Actinium Pharmaceuticals : Actimab-A, a CD33-Targeted Actinium-225 Radioconjugate, Drives Mutation-Agnostic Anti-Leukemic Activity and Synergizes with Standard Therapies in AML Through Transcriptional Reprogramming

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‌Actimab-A, a CD33-Targeted Actinium-225 Radioconjugate, Drives Mutation-Agnostic Anti-Leukemic Activity and Synergizes with Standard Therapies in AML Through Transcriptional Reprogramming‌ Amanda S. Chin 1 , Merve Sahin 2 , Jason Li 1 , Sumit Mukherjee 1 , Karina Peregrina 1 , Debbie Lewis 1 , Kaitlyn H. Ko 2 , Monideepa Roy 1 , Wenbin Xiao 2 , Shiva Kazerounian 1 , Adeela Kamal 1 , Sheng F. Cai 2 1 Actinium Pharmaceuticals, Inc. New York, NY; 2 Memorial Sloan Kettering Cancer Center New York, NY, USA Tumor Volume MV-4-11 Tumor Volume MV-4-11 2500 3000 Vehicle (PBS) 1500 2000 IgG-Ac225 (0.2 μCi) Lint-Ac255 (0.2 μCi) Vehicle (PBS) IgG-Ac225 (0.2 μCi) Lint-Ac225 (0.2 μCi) Gilteritinib (3 mg/kg) Combination Tumor Volume OCI-AML3 Vehicle (PBS) IgG-Ac225 (0.2 μCi) 2000 Lint-Ac225 (0.2 μCi) Revumenib (25 mg/kg) 1500 Revumenib (25 mg/kg) 1000 Combination ✱✱ Combination ✱✱✱ 1000 1000 500 500 ✱✱ ✱✱✱ 0 0 0 20 30 40 10 20 30 40 10 20 30 Days Post Tumor Implant Days Post Tumor Implant Days Post Tumor Implantation 2000 Tumor Volume HL-60 Survival HL-60 1500 100 1000 ✱ ✱✱✱✱ 50 *** 500 0 0 0 5 10 15 0 5 10 15 20 25 Lint-Ac225 Dose Days Post Treatment Azacitidine Dose Days Post Treatment Lintuzumab-Ac225 potentiates cell death in tumor-bearing mouse models of AML when combined with revumenib, gilteritinib, and azacitidine. Combination of Lintuzumab-Ac225 with SOC Inhibitors Potentiates In Vivo AML Cell Death Independent of Mutations Combination vs Gilteritinib alone Combination vs Revumenib alone Combination vs Revumenib alone Combination vs Azacitidine alone MV-4-11 MV-4-11 OCI-AML3 HL60 P53 Pathway Glycolysis MTORC1 Signaling G2M Checkpoint setSize ≤ 150.00 171.03 P53 Pathway setSize 147.00 169.31 195.00 Adjusted p-value Apoptosis 195.00 Adjusted p-value E2F Targets MYC Targets V1 0.01 P53 Pathway Apoptosis E2F Targets MYC Targets V1 G2M Checkpoint miR-34 EGFR Signaling setSize ≤ 150.00 249.50 MYC Targets V1 setSize ≤ 150.00 171.46 415.00 Adjusted p-value Oxidative Phosphorylation 196.00 Adjusted p-value MYC Targets V1 Hypoxia 0.015 0.015 0.01501 0.015 E2F Targets 0.01 0.01001 MTORC1 Signaling 0.01 0.005 G2M Checkpoint 0.005 0.00501 TNF-α signaling via NF-κB 0.005 0.00001 -2 0 2 NES -4 -2 0 NES 2 4 -3 -2 -1 0 1 2 3 NES -3 -2 -1 0 NES 1 2 Revumenib Revumenib Azacitidine NES 2.280 FDR 0.00011 NES 2.044 FDR 1.11x10 -6 NES 1.859 FDR 7.2x10 -5 Combination monotherapy. treatment produced consistent pathway-level changes compared with Gene set enrichment analyses (GSEA) showed enhanced myeloid differentiation