Actinium Pharmaceuticals : Preclinical Development of ATNM-400, a First-in-Class Actinium-225 Radioconjugate with Pan-Tumor Efficacy in Solid Tumors

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‌Preclinical Development of ATNM-400, a First-in-Class Actinium-225 Radioconjugate with Pan-Tumor Efficacy in Solid Tumors Sumit Mukherjee , Amanda S. Chin, Karina Peregrina, Debbie Lewis, Jason Li, Victor Sanz Chavez, Monideepa Roy, Shiva Kazerounian, Adeela Kamal Actinium Pharmaceuticals, Inc. New York, NY PSMA MFI (BV421) Target MFI (PE) Survival fraction (%) Tumor Volume +/-SE (mm 3 ) Target (MFI) %Cell Viability MFI (PE) Viability (%) Denisty (arbitraty units) Viability (%) Denisty (arbitraty units) Denisty (arbitraty units) Nontreated 0.01 μM Osi 0.1 μM Osi 1 μM Osi 5 μM Osi 2 μCi/mL ATNM-400 0.01 μM Osi + 2 μCi/mL ATN M-400 0.1 μM Osi + 2 μCi/mL ATNM -400 1 μM Osi + 2 μCi/mL ATNM- 400 5 μM Osi + 2 μCi/mL ATNM- 400 0.00001 0.0001 0.001 0.01 0.1 1 10 100 1,000 10,000 Untreated 1 μg/mL Trastuzumab 5 μg/mL Trastuzumab 10 μg/mL Trastuzumab ATNM-400 1 μg/mL Trastuzumab + ATNM-400 BT474 5 μg/mL Trastuzumab + ATNM-400 BT474-Clone5 10 μg/mL Trastuzumab + ATNM-400 BT474 BT474-Clone5 Untreated 1 μg/mL 5 μg/mL No Treatment 10 μg/mL 2 μCi ATNM-400 10 nCi/mL 125 nCi/mL 800 nCi/mL 1 μg/mL + 10 nCi/mL 5 μg/mL + 125 nCi/mL 10 μg/mL + 800 nCi/mL Presentation Number: 5824 BACKGROUND Therapeutic resistance limits durable responses to standard of care (SOC) therapies in prostate, lung, and breast cancers. ATNM-400, a first-in-class Actinium-225 (225Ac) antibody radioconjugate, targets a novel non-PSMA membrane antigen often overexpressed in advanced and therapy-refractory solid tumors across these indications, offering a strategy to overcome resistance. Prostate Cancer (PCa): PSMA-targeted 177Lu-PSMA-617 is approved for metastatic castration resistant PCa (mCRPC), but resistance develops in many patients, correlating with rapid progression and poor survival. The ATNM-400 target is a non-PSMA antigen overexpressed in prostate tumors; its expression correlates with rapid disease progression, earlier onset of castration resistance, and poor overall survival in mCRPC. The target also drives tumor survival and castration resistance in advanced PCa models (e.g., 22Rv1, C4-2), providing a rationale for targeted alpha radiotherapy. Therapeutic targeting with ATNM-400 leads to preclinical efficacy surpassing PSMA targeted agents in PCa models with varying target and PSMA expression levels. Lung Cancer (LC): In EGFR-mutant (EGFR-m) LC, EGFR TKIs such as Osimertinib (Osi), as well as agents like Dato-DXd (TROP2-ADC) and Amivantamab (EGFR-cMET bispecific), have transformed care but are limited by acquired resistance and disease progression. The target for ATNM-400 is linked to Osimertinib resistance and poor prognosis. We therefore evaluated ATNM-400 as a targeted alpha radiotherapy in EGFR-m NSCLC preclinical models, benchmarking superior antitumor activity against approved therapies Osi (1L), Amivantamab (2L), and Dato-DXd (3L) to address current therapeutic limitations. ATNM-400, as monotherapy or combined with Osi delivers robust tumor control that exceeds established EGFR-and HER3/EGFR-targeted regimens (including Osimertinib + chemotherapy and Izalontamab-based ADCs), supporting its potential as a best-in-class targeted radiotherapy backbone in EGFR-m NSCLC models. Breast Cancer (BC): The target of ATNM-400 is overexpressed in breast cancer subtypes, including HER2-therapy (example: trastuzumab) resistant disease. ATNM-400 demonstrates robust anti-tumor activity in vivo across hormone receptor+ (HR+), triple-negative (TNBC), and trastuzumab-resistant breast cancer models. Collectively, these data support ATNM-400 as a pan-tumor, tumor agnostic, resistance-focused targeted alpha radiotherapy with translational potential to overcome limitations of current SOCs in advanced PCa, LC and BC. Cell Line PSMA Expression 177Lu-PSMA-617 IC50 (μCi/mL) ATNM-400 IC50 (μCi/mL) C4-2 High 39.22 0.0094 LNCaP High 17.17 0.0038 22Rv1 Low 163 0.0035 DU145 Negative 1,216 1.0838 PSMA Expression Target Expression Target Expression Post-Osimertinib Treatment ATNM-400 Post-Osimertinib Cellular Target Antigen Binding Clonogenic Efficacy p-AKT Target 10000 10000 150 20000 ✱✱✱✱ Week 1: Osimertinib (7d) Week 2: Media Only pH2AX ✱✱✱✱ 40000 8000 8000 100 15000 6000 100 6000 Week 1: Media Only Week 2: ATNM-400 (3h) Unstained Secondary Antibody only Human IgG Control Cold target mAb ATNM400-DOTA ATNM-400 ✱✱✱✱ 30000 GAPDH 5 p-AKT ✱✱✱✱ 4 GAPDH 2.5 Target ✱✱✱✱ 4000 4000 50 10000 20000 2.0 GAPDH 2.0 pH2AX ✱✱ 1.5 50 2000 2000 Week 1: Osimertinib (7d) Week 2: ATNM-400 (3h) 3 1.5 5000 10000 1.0 0 0 0 **** C4-2 DU145 22RV1 LNCaP C4-2 **** **** **** * ** * 2 1.0 DU145 22RV1 LNCaP **** **** ** 0 0 0.5 0 MDA-MB-468 MCF7 MCF7-Tam1 BT474 BT474-Clone 5 1 0.5 Unstained PSMA-Stained Unstained Target-Stained Dose (μCi/mL) NCI-H1975 Nontreated, Unstained Nontreated, Stained 0 0.0 0.0 C4-2 + ATNM-400 C4-2 + 177Lu-PSMA-617 LNCaP + ATNM-400 LNCaP + 177Lu-PSMA-617 22Rv1 + ATNM-400 22Rv1 + 177Lu-PSMA-617 DU145 + ATNM-400 DU145 + 177Lu-PSMA-617 High Target High PSMA DMSO 0.02μM Osimertinib 150 Post-Trastuzumab Failure Week 1: Trastuzumab (7d) Week 2: Media Only Week 1: Media Only Week 2: 2 μCi/mL ATNM-400 (3h) Week 1: Trastuzumab (7d) Week 2: 2 μCi/mL ATNM-400 (3h) Combination: ATNM-400 & Trastuzumab Med Target Low PSMA 100 Osimertinib treatment elevates target expression and causes synergistic 100 **** * n * s ** Low Target PSMA Negative **** **** No Treatment Trastuzumab ATNM-400 Combination Trastuzumab + ATNM-400 ns combination activity in EGFR-mutant LC NCI-H1975 cells. 50 50 ** * * * * **** **** 1000 NCI-H1975 EGFR-m Lung Cancer **** **** 0 High PSMA cells (LNCaP & C4-2) were more responsive to 177Lu-PSMA-617 than low PSMA cells (22Rv1) and PSMA negative (DU145), as expected. ATNM-400 is cytotoxic in both low and high PSMA PCa cells, and which have low, medium and high levels of the ATNM-400 target. 0 800 TGI = -14% 600 TGI = 16 % TGI = 22 % 400 TGI = 71 % 22Rv1: Moderate target expression and low PSMA C4-2: High target and high PSMA expression 200 Trastuzumab resistance activated phosphorylation of AKT (pAKT) and induced a significant increase in total target protein level. 2000 Vehicle (PBS) 177Lu-PSMA-617 40 mCi/kg ATNM-400 40 μCi/kg 2000 TGI= -19% Vehicle (PBS) 177Lu-PSMA-617 40 mCi/kg ATNM-400 40 μCi/kg 0 0 5 10 15 20 25 1500 1500 ATNM-400 dy 0 Osi dy 0-3, 5-7 Dato-DXd dy 0 Amivantamab dy 0, 2, 7, 9, 14, 16 Days Post Dosing Trastuzumab resistance-driven target susceptibility to ATNM-400 in BC cells. BT474 Clone-5 BC head-on 1500 TGI= -20% overexpression confers increased BT474 Clone-5 BC Post-Trastuzumab Failure 1000 1000 1500 1000 TGI= 62% 1500 NCI-H1975 EGFR-m Lung Cancer NCI-H1975 