Volume 13 Issue 4
Apr.  2023
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Yan Chen, Xingguo Hou, Dapeng Li, Jin Ding, Jiayue Liu, Zilei Wang, Fei Teng, Hongjun Li, Fan Zhang, Yi Gu, Steven Yu, Xueming Qian, Zhi Yang, Hua Zhu. Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumors[J]. Journal of Pharmaceutical Analysis, 2023, 13(4): 367-375. doi: 10.1016/j.jpha.2023.02.011
Citation: Yan Chen, Xingguo Hou, Dapeng Li, Jin Ding, Jiayue Liu, Zilei Wang, Fei Teng, Hongjun Li, Fan Zhang, Yi Gu, Steven Yu, Xueming Qian, Zhi Yang, Hua Zhu. Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumors[J]. Journal of Pharmaceutical Analysis, 2023, 13(4): 367-375. doi: 10.1016/j.jpha.2023.02.011

Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumors

doi: 10.1016/j.jpha.2023.02.011

The research was funded by the National Natural Science Foundation of China (Grant Nos.: 82171973, 82171980, and 82102092) and Beijing Millions of Talent Projects A Level Funding (Grant No.: 2019A38). The study was also supported by Beijing Hospitals Authority Dengfeng Project (Grant No.: DFL20191102), the Pilot Project (4th Round) to Reform Public Development of Beijing Municipal Medical Research Institute (2021−1), and the Third Foster Plan in 2019 “Molecular Imaging Probe Preparation and Characterization of Key Technologies and Equipment” for the Development of Key Technologies and Equipment in Major Science and Technology Infrastructure in Shenzhen, China.

  • Received Date: Nov. 17, 2022
  • Accepted Date: Feb. 23, 2023
  • Rev Recd Date: Feb. 13, 2023
  • Publish Date: Feb. 28, 2023
  • Claudin18.2 (CLDN18.2) is a tight junction protein that is overexpressed in a variety of solid tumors such as gastrointestinal cancer and oesophageal cancer. It has been identified as a promising target and a potential biomarker to diagnose tumor, evaluate efficacy, and determine patient prognosis. TST001 is a recombinant humanized CLDN18.2 antibody that selectively binds to the extracellular loop of human Claudin18.2. In this study, we constructed a solid target radionuclide zirconium-89 (89Zr) labled-TST001 to detect the expression of in the human stomach cancer BGC823CLDN18.2 cell lines. The [89Zr]Zr-desferrioxamine (DFO)-TST001 showed high radiochemical purity (RCP, >99%) and specific activity (24.15±1.34 GBq/μmol), and was stable in 5% human serum albumin, and phosphate buffer saline (>85% RCP at 96h). The EC50 values of TST001 and DFO-TST001 were as high as 0.413±0.055 and 0.361±0.058nM(P>0.05), respectively. The radiotracer had a significantly higher average standard uptake values in CLDN18.2-positive tumors than in CLDN18.2-negative tumors (1.11±0.02 vs. 0.49±0.03, P=0.0016) 2 days post injection (p.i.). BGC823CLDN18.2 mice models showed high tumor/muscle ratios 96h p.i. with [89Zr]Zr-DFO-TST001 was much higher than those of the other imaging groups. Immunohistochemistry results showed that BGC823CLDN18.2 tumors were highly positive (+++) for CLDN18.2, while those in the BGC823 group did not express CLDN18.2 (-). The results of exvivo biodistribution studies showed that there was a higher distribution in the BGC823CLDN18.2 tumor bearing mice (2.05±0.16 %ID/g) than BGC823 mice (0.69±0.02 %ID/g) and blocking group (0.72±0.02 %ID/g). A dosimetry estimation study showed that the effective dose of [89Zr]Zr-DFO-TST001 was 0.0705 mSv/MBq, which is within the range of acceptable doses for nuclear medicine research. Taken together, these results suggest that Good Manufacturing Practices produced by this immuno-positron emission tomography probe can detect CLDN18.2-overexpressing tumors.
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