First target disclosure for the preclinical development of ATNM-400, a first-in-class actinium-225 radioconjugate with pan-tumor efficacy in solid tumors
Presenter: Sumit Mukherjee Session: Radiopharmacuetical Platforms for Theranostic Precision Oncology Time: 4/21/2026 2:00:00 PM → 4/21/2026 5:00:00 PM
Authors
Amanda S. Chin , Sumit Mukherjee , Jason Li , Karina Peregrina , Debbie Lewis , Le-Cun Xu , Dhiren Patel , Madhuri Vusirikala , Monideepa Roy , Adeela Kamal Actinium Pharmaceuticals, Inc., New York, NY
Abstract
Background: Therapeutic resistance is a major barrier to durable cancer control across solid tumors. We report the first disclosure of a novel membrane target and the preclinical development of ATNM-400, a first-in-class Actinium-225 (225Ac) antibody radioconjugate designed to selectively eradicate therapy-refractory cancer cells. This target is overexpressed and functionally linked to resistance mechanisms in prostate, lung, and breast tumors. We evaluated the pan-tumor efficacy, mechanism of action, and translational potential of ATNM-400 in preclinical models representing advanced and therapy-resistant disease. Methods: A full-length antibody specific to the novel target was conjugated to p-SCN-Bn-DOTA and radiolabeled with the alpha-emitter 225Ac (>98% purity). Target expression, binding affinity, and cellular internalization kinetics were tested across therapy-resistant tumor models, including enzalutamide- and 177Lu-PSMA-617-resistant prostate cancer, osimertinib-resistant EGFR-mutant lung cancer, hormone positive (HR+) breast cancer, triple-negative breast cancer (TNBC) and tamoxifen- or trastuzumab-resistant breast cancer. In vivo biodistribution, tumor retention, and efficacy were evaluated as monotherapy or in combination with standard-of-care agents. Results: ATNM-400 selectively bound and rapidly internalized into target-positive tumor cells, inducing robust alpha-particle mediated DNA double-strand breaks. Notably, tumors resistant to other standard of care therapies showed increased target expression, thereby sensitizing the resistant tumors to ATNM-400. In vivo, ATNM-400 demonstrated sustained tumor uptake with off-target exposure in normal tissues, driving potent anti-tumor activity in: • Prostate cancer: ATNM-400 outperformed androgen receptor (AR) pathway inhibitor enzalutamide, 177Lu-PSMA-617, and 225Ac-PSMA-617, producing durable regressions and complete responses in enzalutamide- and 225Ac-PSMA-617-resistant models. • EGFR-mutant lung cancer: ATNM-400 synergized with EGFR inhibitor osimertinib, achieving complete cures in animals, correlating with increased target expression in osimertinib-resistant models. • Breast cancer: ATNM-400 exhibited tumor regressions in HR+ breast cancer, TNBC and combination activity in estrogen receptor (ER) inhibitor tamoxifen- and HER2 antibody trastuzumab-resistant tumors, correlating with increased target expression. No significant toxicity or weight loss was observed at therapeutic doses. Conclusions: ATNM-400 exhibits robust pan-tumor activity, overcomes resistance to AR, EGFR, and HER2/ER-targeted therapies, and demonstrates a favorable safety profile. These findings support ATNM-400 as a next-generation 225Ac radiotherapeutic platform with broad potential across many refractory solid tumors.
Disclosure
A. S. Chin, Actinium Pharmaceuticals, Inc. Employment. S. Mukherjee, Actinium Pharmaceuticals, Inc. Employment. J. Li, Actinium Pharmaceuticals, Inc. Employment. K. Peregrina, Actinium Pharmaceuticals, Inc. Employment. D. Lewis, Actinium Pharmaceuticals, Inc. Employment. L. Xu, Actinium Pharmaceuticals, Inc. Employment. D. Patel, Actinium Pharmaceuticals, Inc. Employment. M. Vusirikala, Actinium Pharmaceuticals, Inc. Employment. M. Roy, Actinium Pharmaceuticals, Inc. Employment. A. Kamal, Actinium Pharmaceuticals, Inc. Employment.
Cited in
Control: 4754 · Presentation Id: 3919 · Meeting 21436