EGFR-m Lung Cancer TGI= 50% 500 500 1600 1400 1200 1000 800 600 400 200 0 Post-Failure Dosing day 20 TGI= 64% 500 TGI= 87% TGI= -29% 1000 0 TGI= 97% TGI= 100% TGI= 111% 30 TGI= 93% 0 5 10 15 20 25 TGI= 102% 1000 Days Post Dosing 0 5 10 15 20 25 30 35 40 45 50 55 60 65 0 TGI= 31% ALL GROUPS SINGLE DOSE Trastuzumab (9 doses) day 0 in 11 days 0 5 10 15 20 25 Day 0 all dosing Days Post Dosing 0 Day 0 all dosing HER2-DXd, (1Q7dx3) Trastuzumab HER2-DXd, 0 5 10 15 20 25 500 Days Post Dosing 500 TGI= 49% TGI= 66% TGI= 80% DU145: Low target expression and PSMA negative 1000 TGI= 80% TGI= 89% 0 Vehicle (PBS) Cold target mAb 2.5 mg/kg Trastuzumab (5 mg/kg/dy) ATNM-400 40 μCi/kg Trastuzumab (5 mg/kg/dy) + ATNM-400 (40 μCi/kg) HER2-Dxd 10 mg/kg/dy 0 0 5 10 15 20 25 (9 doses in 11 days) (1Q7dx3) day 20, 27, 34 5 mg/kg/dy Days Post Dosing Vehicle post-Trastuzumab failure HER2-DXd (10 mg/kg/dy) post-Trastuzumab failure ATNM-400 (40 μCi/kg) post-Trastuzumab failure 0 5 10 15 20 25 Days Post Dosing 800 Day 0 all dosing Days Post Dosing Day 0 all dosing MCF7 (HR+) Breast Cancer Model MDA-MB-468 (TNBC) Breast Cancer Model 800 500 600 400 Vehicle (PBS) Cold ATNM400 (2.5 mg/kg) ATNM-400 (40 μCi/kg) Vehicle (PBS) Osimertinib 2 mg/kg/day (Q1W) ATNM-400 30 μCi/Kg ATNM-400 (30 μCi/Kg) + Osi (2 mg/kg/day (Q1W)) Osi (2 mg/kg/day (Q1W)) + Pemtrexed 100 mg/kg/day ((Q1Wx2)(x3)) + Cisplatin 4 mg/kg/day ((Q1Wx2)(x3)) Vehicle (PBS) Dato-DXd 3mg/kg ATNM-400 30 μCi/Kg Izalontamab 10 mg/kg ((Q1W )x4) Vehicle Cold target mAb (2.5 mg/kg) ATNM-400 (20 μCi/kg) 600 ATNM-400 (40 μCi/kg) Vehicle Cold target mAb (2.5 mg/kg) 400 ATNM-400 (20 μCi/kg) ATNM-400 (40 μCi/kg) 300 400 200 %TGI = 66 TGI= 56% 200 TGI = 76% 100 %TGI = 103 200 TGI = 111% 0 0 10 15 20 25 30 0 5 10 15 20 25 30 0 All groups single dose day 0 Days Post Dosing All groups single dose day 0 Days Post Dosing 0 Day 0 all dosing 5 10 15 20 25 30 35 Days Post Dosing ATNM-400 demonstrates superior anti-tumor efficacy compared to Vehicle control, unconjugated ("cold") antibody, and 177Lu-PSMA-617 in preclinical PCa models with high (C4-2) or low (22Rv1) PSMA expression. ATNM-400 demonstrates efficacy in DU145 PCa model that is PSMA negative and has low levels of ATNM-400 target. ATNM-400 exhibits superior efficacy as monotherapy versus approved drugs Osimertinib (1L), Amivantamab (2L), and Dato-DXd (3L) in EGFR-m LC model. ATNM-400 (monotherapy or combination with Osimertinib) surpasses Osi + chemotherapy combination. ATNM-400 monotherapy surpasses Dato-DXd (TROP-2 ADC) and Izalontamab (HER3-EGFR bispecific ADC) in efficacy. These results indicate that ATNM-400, as monotherapy or combined with 1L SOC agent, achieves anti-tumor efficacy that surpasses benchmark targeted agents, administered either as single agents or in combination, in EGFR-m LC. ATNM-400 monotherapy and combination with trastuzumab (SOC) showed robust antitumor effect in trastuzumab resistant BT474 Clone-5 BC model alone or in combination with trastuzumab. ATNM-400 efficacy versus HER2-ADC (DXd) was comparable. ATNM-400 potently inhibits tumor growth post-trastuzumab failure in trastuzumab-resistant model compared to control and HER2-ADC (DXd). ATNM-400 caused dose-dependent tumor inhibition in MCF7 HR+ BC model and MDA-MB-468 TNBC model. RESULTS ATNM-400 has Efficacy in HR+, TNBC and Trastuzumab-Resistant Breast Cancer Models ATNM-400 has Robust Efficacy in EGFR-mutant Lung