Actinium Pharmaceuticals, Inc. (delaware)AMEX: ATNM

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

Apr 22, 2026 at 12:34 AM UTC · Issued by Actinium Pharmaceuticals, Inc. (delaware)

‌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 (mm3)

Target (MFI)

%Cell Viability

MFI (PE)

Viability (%)

Denisty (arbitraty units)

Viability (%)

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 ATNM-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

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

150

20000

✱✱✱✱

Week 1: Osimertinib (7d) Week 2: Media Only

pH2AX

✱✱✱✱

40000

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

✱✱✱✱

GAPDH

2.5

Target

✱✱✱✱

4000

10000

20000

2.0

GAPDH

2.0 pH2AX

✱✱

1.5

2000

Week 1: Osimertinib (7d) Week 2: ATNM-400 (3h)

1.5

5000

10000

1.0

****

C4-2

DU145 22RV1 LNCaP

C4-2

**** **** **** ****

1.0

DU145 22RV1 LNCaP

**** **** **

0.5

MDA-MB-468 MCF7 MCF7-Tam1 BT474 BT474-Clone 5

0.5

Unstained

PSMA-Stained

Unstained Target-Stained

Dose (μCi/mL)

NCI-H1975

Nontreated, Unstained Nontreated, Stained

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

combination activity in EGFR-mutant LC NCI-H1975 cells.

******

****

1000

NCI-H1975 EGFR-m Lung Cancer

****

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.

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 5 10 15 20 25

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

1500

1000

TGI= 62%

1500

NCI-H1975 EGFR-m Lung Cancer NCI-H1975 EGFR-m Lung Cancer

TGI= 50%

500

1600

1400

1200

1000

800

600

400

200

Post-Failure Dosing day 20

TGI= 64%

500

TGI= 87%

TGI= -29%

1000

TGI= 97% TGI= 100%

TGI= 111%

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

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

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%

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 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%

10 15 20 25

0 5 10 15 20 25 30

All groups single dose day 0

Days Post Dosing

All groups single dose day 0

Days Post Dosing

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 (mm3)

Tumor Volume +/-SE (mm3)

Tumor Volume +/-SE (mm3)

Tumor Volume +/-SE (mm3) Tumor Volume +/-SE (mm3)

Tumor Volume +/-SE (mm3)

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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