Abstract
Aggressive variant prostate cancer (AVPC) originates from metastatic prostate cancer (mPCa) following androgen receptor-targeted therapies, leading to diverse pathological subtypes, notably castration-resistant prostate cancer (CRPC). Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), is consistently expressed across AVPC phenotypes, including neuroendocrine prostate carcinoma (NEPC) and double-negative prostate carcinoma (DNPC), which are significant subtypes of CRPC, making it a promising therapeutic target. In this study, A high-affinity nanobody, B12, specific to CEACAM5, was discovered through phage library screening. B12 exhibited robust binding capabilities, enhanced tumor accumulation, and effective tissue penetration, facilitating rapid in vivo imaging of AVPC. The conjugation of B12 with PE38 to create the immunotoxin B12-PE38 showed significant anti-tumor activity in AVPC xenograft models, including one that mimics bone metastasis. When B12-PE38 was combined with docetaxel, it elicited enhanced tumor inhibitory effects, effectively inhibiting tumor progression. This study underscores CEACAM5 as a target for precise imaging and targeted therapy in AVPC, introducing novel diagnostic and therapeutic strategies for a disease that currently faces a dearth of effective treatment options due to the scarcity of well-defined targets.