Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumors
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....
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Elsevier
2023-04-01
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| Series: | Journal of Pharmaceutical Analysis |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2095177923000357 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yan Chen |
| collection | DOAJ |
| description | 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 96 h). The EC50 values of TST001 and DFO-TST001 were as high as 0.413 ± 0.055 and 0.361 ± 0.058 nM (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 96 h 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 ex vivo 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. |
| first_indexed | 2024-04-09T15:30:12Z |
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| id | doaj.art-77e85538b05d490ba417434da0a4bce5 |
| institution | Directory Open Access Journal |
| issn | 2095-1779 |
| language | English |
| last_indexed | 2024-04-09T15:30:12Z |
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| spelling | doaj.art-77e85538b05d490ba417434da0a4bce52023-04-28T08:55:22ZengElsevierJournal of Pharmaceutical Analysis2095-17792023-04-01134367375Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumorsYan Chen0Xingguo Hou1Dapeng Li2Jin Ding3Jiayue Liu4Zilei Wang5Fei Teng6Hongjun Li7Fan Zhang8Yi Gu9Steven Yu10Xueming Qian11Zhi Yang12Hua Zhu13Guizhou University Medicine College, Guiyang, 550025, China; The Ministry of Education Key Laboratory of Carcinogenesis and Translational Research; NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, ChinaThe Ministry of Education Key Laboratory of Carcinogenesis and Translational Research; NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, ChinaGuizhou University Medicine College, Guiyang, 550025, China; The Ministry of Education Key Laboratory of Carcinogenesis and Translational Research; NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, ChinaThe Ministry of Education Key Laboratory of Carcinogenesis and Translational Research; NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, ChinaThe Ministry of Education Key Laboratory of Carcinogenesis and Translational Research; NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, ChinaThe Ministry of Education Key Laboratory of Carcinogenesis and Translational Research; NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, 646000, ChinaSuzhou Transcenta Therapeutics Co., Ltd, Suzhou, Jiangsu, 215127, ChinaSuzhou Transcenta Therapeutics Co., Ltd, Suzhou, Jiangsu, 215127, ChinaSuzhou Transcenta Therapeutics Co., Ltd, Suzhou, Jiangsu, 215127, ChinaSuzhou Transcenta Therapeutics Co., Ltd, Suzhou, Jiangsu, 215127, ChinaSuzhou Transcenta Therapeutics Co., Ltd, Suzhou, Jiangsu, 215127, ChinaSuzhou Transcenta Therapeutics Co., Ltd, Suzhou, Jiangsu, 215127, China; Corresponding author.Guizhou University Medicine College, Guiyang, 550025, China; The Ministry of Education Key Laboratory of Carcinogenesis and Translational Research; NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Institute of Biomedical Engineering, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055, China; Corresponding author. Guizhou University Medicine College, Guiyang, 550025, China.Guizhou University Medicine College, Guiyang, 550025, China; The Ministry of Education Key Laboratory of Carcinogenesis and Translational Research; NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China; Institute of Biomedical Engineering, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055, China; Corresponding author. Guizhou University Medicine College, Guiyang, 550025, China.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 96 h). The EC50 values of TST001 and DFO-TST001 were as high as 0.413 ± 0.055 and 0.361 ± 0.058 nM (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 96 h 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 ex vivo 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.http://www.sciencedirect.com/science/article/pii/S2095177923000357Claudin18.2Gastrointestinal cancersZirconium-89Positron emission tomographyGood Manufacturing Practices |
| spellingShingle | 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 Journal of Pharmaceutical Analysis Claudin18.2 Gastrointestinal cancers Zirconium-89 Positron emission tomography Good Manufacturing Practices |
| title | Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumors |
| title_full | Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumors |
| title_fullStr | Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumors |
| title_full_unstemmed | Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumors |
| title_short | Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumors |
| title_sort | development of a cldn18 2 targeting immuno pet probe for non invasive imaging in gastrointestinal tumors |
| topic | Claudin18.2 Gastrointestinal cancers Zirconium-89 Positron emission tomography Good Manufacturing Practices |
| url | http://www.sciencedirect.com/science/article/pii/S2095177923000357 |
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