Auger Electron Radioimmunotherapeutic Agent Specific for the CD123<sup>+</sup>/CD131<sup>−</sup> Phenotype of the Leukemia Stem Cell Population
Bibliographic record
Abstract
UNLABELLED: 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. METHODS: 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. RESULTS: 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. CONCLUSION: (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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".