CD123 (IL-3 Receptor α Chain) Neutralization by a Monoclonal Antibody Selectively Eliminates Human Acute Myeloid Leukemic Stem Cells.
Bibliographic record
Abstract
Abstract Development of effective therapies against acute myeloid leukemia (AML) will likely require elimination of the leukemic stem cell (LSC), which maintains the AML hierarchy. Based on high expression of the IL-3 receptor α chain (CD123) on AML-LSC, we tested a neutralizing antibody against CD123 (7G3) for its in vitro and in vivo effects on AML cells. By flow cytometric analysis, high expression of CD123 on CD34+/38− AML-LSC was confirmed. In vitro, 7G3 inhibited IL-3-induced proliferation in 31/34 primary AML specimens tested. Moreover, exposure of primary AML cells to 7G3 in vitro caused inhibition of IL-3-induced tyrosine phosphorylation and downstream signaling of the IL-3 receptor βc chain in a concentration-dependent fashion. Ex vivo treatment of primary AML cells with 7G3 (10 μg/ml, 2 h) profoundly reduced leukemic engraftment of human CD45+ (huCD45+) cells in non-obese diabetic/severe-combined immunodeficient (NOD/SCID) mice in 9/10 evaluable samples (mean ± SEM, 89.7 ±1.9% inhibition relative to IgG2a control, P=0.013), establishing that the AML-LSC was targeted. The overall survival of engrafted mice was significantly improved (median survival of control IgG2a-treated group 11.5 weeks versus 24 weeks for the 7G3-treated group, n = 10 per group, P=0.019). Moreover, ex vivo 7G3 treatment reduced the short-term homing efficiency of AML cells to the bone marrow by 65% compared with IgG2a control-treated cells, measured at 24 h post inoculation. In contrast, ex vivo exposure to 7G3 had minor, if any, effects on the engraftment of normal bone marrow cells (23.5 ±8.9% inhibition relative to IgG2a control, n=5). Direct delivery of 7G3-treated AML cells into the bone marrow by intra-femoral injection did not completely restore engraftment, suggesting a specific biological role of 7G3 in inhibiting homing, lodgement and proliferation of AML-LSC. Despite some sample to sample heterogeneity, thrice-weekly administration of 7G3 to NOD/SCID mice with pre-established AML consistently reduced AML dissemination to peripheral blood, spleen and liver, and reduced infiltration of a single AML sample in the bone marrow. 7G3 treatment was also associated with down-regulation of CD123 expression on AML cells in vivo. AML cells harvested from 7G3-treated mice were unable to repopulate secondary recipient mice, with engraftment reduced to 5.7 ±4.1% (n=7) huCD45+ cells in the femoral bone marrow compared with 26.8 ±6.6% in IgG2a-treated controls (n=9, P=0.024), indicating that CD123 neutralization targeted AML-LSC self-renewal ability, specifically reducing the proportion of AML-LSC. These results suggest that blocking CD123 inhibits homing, lodgement and proliferation of AML-LSC in the bone marrow microenvironment and prevents subsequent organ infiltration, and support additional investigations into 7G3 and its potential as a novel therapy for AML.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 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 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".