Validation, Detection & Molecular Imaging of Death Receptor 5 in Gastrointestinal Cancer Patients

Purpose: CTB006 is a humanized chimeric recombinant anti-human death receptor 5(DR5) agonistic antibody and can specifically bind to DR5. The purpose of this study was to validate the DR 5 expression in human. And investigates the potential of the ⁸⁹Zr-CTB006 PET/CT to reveal tumor lesions and detect the DR5 expression to screen the DR5 over-expression patients with gastrointestinal cancers. Patients and Methods: Patients with gastrointestinal cancer that would undergo surgical operation were enrolled. All patients would undergo ¹⁸F-FDG PET/CT and ⁸⁹Zr-CTB006 PET/CT. ⁸⁹Zr-CTB006 PET/CT of the first six patients was undertaken 2 hours, 24 hours, 48 hours, 72 hours, 120 hours after 52.77±11MBq ⁸⁹Zr-CTB006 injection. The other patients underwent ⁸⁹Zr-CTB006 PET/CT 2 hours, 48 hours, 72 hours after the ⁸⁹Zr-CTB006 injection. Then the tumor tissues were obtained through surgical operation and the DR5 expression levels were detected by RNAscope.

Results: Twenty-one patients were enrolled including nine gastric cancers and twelve colorectal cancers. Three patients with colorectal cancers had received chemotherapy or radiotherapy. One patient with gastric cancer withdrew for individual reasons. The biodistribution of ⁸⁹Zr-CTB006 was evaluated. Except the expected high accumulation in blood, liver and spleen, there was an astonishing finding that the adrenal glands maintained stable high uptake over the whole examination in all patients. The ⁸⁹Zr-CTB006 was generally high uptake in primary tumor lesions and the metastatic lesions which was more heterogeneous than ¹⁸F-FDG and the uptake of ⁸⁹Zr-CTB006 correlates with that of ¹⁸F-FDG significantly(48 h R 0.785, P<0.001;72 hours R 0.791, P<0.001). Both SUVmax of ¹⁸F-FDG (SUV_max: 15.26±5.78 vs 6.80±3.35, P 0.04) and ⁸⁹Zr-CTB006 on 48 hours (SUV_max: 8.94±3.23 vs 4.83±0.51, P 0.005) in previously treated patients were significantly lower than untreated patients with colorectal cancers. The tumor tissue of 9 patients were obtained and the RNAscope results showed that two patients (22.2%) were 2-4 and seven patients (77.8%) were 0-1. The ⁸⁹Zr-CTB006 uptake in patients with RNAscope results of 2-4 were significantly higher than patients with 0-1 both on 48 hours (SUV_max: 12.35±2.05 vs 4.75±2.21, P 0.005) and 72 hours (SUV_max: 15.48±2.15 vs 5.87±3.18, P 0.005). The tumors with higher uptake than adrenal glands were more likely to be DR5 overexpressed. Conclusion: ⁸⁹Zr-CTB006 PET/CT can reveal the primary and metastatic tumor lesions with heterogenous uptake and this is the first time to find high uptake in adrenal glands. Higher ⁸⁹Zr-CTB006 uptake of tumors than adrenal glands is predictive of DR5 over-expression suggesting that the uptake of adrenal glands might be the cutoff value to distinguish DR5 over-expression. Only 22.2% of the patients were DR5 overexpressed, which is much lower than expected. The DR5 expression can be downregulated by chemotherapy and radiotherapy. The study developed a noninvasive approach ⁸⁹Zr-CTB006 PET/CT to detect the DR5 overexpressed tumors based on the molecular imaging. Key words: Death receptor 5; ⁸⁹Zr-CTB006 PET/CT; Gastrointestinal cancer; molecular imaging. Foundation Support: National Natural Science Foundation of China (81671733, 81871386), Beijing Natural Science Foundation(7171002). Ethical approval: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent was obtained from all patients. The clinical study was approved by the Ethics Committee of the Beijing Cancer Hospital (Ethics Approval License: 2018YJZ64)