Abstract 594: Lintuzumab-Ac225 has potent mutation agnostic antileukemic activity in preclinical models of AML
Bibliographic record
Abstract
Abstract Introduction: Acute myeloid leukemia (AML) is a complex and aggressive blood cancer with a poor prognosis, driven by genetic mutations that complicate treatment and often lead to relapse. Lintuzumab-Ac225 is a promising investigational antibody radio-conjugate that targets CD33. The payload, actinium-225 (Ac-225) is an alpha particle-emitting radionuclide that causes lethal DNA damage. In clinical trials, lintuzumab-Ac225 had positive responses when combined with CLAG-M chemotherapy in relapsed/refractory AML patients, including those with high-risk features like venetoclax resistance and TP53 mutations. Here we tested the hypothesis that lintuzumab-Ac225 has anti-leukemic activity in AML cells regardless of mutations (FLT3, TP53, NPM1, and KMT2A). Also, we explored its potential as a single agent or in combination with other therapies to enhance the treatment response for AML. Methods: Lintuzumab-Ac225 was made by conjugating lintuzumab with p-SCN-Bn-DOTA and subsequently radiolabeled with Ac-225. A flow cytometry viability assay was performed in vitro with test drugs to assess the response across genetically altered human AML cell lines (mutant FLT3, KMT2A: MV-4-11, MOLM-13 cells, mutant NPM1: OCI-AML3, and mutant TP53: Kasumi-1, HL-60 cells). FLT3 inhibitors (gilteritinib, quizartinib), KMT2A inhibitors (revumenib, ziftomenib) and azacitidine were evaluated as single agents and in combination with Lintuzumab-Ac225. The modulation of DNA damage markers in response to lintuzumab-Ac225 was analyzed by Western blots. The effect of lintuzumab-Ac225 on AML growth in vivo was investigated in subcutaneous MV-4-11 leukemia xenograft models. Results: Treatment with lintuzumab-Ac225 showed a potent, dose-dependent decrease in leukemia cell viability in vitro, across all tested AML models, regardless of mutation status (FLT3, KMT2A, NPM1, TP53). IC50 values ranged from 0.5 to 5 nCi/mL, showing that lintuzumab-Ac225 induces cell death independent of these mutations. The treatment also triggered DNA damage and apoptosis in mutant cells, with increased phosphorylation of H2A.X and p21. While FLT3 inhibitors, KMT2A inhibitors, and azacitidine showed variable single-agent efficacy in mutation-carrying AML cells, combining these with lintuzumab-Ac225 in vitro enhanced their effects (p<0.01). In the MV-4-11 in vivo AML model, lintuzumab-Ac225 combined with FLT3 or KMT2A inhibitors significantly reduced tumor growth compared to monotherapy (p<0.002). Conclusions: Lintuzumab-Ac225 shows broad anti-leukemic activity in AML cell lines, in a mutation (FLT3, KMT2A, NPM1, TP53) agnostic manner. It improves AML control in high-risk cases and enhances response durability when combined with standard of care treatments. These findings support its potential as a backbone therapy for relapsed/refractory AML, warranting further clinical evaluation. Citation Format: Amanda S. Chin, Rubin Jiao, Kevin J. Allen, Jason Li, Madhuri Vusirikala, Avinash Desai, Le-Cun Xu, Monideepa Roy, Mackenzie Malo, Denis Beckford-Vera, Ekaterina Dadachova, Adeela Kamal. Lintuzumab-Ac225 has potent mutation agnostic antileukemic activity in preclinical models of AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 594.
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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) | 0.002 | 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".