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. Citation Format: Amanda S. Chin, Sumit Mukherjee, Jason Li, Karina Peregrina, Debbie Lewis, Le-Cun Xu, Dhiren Patel, Madhuri Vusirikala, Monideepa Roy, Adeela Kamal, . First target disclosure for the preclinical development of ATNM-400, a first-in-class actinium-225 radioconjugate with pan-tumor efficacy in solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5824.
Chin et al. (Fri,) studied this question.