Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
European Journal of Nuclear Medicine and Molecular Imaging
Published in: European Journal of Nuclear Medicine and Molecular Imaging 9/2023

26-04-2023 | Gastric Cancer | Original Article

First-in-human CLDN18.2 functional diagnostic pet imaging of digestive system neoplasms enables whole-body target mapping and lesion detection

Authors: Shujing Wang, Changsong Qi, Jin Ding, Dan Li, Miao Zhang, Congcong Ji, Fangli Jiang, Fei Teng, Jie Yu, Xueming Qian, Feng Wang, Lin Shen, Jing Gao, Zhi Yang, Cheng Zhang, Hua Zhu

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 9/2023

Login to get access

Abstract

Purpose

Claudin 18.2 (CLDN18.2) is a reliable target for lesion detection and could have clinical implications for epithelial tumors, especially digestive system neoplasms. However, there is no predictive technology for accurate whole-body mapping of CLDN18.2 expression in patients. This study assessed the safety of the 124I-18B10(10L) tracer and the feasibility of mapping whole-body CLDN18.2 expression using PET functional imaging.

Methods

The 124I-18B10(10L) probe was synthesized manually, and preclinical experiments including binding affinity and specific targeting ability were conducted after testing in vitro model cells. Patients with pathologically confirmed digestive system neoplasms were enrolled in an ongoing, open-label, single-arm, first-in-human (FiH) phase 0 trial (NCT04883970). 124I-18B10(10L) PET/CT or PET/MR and 18F-FDG PET were performed within one week.

Results

124I-18B10(10L) was successfully constructed with an over 95% radiochemical yield. The results of preclinical experiments showed that it had high stability in saline and high affinity in CLDN18.2 overexpressing cells (Kd = 4.11 nM). Seventeen patients, including 12 with gastric cancers, 4 with pancreatic cancers, and 1 with cholangiocarcinoma were enrolled. 124I-18B10(10L) displayed high uptake in the spleen and liver, and slight uptake in the bone marrow, lung, stomach and pancreas. The tracer uptake SUVmax in tumor lesions ranged from 0.4 to 19.5. Compared with that in lesions that had been treated with CLDN18.2-targeted therapy, 124I-18B10(10L) uptake was significantly higher in lesions that had not. Regional 124I-18B10(10L) PET/MR in two patients showed high tracer uptake in metastatic lymph nodes.

Conclusions

124I-18B10(10L) was successfully prepared and exhibited a high binding affinity and CLDN18.2 specificity in preclinical studies. As an FiH CLDN18.2 PET tracer, 124I-18B10(10L) was shown to be safe with acceptable dosimetry and to clearly reveal most lesions overexpressing CLDN18.2.

