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Synthesis, preclinical evaluation and pilot clinical translation of [68Ga]Ga-PMD22, a novel nanobody PET probe targeting CLDN18.2 of gastrointestinal cancer

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

Abstract

Purpose

Claudin18.2 (CLDN18.2) is a novel target for diagnosis and therapy of gastrointestinal cancer. This study aimed to evaluate the safety and feasibility of a novel CLDN18.2-targeted nanobody, PMD22, labeled with gallium-68 ([68Ga]Ga), for detecting CLDN18.2 expression in patients with gastrointestinal cancer using PET/CT imaging.

Methods

[68Ga]Ga-PMD22 was synthesized based on the nanobody, and its cell binding properties were assayed. Preclinical pharmacokinetics were determined in CLDN18.2-positive xenografts using microPET/CT. Effective dosimetry of [68Ga]Ga-PMD22 was evaluated in 5 gastrointestinal cancer patients, and PET/CT imaging of [68Ga]Ga-PMD22 and [18F]FDG were performed head-to-head in 16 gastrointestinal cancer patients. Pathological tissues were obtained for CLDN18.2 immunohistochemical (IHC) staining and comparative analysis with PET/CT findings.

Results

Cell binding assay showed that [68Ga]Ga-PMD22 had a higher binding ability to AGSCLDN18.2 and BGC823CLDN18.2 cells than to AGS and BGC823 cells (p < 0.001). MicroPET/CT images showed that [68Ga]Ga-PMD22 rapidly accumulated in AGSCLDN18.2 and BGC823CLDN18.2 tumors, and high contrast tumor to background imaging was clearly observed. In the pilot study, the effective dose of [68Ga]Ga-PMD22 was 1.68E-02 ± 1.45E-02 mSv/MBq, and the CLDN18.2 IHC staining result was highly correlated with the SUVmax/BKGstomach of [68Ga]Ga-PMD22 (rs = 0.848, p < 0.01).

Conclusion

A novel [68Ga]Ga-labeled nanobody probe targeting CLDN18.2, [68Ga]Ga-PMD22, was established and preliminarily proved to be safe and effective in revealing CLDN18.2-positive gastrointestinal cancer, providing a basis for the clinical translation of the agent.

Clinical trial registration

This study was registered on the ClinicalTrials.gov (NCT05937919).

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Data availability

The data included in this article is available from the corresponding author on reasonable request.

References

  1. Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet (London England). 2020;396:635–48. https://doi.org/10.1016/s0140-6736(20)31288-5.

    Article  CAS  PubMed  Google Scholar 

  2. Alsina M, Arrazubi V, Diez M, Tabernero J. Current developments in gastric cancer: from molecular profiling to treatment strategy. Nat Rev Gastroenterol Hepatol. 2023;20:155–70. https://doi.org/10.1038/s41575-022-00703-w.

    Article  CAS  PubMed  Google Scholar 

  3. Yuan DD, Zhu ZX, Zhang X, Liu J. Targeted therapy for gastric cancer: current status and future directions (review). Oncol Rep. 2016;35:1245–54. https://doi.org/10.3892/or.2015.4528.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang D, Huang G, Liu J, Wei W. Claudin18.2-targeted cancer theranostics. Am J Nucl Med Mol Imaging. 2023;13:64–9.

    PubMed  PubMed Central  Google Scholar 

  5. Lei ZN, Teng QX, Tian Q, Chen W, Xie Y, Wu K, et al. Signaling pathways and therapeutic interventions in gastric cancer. Signal Transduct Target Ther. 2022;7:358. https://doi.org/10.1038/s41392-022-01190-w.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sahin U, Türeci Ö, Manikhas G, Lordick F, Rusyn A, Vynnychenko I, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Annals Oncology: Official J Eur Soc Med Oncol. 2021;32:609–19. https://doi.org/10.1016/j.annonc.2021.02.005.

