Abstract 594: Lintuzumab-Ac225 has potent mutation agnostic antileukemic activity in preclinical models of AML

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.