signatures with the addition of lintuzumab-Ac225 to revumenib, gilteritinib, and azacitidine. Across models, combinations were associated with downregulation of proliferative programs, including MYC target genes, E2F targets, and G2/M checkpoint signatures, together with enrichment of p53-associated stress response and apoptosis pathways. Transcriptional Profiling Shows Combination Treatment caused p53 Pathway Activation, Apoptosis, and Myeloid Differentiation Signatures MV-4-11 100 Gilteritinib Lintuzumab-Ac225 Combination Lint-Ac225 + Gilt MV-4-11 100 Revumenib Lintuzumab-Ac225 Combination Lint-Ac225 + Revu OCI-AML3 Revumenib Lintuzumab-Ac225 HL60 100 Combination Lint-Ac225 + Revu **** **** *** **** **** 100 5-Azacytidine Lintuzumab-Ac225 Combination Lint-Ac225 + 5-AZA **** *** **** * 50 **** **** 50 **** **** **** **** **** ** 50 50 *** **** **** *** **** **** ** **** **** **** **** **** **** **** **** 0 0 0 0 Combining lintuzumab-Ac225 with targeted agents significantly increased cytotoxicity compared with monotherapy, demonstrating broad, mutation-independent potentiation of anti-leukemic activity. Lintuzumab-Ac225 Combination with SOC Enhances AML Cytotoxicity Viability (%) Viability (%) Viability (%) Viability (%) Mean Tumor Volume +/-SE (mm 3 ) Mean Tumor Volume +/-SE (mm 3 ) Mean Tumor Volume +/- SE (mm 3 ) Probability of Survival Mean Tumor Volume +/-SE (mm 3 ) Untreated 2.6 nM 4.4 nM 1.4 nCi/mL 4 nCi/mL 1.4 nCi/mL + 2.6 nM 1.4 nCi/mL + 4.4 nM 4 nCi/mL + 2.6 nM 4 nCi/mL + 4.4 nM Untreated 7.1 nM 35.7 nM 1.4 nCi/mL 4 nCi/mL 1.4 nCi/mL + 7.1 nM 1.4 nCi/mL + 35.7 nM 4 nCi/mL + 7.1 nM 4 nCi/mL + 35.7 nM Untreated 8.6 μM 21.1 μM 0.5 nCi/mL 3.5 nCi/mL 0.5 nCi/mL + 8.6 μM 0.5 nCi/mL + 21.1 μM 3.5 nCi/mL + 8.6 μM 3.5 nCi/mL + 21.1 μM Untreated 1,000 nM 10,000 nM 3.8 nCi/mL 22.4 nCi/mL 3.8 nCi/mL + 1,000 nM 3.8 nCi/mL + 10,000 nM 22.4 nCi/mL + 1,000 nM 22.4 nCi/mL + 10,000 nM Background Acute myeloid leukemia (AML) is a genetically heterogeneous and aggressive malignancy with limited durable treatment options. Actimab-A (Lintuzumab-Ac225, Lint-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. Lintuzumab-Ac225 has shown potent anti-leukemic activity 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 standard of care (SOC) 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. Poster Number: 5827 Combination therapies with lintuzumab-Ac225 induce double-stranded DNA damage, which causes Myc to be downregulated and p53 to be upregulated in AML models. Cyclin B-CDK1 complex degradation leads to G2-M arrest and prevents retinoblastoma protein phosphorylation and downregulates E2F target genes. Mechanism of Action: Lintuzumab-Ac225 Combination with SOC AML Cell Line Menin Inhibitors FLT3 Inhibitors Targeting CD33 AML Cell Line Chemo Agent Targeting CD33 