    Article  CAS  Google Scholar 

  7. Wang DW, Zhang WH, Danil G, Yang K, Hu JK. The role and mechanism of claudins in cancer. Front Oncol. 2022;12:1051497. https://doi.org/10.3389/fonc.2022.1051497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cao W, Xing H, Li Y, Tian W, Song Y, Jiang Z, et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark Res. 2022;10:38. https://doi.org/10.1186/s40364-022-00385-1.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Maron SB, Catenacci DV. Novel targeted therapies for Esophagogastric Cancer. Surg Oncol Clin N Am. 2017;26:293–312. https://doi.org/10.1016/j.soc.2016.10.002.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Klempner SJ, Janjigian YY, Wainberg ZA. Claudin18.who? Examining biomarker overlap and outcomes in claudin18.2-positive gastroesophageal adenocarcinomas. ESMO Open. 2023;8:100778. https://doi.org/10.1016/j.esmoop.2022.100778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhu G, Foletti D, Liu X, Ding S, Melton Witt J, Hasa-Moreno A, et al. Author correction: Targeting CLDN18.2 by CD3 bispecific and ADC modalities for the treatments of gastric and pancreatic Cancer. Sci Rep. 2019;9:16735. https://doi.org/10.1038/s41598-019-53130-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhu G, Foletti D, Liu X, Ding S, Melton Witt J, Hasa-Moreno A, et al. Targeting CLDN18.2 by CD3 bispecific and ADC modalities for the treatments of gastric and pancreatic Cancer. Sci Rep. 2019;9:8420. https://doi.org/10.1038/s41598-019-44874-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Türeci Ӧ, Mitnacht-Kraus R, Wöll S, Yamada T, Sahin U. Characterization of zolbetuximab in pancreatic cancer models. Oncoimmunology. 2019;8:e1523096. https://doi.org/10.1080/2162402x.2018.1523096.

    Article  CAS  PubMed  Google Scholar 

  14. Qi C, Gong J, Li J, Liu D, Qin Y, Ge S, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med. 2022;28:1189–98. https://doi.org/10.1038/s41591-022-01800-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Arnold A, Daum S, von Winterfeld M, Berg E, Hummel M, Rau B, et al. Prognostic impact of Claudin 18.2 in gastric and esophageal adenocarcinomas. Clin Transl Oncol. 2020;22:2357–63. https://doi.org/10.1007/s12094-020-02380-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Arpa G, Fassan M, Guerini C, Quaquarini E, Grillo F, Angerilli V, et al. Claudin-18 expression in small bowel adenocarcinoma: a clinico-pathologic study. Virchows Arch. 2022;481:853–63. https://doi.org/10.1007/s00428-022-03393-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Massoud TF, Gambhir SS. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev. 2003;17:545–80. https://doi.org/10.1101/gad.1047403.

    Article  CAS  PubMed  Google Scholar 

  18. Chen Y, Hou X, Li D, Ding J, Liu J, Wang Z, et al. Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumors. J Pharm Anal. 2023;13:367–75. https://doi.org/10.1016/j.jpha.2023.02.011.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hu G, Zhu W, Liu Y, Wang Y, Zhang Z, Zhu S, et al. Development and comparison of three (89)Zr-labeled anti-CLDN18.2 antibodies to noninvasively evaluate CLDN18.2 expression in gastric cancer: a preclinical study. Eur J Nucl Med Mol Imaging. 2022;49:2634–44. https://doi.org/10.1007/s00259-022-05739-3.

    Article  CAS  PubMed  Google Scholar 

  20. Wang S, Qi C, Ding J, Li D, Zhang M, Ji C, 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. 2023. https://doi.org/10.1007/s00259-023-06234-z.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wei W, Zhang D, Zhang Y, Li L, Jin Y, An S, et al. Development and comparison of (68)Ga/(18)F/(64)Cu-labeled nanobody tracers probing Claudin18.2. Mol Ther Oncolytics. 2022;27:305–14. https://doi.org/10.1016/j.omto.2022.11.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhao C, Rong Z, Ding J, Wang L, Wang B, Ding L, et al. Targeting Claudin 18.2 using a highly specific antibody enables Cancer diagnosis and guided surgery. Mol Pharm. 2022;19:3530–41. https://doi.org/10.1021/acs.molpharmaceut.1c00947.

    Article  CAS  PubMed  Google Scholar 

  23. Harmand TJ, Islam A, Pishesha N, Ploegh HL. Nanobodies as in vivo, non-invasive, imaging agents. RSC Chem Biol. 2021;2:685–701. https://doi.org/10.1039/d1cb00023c.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Keyaerts M, Xavier C, Heemskerk J, Devoogdt N, Everaert H, Ackaert C, et al. Phase I study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 expression in breast carcinoma. J Nucl Med. 2016;57:27–33. https://doi.org/10.2967/jnumed.115.162024.

