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First-in-human CLDN18.2 functional diagnostic pet imaging of digestive system neoplasms enables whole-body target mapping and lesion detection

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

Abstract

Purpose

Claudin 18.2 (CLDN18.2) is a reliable target for lesion detection and could have clinical implications for epithelial tumors, especially digestive system neoplasms. However, there is no predictive technology for accurate whole-body mapping of CLDN18.2 expression in patients. This study assessed the safety of the 124I-18B10(10L) tracer and the feasibility of mapping whole-body CLDN18.2 expression using PET functional imaging.

Methods

The 124I-18B10(10L) probe was synthesized manually, and preclinical experiments including binding affinity and specific targeting ability were conducted after testing in vitro model cells. Patients with pathologically confirmed digestive system neoplasms were enrolled in an ongoing, open-label, single-arm, first-in-human (FiH) phase 0 trial (NCT04883970). 124I-18B10(10L) PET/CT or PET/MR and 18F-FDG PET were performed within one week.

Results

124I-18B10(10L) was successfully constructed with an over 95% radiochemical yield. The results of preclinical experiments showed that it had high stability in saline and high affinity in CLDN18.2 overexpressing cells (Kd = 4.11 nM). Seventeen patients, including 12 with gastric cancers, 4 with pancreatic cancers, and 1 with cholangiocarcinoma were enrolled. 124I-18B10(10L) displayed high uptake in the spleen and liver, and slight uptake in the bone marrow, lung, stomach and pancreas. The tracer uptake SUVmax in tumor lesions ranged from 0.4 to 19.5. Compared with that in lesions that had been treated with CLDN18.2-targeted therapy, 124I-18B10(10L) uptake was significantly higher in lesions that had not. Regional 124I-18B10(10L) PET/MR in two patients showed high tracer uptake in metastatic lymph nodes.

Conclusions

124I-18B10(10L) was successfully prepared and exhibited a high binding affinity and CLDN18.2 specificity in preclinical studies. As an FiH CLDN18.2 PET tracer, 124I-18B10(10L) was shown to be safe with acceptable dosimetry and to clearly reveal most lesions overexpressing CLDN18.2.

Trial registration

NCT04883970; URL: https://register.clinicaltrials.gov/. Registered 07 May 2021.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. 

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Acknowledgements

We acknowledge the staff of the Department of Nuclear Medicine, and the Department of Gastrointestinal Oncology, Peking University Cancer Hospital for their help.

Funding

This work was supported by the National Natural Science Foundation of China (82171980, 82171973, 82102091, 82072728), Beijing Hospitals Authority’ Ascent Plan (DFL20191102), Beijing Millions of Talent Projects A level funding (No. 2019A38), The Pilot Project (4 th Round) to Reform Public Development of Beijing Municipal Medical Research Institute (2021–1). The authors declare that there is no conflict of interest regarding the publication of this article. Intellectual property protection has been filed by Suzhou Transcenta Therapeutics Company and Peking University Cancer Hospital.

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Author notes

  1. Shujing Wang, Changsong Qi and Jin Ding contributed equally to this work.

Authors and Affiliations

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

    Shujing Wang, Jin Ding, Dan Li, Feng Wang, Zhi Yang & Hua Zhu

  2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China

    Changsong Qi, Miao Zhang, Congcong Ji, Fangli Jiang, Lin Shen & Cheng Zhang

  3. Suzhou Transcenta Therapeutics Co., Ltd, Suzhou, China

    Fei Teng, Jie Yu & Xueming Qian

  4. Department of Oncology, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, China

    Jing Gao

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  1. Shujing Wang
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [Shujing Wang], [Changsong Qi] and [Jin Ding]. The first draft of the manuscript was written by [Shujing Wang], [Changsong Qi] and [Jin Ding] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jing Gao, Zhi Yang, Cheng Zhang or Hua Zhu.

Ethics declarations

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The clinical study was approved by the Ethics Committee of Peking University Cancer Hospital (2021KT57) and was registered at ClinicalTrial.gov (NCT04883970).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Conflict of interest

None declared. Intellectual property protection has been filed by Suzhou Transcenta Therapeutics Company and Peking University Cancer Hospital.

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Wang, S., Qi, C., Ding, J. et al. First-in-human CLDN18.2 functional diagnostic pet imaging of digestive system neoplasms enables whole-body target mapping and lesion detection. Eur J Nucl Med Mol Imaging 50, 2802–2817 (2023). https://doi.org/10.1007/s00259-023-06234-z

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