Revumenib (nM) Gilteritinib (nM) Lintuzumab-Ac225 (nCi/mL) 5-Azacitidine (μM) Lintuzumab-Ac225 (nCi/mL) IC25 IC50 IC25 IC50 IC25 IC50 IC25 IC50 IC25 IC50 MV-4-11 7.1 35.7 2.6 4.4 1.4 4 HL60 8.6 21.1 0.5 3.5 OCI-AML3 ~1,000 ~10,000 3.8 22.4 Conclusions Actimab-A (lintuzumab-Ac225) shows broad mutation- independent anti-leukemic activity in AML cell lines and Actinium Pharmaceuticals primary AML patient samples. posters are available at the following QR code: When combined with standard therapies, Actimab-A drives complementary transcriptional programs that enhance depth and durability of response. These findings support the clinical evaluation of Actimab-A combinations as a strategy to overcome resistance and enhance therapeutic efficacy in AML. Preparation of Lintuzumab-Ac225 MV-4-11 OCI-AML3 HL60 NCI-H1975 Unstained Lint Lint-DOTA Lint-Ac225 KMT2A / NPM1 FLT3 TP53 CD33 ARC 120 120 100 80 60 40 20 120 120 100 80 100 100 80 80 60 60 60 40 40 40 20 0 20 0 20 0 0 Concentration (nM) MV-4-11 Revumenib MV-4-11 Vehicle (DMSO) Concentration (nM) MV-4-11 Gilteritinib MV-4-11 Vehicle (DMSO) Concentration (μM) HL60 5-Azacitidine HL60 Vehicle (DMSO) OCI-AML3 Revumenib OCI-AML3 Vehicle (DMSO) Concentration (nCi/mL) MV-4-11 Lintuzumab-Ac225 MV-4-11 Lintuzumab OCI-AML3 Lintuzumab-Ac225 OCI-AML3 Lintuzumab HL60 Lintuzumab-Ac225 HL60 Lintuzumab Lintuzumab-Ac225 has Potent Binding and Robust Cytotoxicity in AML Cell Line Panel with Different Mutations Patient 1 (FLT3 & IDH1) Patient 2 (NPM1) Patient 3 (KMT2A & FLT3) Patient 4 (TP53 & IDH1) ✱✱✱✱ ✱ ns ✱✱ ✱✱✱✱ ✱✱✱✱ ✱ 100 100 ✱✱ 100 100 50 50 50 50 0 0 0 0 Lintuzumab-Ac225 showed a robust cytotoxicity in primary AML patient samples, irrespective of FLT3, KMT2A, NPM1, IDH1 or TP53 status. Combining SOC therapies with lintuzumab-Ac225 enhanced efficacy. Lintuzumab-Ac225 Combination with SOC Enhances Cytotoxicity in Primary AML Patient Samples Cell Viability (% of control) Cell Viability (% of control) Cell Viability (% of control) Cell Viability (% of control) Viability (%) Viability (%) Viability (%) Viability (%) 0.001 0.01 0.1 1 10 100 1,000 10,000 100,000 Untreated Lintuzumab DMSO Lint-Ac225 1,000 nCi/mL Gilt 2,000 nM Combination Untreated Lintuzumab DMSO Lint-Ac225 500 nCi/mL Revu 50 nM Combination 0.01 0.1 1 10 100 1,000 10,000 100,000 0.001 0.01 0.1 1 10 100 1000 10000 0.001 0.01 0.1 1 10 100 1,000 No Treatment Lint DMSO 2,000 nCi/mL 225Ac-Lin t 100 nM Revu Combination Untreated Lintuzumab DMSO Lint-Ac225 2,000 nCi/m L 5-AZA 5 μM Combination AML Cell Line Panel Cell Line KMT2A FLT3 NPM1 TP53 CD33 MV-4-11 MLL-AFF1 ITD WT Positive OCI-AML3 NPM1 WT Positive HL60 Deletion Positive NCI-H1975 Negative American Association for Cancer Research (AACR). San Diego, CA April 17-22, 2026

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