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Abstract <p>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. [<sup>68</sup>Ga]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 <sup>18</sup>F-FDG PET/CT. In preclinical studies, [<sup>177</sup>Lu]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.</p> Graphical abstract <p></p>

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A high-affinity CEA-targeted nanobody for 68Ga PET imaging and 177Lu-based radioisotope therapy: preclinical and first-in-human evaluation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月22日

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  • 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,
  • Peixun Gao,
  • Wenhu Zhou,
  • Shuo Hu,
  • Longlong Luo

摘要

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.

Graphical abstract