Cancer Models and is Superior to Approved Agents ATNM-400 has Robust Efficacy in Prostate Cancer Models with Varying Target Levels ATNM-400: MECHANISM OF ACTION ATNM-400 binds to the target receptor, internalizes and causes potent alpha particle-mediated double-stranded DNA (dsDNA) breaks which increase phosho-H2AX (p-H2AX) leading to apoptosis of target-positive tumor cells. PCa: In models with varying levels of PSMA and target expression, ATNM-400 binds to the target receptor based on target expression, internalizes and delivers potent alpha particle-mediated dsDNA breaks leading to apoptosis. LC: In Osi-resistant EGFR-m models, acquired resistance to Osimertinib increases expression of target antigen, enabling enhanced binding and internalization of ATNM-400 and leading to dsDNA breaks and tumor cell killing. BC: In trastuzumab-resistant models, expression of target antigen increases as does phospho-AKT, thus enhancing ATNM-400 binding and internalization, resulting in potent dsDNA breaks and tumor cell killing. Tumor Volume +/-SE (mm 3 ) Tumor Volume +/-SE (mm 3 ) Tumor Volume +/-SE (mm 3 ) Tumor Volume +/-SE (mm 3 ) Tumor Volume +/-SE (mm 3 ) Tumor Volume +/-SE (mm 3 ) Tumor Volume +/-SE (mm 3 ) Tumor Volume +/-SE (mm 3 ) Tumor Volume +/-SE (mm 3 ) CONCLUSIONS ATNM-400 delivers robust pan-tumor activity across PCa, LC, and BC models, with consistent efficacy in settings of mCRPC, EGFR-m LC, and HER2-targeted BC therapy resistance. In PCa, ATNM-400 shows potent activity across PSMA-high/PSMA-low mCRPC, and in PSMA-negative models, with superior tumor growth inhibition versus vehicle, cold antibody, and 177Lu-PSMA-617, supporting its potential to treat both PSMA-high and PSMA-low mCRPC. ATNM-400 doses in all three PCa models were well-tolerated. In EGFR-m LC, ATNM-400 monotherapy outperforms Osi (1L), Amivantamab (2L), and Dato-DXd (3L), while ATNM-400 combination with Osi exceeds the efficacy of current benchmark regimens (Osi + chemotherapy and Izalontamab (HER3-EGFR bispecific ADC) when given monotherapy or in combination. Osi-induced upregulation of ATNM-400's target antigen and the observed synergistic activity of ATNM-400 + Osi combination highlight a rational strategy to exploit adaptive resistance mechanisms for enhanced EGFR-m LC control. ATNM-400 doses in all LC studies were well tolerated. In BC, ATNM-400 target upregulation in trastuzumab-resistant cells increases susceptibility to ATNM-400, which demonstrates strong antitumor activity as monotherapy and in combination with trastuzumab, with efficacy comparable to HER2-ADC. ATNM-400 also had superior efficacy post-Trastuzumab failure in this model compared to control and HER2-ADC. ATNM-400 also drives dose-dependent tumor inhibition in HR+ (MCF7) and TNBC (MDA-MB-468) models, indicating tumor agnostic broad activity across molecular subtypes and supporting its potential utility beyond HER2-positive disease. ATNM-400 doses in three BC models were well-tolerated. Overall, these data position ATNM-400 as a next-generation 225Ac targeted alpha radiotherapeutic backbone with broad translational potential to overcome resistance and improve outcomes across multiple refractory solid tumor indications. Actinium Pharmaceuticals posters are available at the following QR code: American Association for Cancer Research (AACR). San Diego, CA April 17-22, 2026

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