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

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

doi:10.1016/j.jpha.2023.02.011

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

J Pharm Anal. 2023 Apr;13(4):367-375. doi: 10.1016/j.jpha.2023.02.011. Epub 2023 Feb 28.

Authors

Yan Chen^{1

2}, Xingguo Hou², Dapeng Li^{1

2}, Jin Ding², Jiayue Liu², Zilei Wang^{2

3}, Fei Teng⁴, Hongjun Li⁴, Fan Zhang⁴, Yi Gu⁴, Steven Yu⁴, Xueming Qian⁴, Zhi Yang^{1

2

5}, Hua Zhu^{1

2

5}

Affiliations

¹ Guizhou University Medicine College, Guiyang, 550025, China.
² 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.
³ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, 646000, China.
⁴ Suzhou Transcenta Therapeutics Co., Ltd, Suzhou, Jiangsu, 215127, China.
⁵ Institute of Biomedical Engineering, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055, China.

Abstract

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 BGC823^CLDN18.2 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.). BGC823^CLDN18.2 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 BGC823^CLDN18.2 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 BGC823^CLDN18.2 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.

Keywords: Claudin18.2; Gastrointestinal cancers; Good Manufacturing Practices; Positron emission tomography; Zirconium-89.