLS of SV-40 large T-antigen and with diethylenetriaminepentaacetic acid for labeling with (111)In. Immunoreactivity was evaluated in a competition radioligand binding assay and by flow cytometry. Nuclear localization of (111)In-NLS-7G3 was studied by cell fractionation in CD123(+)/CD131(-) acute myelogenous leukemia (AML)-3, -4, and -5 cells or in primary AML or normal leukocytes. Micro-SPECT was performed in nonobese diabetic (NOD)/severe combined immune deficient (SCID) mice engrafted subcutaneously with Raji-CD123 tumors or with disseminated AML-3 or -5 cells. The cytotoxicity of (111)In-NLS-7G3 on AML-5 cells was studied after 7 d in culture by trypan blue dye exclusion. DNA damage was assessed using the γ-H2AX assay. NLS-7G3 exhibited preserved CD123 immunoreactivity (affinity, 4.6 nmol/L). Nuclear importation of (111)In-NLS-7G3 in AML-3, -4, or -5 cells was specific and significantly higher than unmodified (111)In-7G3 and was greater in primary AML cells than in normal leukocytes. Rapid elimination of (111)In-NLS-7G3 in NOD/SCID mice prevented imaging of subcutaneous Raji-CD123 tumors. This phenomenon was Fc-dependent and IgG(2a) isotype-specific and was overcome by the preadministration of excess IgG(2a) or using (111)In-NLS-7G3 F(ab')(2) fragments. AML-3 and -5 cells were engrafted into the bone marrow or spleen or at extramedullary sites in NOD/SCID mice. Micro-SPECT/CT with (111)In-NLS-7G3 F(ab')(2) showed splenic involvement, whereas foci of disease were seen in the spine or femur or at extramedullary sites in the brain and lymph nodes using (111)In-NLS-7G3 IgG(2a). The viability of AML-5 cells was reduced by exposure in vitro to (111)In-NLS-7G3; this reduction was associated with an increase in unrepaired DNA double-strand breaks. (111)In-NLS-7G3 is a promising novel Auger electron-emitting radioimmunotherapeutic agent for AML aimed at the leukemia stem cell population. Micro-SPECT/CT was useful for visualizing the engraftment of leukemia in NOD/SCID mice.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 036193193

Download citation: RISBibTeXText

PMID: 21816968

DOI: 10.2967/jnumed.111.087668

Related references

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. Applied Radiation and Isotopes 110: 1-7, 2016

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. Leukemia Research 38(11): 1367-1373, 2014

Bn-DTPA-nimotuzumab with/without modification with nuclear translocation sequence NLS peptides an Auger electron-emitting radioimmunotherapeutic agent for EGFR-positive and trastuzumab Herceptin-resistant breast cancer. 2012

¹¹¹In-Bn-DTPA-nimotuzumab with/without modification with nuclear translocation sequence (NLS) peptides: an Auger electron-emitting radioimmunotherapeutic agent for EGFR-positive and trastuzumab (Herceptin)-resistant breast cancer. Breast Cancer Research and Treatment 135(1): 189-200, 2012

The human polynucleotide kinase/phosphatase (hPNKP) inhibitor A12B4C3 radiosensitizes human myeloid leukemia cells to Auger electron-emitting anti-CD123 ¹¹¹In-NLS-7G3 radioimmunoconjugates. Nuclear Medicine and Biology 41(5): 377-383, 2014

Characteristic CD103 and CD123 expression pattern defines hairy cell leukemia: usefulness of CD123 and CD103 in the diagnosis of mature B-cell lymphoproliferative disorders. American Journal of Clinical Pathology 136(4): 625-630, 2011

New immunotoxins targeting CD123, a stem cell antigen on acute myeloid leukemia cells. Journal of ImmunoTherapy 30(6): 607-613, 2007

N-Cadherin and Tie2 positive CD34⁺CD38⁻CD123⁺ leukemic stem cell populations can develop acute myeloid leukemia more effectively in NOD/SCID mice. Leukemia Research 38(5): 632-637, 2014

Novel conjugates of single-chain Fv antibody fragments specific for stem cell antigen CD123 mediate potent death of acute myeloid leukaemia cells. British Journal of Haematology 148(6): 879-889, 2010

The relationship of the stem cell phenotype and lineage commitment to the multidrug resistance phenotype in acute leukemia. Laboratory Investigation 66(1): 88A, 1992

Projectile K-Auger-electron production by bare, one-electron, and two-electron ions through zero-degree Auger spectroscopy. Physical Review. A General Physics 32(4): 2494-2495, 1985

T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. Blood 122(18): 3138-3148, 2013

Radioimmunotherapeutic strategies in autologous hematopoietic stem-cell transplantation for malignant lymphoma. Best Practice and Research. Clinical Haematology 19(4): 669-684, 2006

CD123 Immunohistochemical Expression Is a Specific But Insensitive Marker of Early T-precursor Leukemia. Applied Immunohistochemistry and Molecular Morphology 24(1): E4-E5, 2016

CD123 redirected multiple virus-specific T cells for acute myeloid leukemia. Leukemia Research 41: 76-84, 2016