225Ac‐labeled CD33‐targeting antibody reverses resistance to Bcl‐2 inhibitor venetoclax in acute myeloid leukemia models
Why this work is in the frame
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Bibliographic record
Abstract
ABSTRACT Purpose Despite the availability of new drugs, many patients with acute myeloid leukemia (AML) do not achieve remission and outcomes remain poor. Venetoclax is a promising new therapy approved for use in combination with a hypomethylating agent or with low‐dose cytarabine for the treatment of newly diagnosed older AML patients or those ineligible for intensive chemotherapy. 225 Actinium‐lintuzumab ( 225 Ac‐lintuzumab) is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single‐agent activity in relapsed/refractory AML. Increased expression of MCL‐1 is a mediator of resistance to venetoclax in cancer. Experimental design Here we investigated the potential for 225 Ac‐lintuzumab‐directed DNA damage to suppress MCL‐1 levels as a possible mechanism of reversing resistance to venetoclax in two preclinical in vivo models of AML. Results We demonstrated that 225 Ac‐lintuzumab in combination with venetoclax induced a synergistic increase in tumor cell killing compared to treatment with either drug alone in venetoclax‐resistant AML cell lines through both an induction of double‐stranded DNA breaks (DSBs) and depletion of MCL‐1 protein levels. Further, this combination led to significant tumor growth control and prolonged survival benefit in venetoclax‐resistant in vivo AML models. Conclusions There results suggest that the combination of 225 Ac‐lintuzumab with venetoclax is a promising therapeutic strategy for the treatment of patients with venetoclax‐resistant AML. Clinical trial of this combination therapy (NCT03867682) is currently ongoing.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it