Abstract Background and Purpose: Radiotheranostics targeting prostate-specific membrane antigen (PSMA) and therapies directed at the androgen receptor (AR) pathway have significantly improved outcomes in metastatic castration-resistant prostate cancer (mCRPC). However, there remains a significant unmet need for safe and potent therapies for AR/PSMA-negative or low-expressing disease. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) has been identified as a promising cell-surface therapeutic target in AR/PSMA-low mCRPC tumors. This study aims to develop a novel CEACAM5-targeted radiotheranostic pair for mCRPC using the high-affinity anti-CEACAM5 IgG1 monoclonal antibody tusamitamab, formulated as 89ZrZr-DFO-tusamitamab for PET imaging and 225AcAc-macropa-tusamitamab for alpha-emitter therapy. Methods: Tusamitamab was conjugated with either desferrioxamine B (DFO) or macropa chelators and subsequently radiolabeled with either zirconium-89 (Zr-89) or actinium-225 (Ac-225), respectively. Proof-of-concept studies were performed in nude mice bearing either cell-line derived xenografts (NCI-H660) or neuroendocrine prostate cancer patient organoid derived xenografts (PDOX). Radioimmunoconjugates were evaluated for stability, immunoreactivity, and in vitro binding. Tumor targeting was assessed using PET/CT imaging and/or ex vivo biodistribution studies. Therapeutic efficacy was evaluated in NCI-H660 tumor-bearing mice across a range of administered activities (single intravenous injection of 1. 85-18. 5 kBq) compared with untreated controls. Results: Tusamitamab-chelator conjugates (chelator-to-antibody ratios of 1-4) retained low-nM affinity comparable to parental tusamitamab, as measured by surface plasmon resonance. 89ZrZr-DFO-tusamitamab and 225AcAc-macropa-tusamitamab were radiolabeled in high yields (30 MBq/nmol and 2. 8 MBq/nmol, respectively) and remained stable in PBS and human serum for up to 240 hours. Both radioimmunoconjugates demonstrated ∼70% immunoreactivity in a magnetic bead radioligand assay. Biodistribution studies showed high CEACAM5-specific tumor uptake at 120 hours (29. 2 ± 3. 2 %IA/g for 89ZrZr-DFO-tusamitamab and 35. 9 ± 7. 8 %IA/g for 225AcAc-macropa-tusamitamab). Efficient tumor targeting was also observed in PDOX xenografts (14. 1 ± 6. 0 %IA/g at 144 hours). Therapy studies demonstrated complete responses by week 3 in all 225AcAc-macropa-tusamitamab-treated mice, with treatment well tolerated through week 4 (studies still ongoing). Comprehensive toxicity and dosimetry assessment studies are ongoing. Conclusion: Proof-of-concept evaluation of 89ZrZr-DFO-tusamitamab and 225AcAc-macropa-tusamitamab in mCRPC mouse models has been completed. Initial therapeutic results with 225AcAc-macropa-tusamitamab indicate strong antitumor activity and a favorable therapeutic window. Citation Format: Ambika Parmar, Samuel F. Ruder, Niloufer Salehi, Edward K. Fung, Hong Su, Sandra Huicochea Castellanos, Nai-Kong V. Cheung, David S. Rickman, Scott T. Tagawa, Sarah M. Cheal. Theranostic 89Zr/225Ac anti-CEACAM5 radioimmunotherapy for metastatic castration-resistant prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB472.
Parmar et al. (Fri,) studied this question.