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[177Lu]Lu-labeled anti-claudin-18.2 antibody demonstrated radioimmunotherapy potential in gastric cancer mouse xenograft models

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Gastric cancer (GC), one of the most prevalent and deadliest tumors worldwide, is often diagnosed at an advanced stage with limited treatment options and poor prognosis. The development of a CLDN18.2-targeted radioimmunotherapy probe is a potential treatment option for GC.

Methods

The CLDN18.2 antibody TST001 (provided by Transcenta) was conjugated with DOTA and radiolabeled with the radioactive nuclide 177Lu. The specificity and targeting ability were evaluated by cell uptake, imaging and biodistribution experiments. In BGC823CLDN18.2/AGSCLDN18.2 mouse models, the efficacy of [177Lu]Lu-TST001 against CLDN18.2-expressing tumors was demonstrated, and toxicity was evaluated by H&E staining and blood sample testing.

Results

[177Lu]Lu-TST001 was labeled with an 99.17%±0.32 radiochemical purity, an 18.50 ± 1.27 MBq/nmol specific activity and a stability of ≥ 94% after 7 days. It exhibited specific and high tumor uptake in CLDN18.2-positive xenografts of GC mouse models. Survival studies in BGC823CLDN18.2 and AGSCLDN18.2 tumor-bearing mouse models indicated that a low dose of 5.55 MBq and a high dose of 11.10 MBq [177Lu]Lu-TST001 significantly inhibited tumor growth compared to the saline control group, with the 11.1 MBq group showing better therapeutic efficacy. Histological staining with hematoxylin and eosin (H&E) and Ki67 immunohistochemistry of residual tissues confirmed tumor tissue destruction and reduced tumor cell proliferation following treatment. H&E showed that there was no significant short-term toxicity observed in the heart, spleen, stomach or other important organs when treated with a high dose of [177Lu]Lu-TST001, and no apparent hematotoxicity or liver toxicity was observed.

Conclusion

In preclinical studies, [177Lu]Lu-TST001 demonstrated significant antitumor efficacy with acceptable toxicity. It exhibits strong potential for clinical translation, providing a new promising treatment option for CLDN18.2-overexpressing tumors, including GC.

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Data availability

The datasets used and/or analyzed in this study can be obtained from the corresponding authors as reasonably required.

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Acknowledgements

The authors sincerely appreciate all the researchers who participated in this study.

Funding

This study was financially supported by the National Natural Science Foundation of China projects (No. 82203612, 82171973, 82171980, 82102092, and 82172604), Capital’s Funds for Health Improvement and Research (No. 2022-2Z-2154 and 2022-2Z-2155).

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Author notes

  1. Ziqing Zeng and Liqiang Li contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, Beijing, 100142, China

    Ziqing Zeng, Liqiang Li, Jinping Tao, Jiayue Liu, Zhi Yang & Hua Zhu

  2. Suzhou Transcenta Therapeutics Co., Ltd, Suzhou, Jiangsu, 215127, China

    Hongjun Li & Xueming Qian

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  1. Ziqing Zeng
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Contributions

Drs. Ziqing Zeng and Liqiang Li contributed equally to this work.

Corresponding authors

Correspondence to Zhi Yang or Hua Zhu.

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Competing interests

Intellectual properties protection have been filed by Suzhou Transcenta Therapeutics Co., Ltd., inventor of Xueming Qian; Hongjun Li, and Beijing Cancer Hospital, inventor of Hua Zhu; Yang Zhi. All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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All animal experiments were approved by the Peking University Cancer Hospital Animal Care and Use Committee (reference number: EAEC 2022-01).

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Zeng, Z., Li, L., Tao, J. et al. [177Lu]Lu-labeled anti-claudin-18.2 antibody demonstrated radioimmunotherapy potential in gastric cancer mouse xenograft models. Eur J Nucl Med Mol Imaging 51, 1221–1232 (2024). https://doi.org/10.1007/s00259-023-06561-1

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