Trial registration

NCT04883970; URL: https://​register.​clinicaltrials.​gov/​. Registered 07 May 2021.
Appendix
Available only for authorised users
Literature
1.
Tsukita S, Furuse M, Itoh M. Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol. 2001;2:285–93.CrossRefPubMed
2.
3.
Zihni C, Mills C, Matter K, et al. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol. 2016;17:564–80.CrossRefPubMed
4.
Niimi T, Nagashima K, Ward JM, et al. claudin-18, a novel downstream target gene for the T/EBP/NKX2.1 homeodomain transcription factor, encodes lung- and stomach-specific isoforms through alternative splicing. Mol Cell Biol. 2001;21:7380–90.CrossRefPubMedPubMedCentral
5.
Sahin U, Koslowski M, Dhaene K, et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res. 2008;14:7624–34.CrossRefPubMed
6.
Iwaya M, Hayashi H, Nakajima T, et al. Colitis-associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy. Histopathology. 2021;79:227–37.CrossRefPubMed
7.
Kyuno D, Takasawa A, Takasawa K, et al. Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials. Tissue Barriers. 2022;10:1967080.
8.
Klempner SJ, Ajani JA, Al-Batran S-E, et al. Phase II study of zolbetuximab plus pembrolizumab in claudin 18.2: Positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ)—ILUSTRO Cohort 3. J Clin Oncol. 2021;39:TPS260–TPS.
9.
Yamaguchi K, Shitara K, Al-Batran SE, et al. 198TiP - SPOTLIGHT: Comparison of zolbetuximab or placebo + mFOLFOX6 as first-line treatment in patients with claudin18.2+/HER2– locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma (GEJ): A randomized phase III study. Annals Oncol. 2019;30:ix66–7.CrossRef
10.
Xu RH, Ajani JA, Al-Batran SE, et al. 195TiP GLOW: Phase III study of first-line zolbetuximab + CAPOX versus placebo + CAPOX in Claudin18.2+/HER2- advanced/metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ). Annals Oncol. 2020;31:S1315–6.CrossRef
11.
Sahin U, Türeci Ö, Manikhas G, et al. FAST: A randomised phase II study of zolbetuximab (IMAB362) plus EOX vs EOX alone for first-line treatment of advanced CLDN18.2 positive gastric and gastro-oesophageal adenocarcinoma. Annals Oncol. 2021;32:609–19.CrossRef
12.
Qi C, Gong J, Li J, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med. 2022;28:1189–98.
13.
Kage H, Flodby P, Zhou B, et al. Dichotomous roles of claudins as tumor promoters or suppressors: lessons from knockout mice. Cell Mol Life Sci. 2019;76:4663–72.CrossRefPubMedPubMedCentral
14.
15.
Zhu H, Ding J, Chong X, et al. Molecular imaging evaluation of a novel Claudin18.2. specific monoclonal antibody labeled with radionuclide. Annals Oncol. 2021;32:S1.CrossRef
16.
Gong J, Li N, Gao W, et al. A phase I study of TST001, a high affinity humanized anti-CLDN18.2 monoclonal antibody, in combination with capecitabine and oxaliplatin (CAPOX) as a first-line treatment of advanced G/GEJ cancer. J Clin Oncol. 2022;40:4062.CrossRef
17.
Divgi CR, Uzzo RG, Gatsonis C, et al. Positron Emission Tomography/Computed Tomography Identification of Clear Cell Renal Cell Carcinoma: Results From the REDECT Trial. J Clin Oncol. 2013;31:187–94.CrossRefPubMed
18.
Wang S, Zhu H, Ding J, et al. Positron emission tomography imaging of programmed death 1 expression in cancer patients using 124I-Labeled toripalimab: a pilot clinical translation study. Clin Nucl Med. 2021;46:382–8.
19.
Guo X, Zhou N, Chen Z, et al. Construction of 124I-trastuzumab for Noninvasive PET Imaging of HER2 Expression: From Patient-derived Xenograft Models to Gastric Cancer Patients. Gastric Cancer. 2020;23:614–26.CrossRefPubMed
20.
Jiang H, Shi Z, Wang P, et al. Claudin18.2-Specific Chimeric Antigen Receptor Engineered T Cells for the Treatment of Gastric Cancer. J Natl Cancer Inst. 2019;111:409–18.CrossRefPubMed
21.
22.
Gerwing M, Herrmann K, Helfen A, et al. The beginning of the end for conventional RECIST - novel therapies require novel imaging approaches. Nat Rev Clin Oncol. 2019;16:442–58.CrossRefPubMed
23.
Bensch F, van der Veen EL, Lub-de Hooge MN, et al. 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nat Med. 2018;24:1852–8.
24.
Niemeijer AN, Leung D, Huisman MC, et al. Whole body PD-1 and PD-L1 positron emission tomography in patients with non-small-cell lung cancer. Nat Commun. 2018;9:4664.CrossRefPubMedPubMedCentral
25.
Kok IC, Hooiveld JS, van de Donk PP, et al. 89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer. Ann Oncol. 2022;33:80–8.
26.
Türeci O, Sahin U, Schulze-Bergkamen H, et al. A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study. Ann Oncol. 2019;30:1487–95.CrossRefPubMedPubMedCentral
27.
Sahin U, Schuler M, Richly H, et al. A phase I dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer. Eur J Cancer. 2018;100:17–26.CrossRefPubMed
Metadata
Title
First-in-human CLDN18.2 functional diagnostic pet imaging of digestive system neoplasms enables whole-body target mapping and lesion detection
Authors
Shujing Wang
Changsong Qi
Jin Ding
Dan Li
Miao Zhang
Congcong Ji
Fangli Jiang
Fei Teng
Jie Yu
Xueming Qian
Feng Wang
Lin Shen
Jing Gao
Zhi Yang
Cheng Zhang
Hua Zhu
Publication date
26-04-2023
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 9/2023
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-023-06234-z

Other articles of this Issue 9/2023

European Journal of Nuclear Medicine and Molecular Imaging 9/2023 Go to the issue

Image of the Month

PET/CT scan without sedation: how to use total-body PET/CT to salvage child’s involuntary movement?

Original Article

Fibroblast activation protein targeted radiotherapy induces an immunogenic tumor microenvironment and enhances the efficacy of PD-1 immune checkpoint inhibition

Original Article

Organotrifluoroborate enhances tumor targeting of fibroblast activation protein inhibitors for targeted radionuclide therapy

Original Article

Preclinical evaluation of a novel EGFR&c-Met bispecific near infrared probe for visualization of esophageal cancer and metastatic lymph nodes

Original Article

The prognostic value of [18F]FDG PET/CT based response monitoring in metastatic melanoma patients undergoing immunotherapy: comparison of different metabolic criteria

Original Article

Detection efficacy of [89Zr]Zr-PSMA-617 PET/CT in [68Ga]Ga-PSMA-11 PET/CT-negative biochemical recurrence of prostate cancer