Actimab-A（一种CD33靶向的锕-225放射性偶联物）通过转录重编程驱动不依赖突变的抗白血病活性，并与标准疗法在AML中产生协同作用

Introduction: Acute myeloid leukemia (AML) is a genetically heterogeneous and aggressive malignancy with limited durable treatment options. Actimab-A (lintuzumab-Ac225), a CD33-targeted antibody radioconjugate, delivers the alpha emitter actinium-225 (Ac-225) to AML cells, inducing potent, localized DNA damage. Clinical studies have shown encouraging responses when combined with CLAG-M chemotherapy in relapsed/refractory AML, including in patients with TP53 mutations or venetoclax resistance. Previously, we have shown the anti-leukemic activity of lintuzumab-Ac225 in AML cells regardless of mutations ( FLT3 , TP53 , NPM1 , and KMT2A ) in both in vitro and in vivo AML models. Here, we demonstrated in primary AML patient samples that lintuzumab-Ac225 has strong translational therapeutic potential both as monotherapy and in combination with other therapies. We also defined the transcriptional profiles of AML cells treated with lintuzumab-Ac225 combination therapies to understand the underlying molecular mechanisms of anti-leukemic activity of these combination treatments. Methods: Lintuzumab was conjugated to p-SCN-Bn-DOTA and radiolabeled with Ac-225. To explore mechanisms of synergy, AML cell lines harboring common mutations ( FLT3 , KMT2Ar : MV-4-11, MOLM-13 cells, NPM1c : OCI-AML3, and mutant TP53 : Kasumi-1, HL-60 cells) were treated for 24 hours with standard-of-care (SOC) therapies: FLT3 inhibitors (gilteritinib, quizartinib), menin inhibitors (revumenib, ziftomenib) or azacitidine alone or in combination with lintuzumab-Ac225. We performed RNA sequencing (RNA-seq), followed by comprehensive gene set enrichment analysis. The cytotoxic potency of SOC was evaluated as monotherapies and in combination with Lintuzumab-Ac225 in primary AML patient samples. Results: Lintuzumab-Ac225 showed a robust, dose-dependent cytotoxicity in primary AML patient samples, irrespective of FLT3, KMT2A, NPM1, or TP53 status. Notably, combining SOC therapies with lintuzumab-Ac225 in vitro enhanced their growth inhibitory effects. Lintuzumab-Ac225 combination versus SOC alone produced significant downregulation of MYC, G2M checkpoint, E2F targets and MTORC1 signaling while activating p53-mediated apoptosis, underscoring the mechanistic rationale for clinical development Conclusions: Lintuzumab-Ac225 shows broad mutation-independent anti-leukemic activity in AML cell lines and primary AML patient samples. When combined with standard therapies, it drives complementary transcriptional programs that enhance depth and durability of response. Together, these findings support the clinical evaluation of lintuzumab-Ac225-based combinations as a strategy to overcome resistance and enhance therapeutic efficacy in AML.