CEACAM5 Radiotheranostics: A Targeted Strategy for PSMA-Negative, Neuroendocrine Prostate Cancer

For prostate cancer patients with low expression of PSMA or with neuroendocrine prostate cancer or NEPC(a population growing in size precisely because better treatments are forcing tumors to adapt), a new preclinical study offers a credible precision-targeted strategy: a radiotheranostic pair built on the CEACAM5 surface antigen that produced complete tumor responses in every treated animal.

The biology driving this approach is sound. As prostate cancer cells shed the androgen receptor and reprogram into neuroendocrine tumor cells, they activate ASCL1, a transcription factor that opens chromatin at the CEACAM5 promoter and switches on its expression. Where PSMA disappears, CEACAM5 appears. This reciprocal relationship makes it a near-ideal rescue target, specific to the very phenotype that has escaped everything else.

The investigators built their radiotheranostic pair around tusamitamab, a high-affinity IgG1 monoclonal antibody that binds CEACAM5 with low-nanomolar affinity and already has a clinical track record as an antibody-drug conjugate in NSCLC Phase 3 trials. Two radioimmunoconjugates were created: ⁸⁹Zr-DFO-tusamitamab for PET imaging, and ²²⁵Ac-macropa-tusamitamab for therapy. The actinium-225 therapeutic agent delivers alpha particles, lethal, ultra-short-range radiation that causes irreparable DNA double-strand breaks independent of oxygenation or drug-resistance mechanisms, making it ideally suited to the hypoxic, treatment-hardened tumors typical of NEPC.

The preclinical numbers are impressive. Tumor uptake reached 29.2%IA/g for the zirconium imaging agent and 35.9%IA/g for the actinium therapeutic at 120 hours in NCI-H660 xenografts, an AR-negative, PSMA-negative, PSA-negative NEPC model that closely mirrors the clinical phenotype. These figures exceed what PSMA radioligand therapies typically achieve in practice. Efficient targeting was also confirmed in patient-derived organoid xenografts grown from actual NEPC patient tissue, a far more stringent translational test than engineered cell lines alone. Both agents remained stable in human serum for up to 240 hours, and approximately 70% immunoreactivity was preserved after conjugation, meaning the antibody still found its target effectively after radiolabeling.

The therapeutic outcome was the most striking result: a single intravenous injection of ²²⁵Ac-macropa-tusamitamab produced complete tumor responses in all treated mice by week three, even at the lowest tested activity of 1.85 kBq, with no significant toxicity through week four. Complete responses, in every animal, for one of the most drug-resistant cancer models in oncology. Comprehensive dosimetry and toxicity studies are ongoing, and those results will be decisive for whether this program can advance toward patients.

The theranostic design mirrors what has made PSMA-targeted therapy so effective: use the imaging agent first to confirm CEACAM5 expression by PET scan, then administer the alpha-emitting therapeutic only to patients confirmed as eligible. A closely analogous program at UCSF targeting CD46 with the same ⁸⁹Zr-DFO + ²²⁵Ac-Macropa scaffold is already in Phase 1 human trials, providing a regulatory roadmap that could accelerate this work considerably.

Source.