A high-affinity CEA-targeted nanobody for 68Ga PET imaging and 177Lu-based radioisotope therapy: preclinical and first-in-human evaluation
Liang Zhang, Ming Zhou, Chenxi Lu, Pinnan Zhao, Ning Shi, Yangyihua Zhou, Chaoyan Yao, Xuechen Yang, Juan Tian, Jie Wang, Yaowei Ma, Qianping Huang, Can Xu, Pu Gao, Wenhu Zhou, Shuo Hu, Longlong Luo
Abstract
Carcinoembryonic antigen (CEA) is a clinically validated biomarker and therapeutic target in colorectal and other epithelial malignancies, yet current antibody-based approaches are hindered by poor pharmacokinetics, limited tumor penetration, and delayed imaging. To overcome these limitations, we identified a novel high-affinity anti-CEA nanobody (CE-21) with picomolar binding affinity and excellent stability using camelid immune library–based phage display. To ensure homogeneity and maintain antigen recognition, a site-specific conjugation strategy was employed, enabling radiolabeling with gallium-68 for PET/CT imaging or lutetium-177 for radionuclide therapy. [68Ga]Ga-CE-21 exhibited rapid renal clearance, low nonspecific uptake, and high tumor-to-background ratios in xenograft models, achieving high-contrast imaging within hours; in healthy volunteers, it was well tolerated, with kidney uptake as the main dose-limiting factor and an effective radiation dose lower than conventional 18F-FDG PET/CT. In preclinical studies, [177Lu]Lu-CE-21 demonstrated significant, dose-dependent tumor growth inhibition and prolonged survival without evident off-target toxicity. Collectively, these findings establish CE-21 as a promising CEA-targeted theranostic platform, combining sensitive PET imaging with effective radionuclide therapy and offering strong potential for clinical translation in precision oncology.