    Article  CAS  PubMed  Google Scholar 

  25. Qi C, Guo R, Chen Y, Li C, Liu C, Zhang M, et al. (68)Ga-NC-BCH whole-body PET imaging rapidly targets Claudin18.2 in lesions in gastrointestinal Cancer patients. J Nucl Med. 2024. https://doi.org/10.2967/jnumed.123.267110.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Li L, Liu T, Shi L, Zhang X, Guo X, Hu B, et al. HER2-targeted dual radiotracer approach with clinical potential for noninvasive imaging of trastuzumab-resistance caused by epitope masking. Theranostics. 2022;12:5551–63. https://doi.org/10.7150/thno.74154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ma X, Zhou X, Hu B, Li X, Yao M, Li L, et al. Preclinical evaluation and pilot clinical study of [(68)Ga]Ga-THP-APN09, a novel PD-L1 targeted nanobody radiotracer for rapid one-step radiolabeling and PET imaging. Eur J Nucl Med Mol Imaging. 2023;50:3838–50. https://doi.org/10.1007/s00259-023-06373-3.

    Article  CAS  PubMed  Google Scholar 

  28. Guimaraes CP, Witte MD, Theile CS, Bozkurt G, Kundrat L, Blom AE, et al. Site-specific C-terminal and internal loop labeling of proteins using sortase-mediated reactions. Nat Protoc. 2013;8:1787–99. https://doi.org/10.1038/nprot.2013.101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Theile CS, Witte MD, Blom AE, Kundrat L, Ploegh HL, Guimaraes CP. Site-specific N-terminal labeling of proteins using sortase-mediated reactions. Nat Protoc. 2013;8:1800–7. https://doi.org/10.1038/nprot.2013.102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wilbs J, Raave R, Boswinkel M, Glendorf T, Rodriguez D, Fernandes EFA, et al. New Long-acting [(89)Zr]Zr-DFO GLP-1 PET Tracers with increased molar activity and reduced kidney Accumulation. J Med Chem. 2023. https://doi.org/10.1021/acs.jmedchem.2c02073.

    Article  PubMed  PubMed Central  Google Scholar 

  31. D’Huyvetter M, Vincke C, Xavier C, Aerts A, Impens N, Baatout S, et al. Targeted radionuclide therapy with a 177Lu-labeled anti-HER2 nanobody. Theranostics. 2014;4:708–20. https://doi.org/10.7150/thno.8156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang Y, Zhang D, An S, Liu Q, Liang C, Li J et al. Development and characterization of Nanobody-derived CD47 theranostic pairs in solid tumors. Research (Wash D C). 2023;6:0077. https://doi.org/10.34133/research.0077.

  33. Wang C, Chen Y, Hou YN, Liu Q, Zhang D, Zhao H, et al. ImmunoPET imaging of multiple myeloma with [(68)Ga]Ga-NOTA-Nb1053. Eur J Nucl Med Mol Imaging. 2021;48:2749–60. https://doi.org/10.1007/s00259-021-05218-1.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to acknowledge Dr. Chun Wang from Jiaxing Pharmadax Genesis Pharmaceutical Technology Co.,Ltd. (Zhejiang, China) for his assistance in this study.

Funding

This study was supported by the National High Level Hospital Clinical Research Funding (2022-PUMCH-C-004, 2022-PUMCH-D-002), Chinese Academy of Medical Science Innovation Fund for Medical Sciences (2021-I2M-1-016, 2022-I2M-C&T-A-008, 2022-I2M-2-002), the National Natural Science Foundation of China (82272046, 81870393, 82172006 and 81871416) and the Fundamental Research Funds for the Central Universities (3332023124). No other potential conflict of interest relevant to this article was reported.

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Author notes

  1. Rongxi Wang, Zhidong Bai and Wentao Zhong contributed equally to this work.

Authors and Affiliations

  1. Department of Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China

    Rongxi Wang, Jiarou Wang, Jialin Xiang & Zhaohui Zhu

  2. Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing, 100191, China

    Zhidong Bai, Chenzhen Li & Bing Jia

  3. Medical Department of General Surgery, The 1st Medical Center, Chinese PLA General Hospital, Beijing, 100853, China

    Wentao Zhong & Junfeng Du

  4. Department of General Surgery, The 7th Medical Center, Chinese PLA General Hospital, Beijing, 100700, China

    Wentao Zhong & Junfeng Du

  5. The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China

    Wentao Zhong & Junfeng Du

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Correspondence to Junfeng Du, Bing Jia or Zhaohui Zhu.

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Ethical approval was obtained from the Institute Review Board of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and this study was conducted in accordance with the principles of the Declaration of Helsinki.

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Wang, R., Bai, Z., Zhong, W. et al. Synthesis, preclinical evaluation and pilot clinical translation of [68Ga]Ga-PMD22, a novel nanobody PET probe targeting CLDN18.2 of gastrointestinal cancer. Eur J Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s00259-024-06808-5

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