靶向肿瘤 CLDN18.2 分子影像探针的研究进展

Research advances in molecular imaging probes targeting CLDN18.2 in tumors

摘要

近年来,以 Claudin 18.2 (CLDN18.2) 为靶点的抗肿瘤治疗已成为研究热点。尽管部分靶向CLDN18.2的药物已进入临床应用,并展现出良好的疗效,但其疗效高度依赖于靶点的表达水平。因此,开发具有高灵敏性与高特异性的 CLDN18.2 分子影像探针,对于实现肿瘤的早期发现、患者筛选与分层治疗以及疗效的动态监测具有重要意义。本文系统梳理了近年来围绕 CLDN18.2 靶点开发的分子影像探针的研究进展,旨在为该类诊断型药物的持续优化及其临床转化提供理论支持与实践参考。

Abstract

Claudin 18.2 (CLDN18.2) has emerged as a promising molecular target for anti-tumor therapy, drawing considerable attention in recent years.Although several CLDN18.2-targeted therapeutics have already entered clinical practice and shown good efficacy, their efficacy is closely correlated with the expression level of the target.Consequently, the development of molecular imaging probes with high sensitivity and specificity for CLDN18.2 is of great significance for the early detection of tumors, stratification of patients, and real-time monitoring of therapeutic response.This review systematically summarizes recent advances in the development of CLDN18.2-targeted molecular imaging probes, aiming to provide a theoretical framework to support the future design and clinical translation of diagnostic radiopharmaceuticals.

关键词

CLDN18.2 / 分子影像探针 / 放射性核素 / 肿瘤诊断 / 靶向治疗 / 临床应用

Key words

CLDN18.2 / molecular imaging probe / radionuclide / tumor diagnosis / targeted therapy / clinical application

[1] SALEH J.CT colonography for early detection of peritoneal metas-tasis in patients with gastric cancer[J].Radiol Imaging Cancer, 2022,4 (2):e229004.
[2] HALLINAN JTPD,VENKATESH SK.Gastric carcinoma:ima-ging diagnosis,staging and assessment of treatment response[J]. Cancer Imaging,2013,13 (2):212-227.
[3] YIN H,ZHANG M,ZHANG Y,et al.Liquid biopsies in cancer[J].Mol Biomed,2025,6 (1): 18.
[4] TÜRECI Ö,MITNACHT-KRAUS R,WÖLL S,et al.Character-ization of zolbetuximab in pancreatic cancer models[J].OncoIm-munology,2019,8 (1):e1523096.
[5] SAHIN U,KOSLOWSKI M,DHAENE K,et al.Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic anti-body development[J].Clin Cancer Res,2008,14 (23): 7624-7634.
[6] SAWADA N.Tight junction-related human diseases[J].Pathol Int,2013,63 (1):1-12.
[7] GÜNZEL D,YU ASL.Claudins and the modulation of tight junction permeability[J].Physiol Rev,2013, 93 (2): 525-569.
[8] KAGE H,FLODBY P,ZHOU BY,et al.Dichotomous roles of claudins as tumor promoters or suppressors:lessons from knock-out mice[J].Cell Mol Life Sci,2019,76 (23):4663-4672.
[9] TANAKA M,SHIBAHARA J,FUKUSHIMA N,et al.Claudin-18 is an early-stage marker of pancreatic carcinogenesis[J].J Histochem Cytochem,2011,59 (10):942-952.
[10] LU YF,WU TL,SHENG YY,et al.Correlation between Clau-din-18 expression and clinicopathological features and prognosis in patients with gastric cancer[J].J Gastrointest Oncol,2020, 11 (6):1253-1260.
[11] COATI I,LOTZ G,FANELLI GN,et al.Claudin-18 expression in oesophagogastric adenocarcinomas:a tissue microarray study of 523 molecularly profiled cases[J].Br J Cancer,2019, 121 (3):257-263.
[12] PARK S,SHIN K,KIM IH,et al.Clinicopathological features and prognosis of resected pancreatic ductal adenocarcinoma pa-tients with claudin-18 overexpression[J].J Clin Med,2023, 12 (16): 5394.
[13] KAYIKCIOGLU E,YÜCEER RO.The role of claudin 18.2 and HER-2 in pancreatic cancer outcomes[J].Medicine (Balti-more),2023,102 (6):e32882.
[14] ZHANG ZW,LIU XD,ZHOU LR,et al.Investigation of clinical application of claudin 18 isoform 2 in pancreatic ductal adenocar-cinoma:a retrospective analysis of 302 Chinese patients[J].His-tol Histopathol,2022,37 (10):1031-1040.
[15] MOENTENICH V,GEBAUER F,COMUT E,et al.Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies[J].Oncol Lett,2020, 19 (6): 3665-3670.
[16] WANG FJ,YANG Y,DU XZ,et al.Claudin18.2 as a potential therapeutic target for primary ovarian mucinous carcinomas and metastatic ovarian mucinous carcinomas from upper gastrointesti-nal primary tumours[J].BMC Cancer,2023,23 (1): 44.
[17] LIU JY,YANG HC,YIN DJ,et al.Expression and prognostic analysis of CLDN18 and Claudin18. 2 in lung adenocarcinoma[J].Pathol Res Pract,2022,238: 154068.
[18] IWAYA M,HAYASHI H,NAKAJIMA T,et al.Colitis-associat-ed colorectal adenocarcinomas frequently express claudin 18 iso-form 2:implications for claudin 18.2 monoclonal antibody thera-py[J].Histopathology,2021,79 (2):227-237.
[19] DOTTERMUSCH M,KRÜGER S,BEHRENS HM,et al.Ex-pression of the potential therapeutic target claudin-18. 2 is fre-quently decreased in gastric cancer:results from a large Cauca-sian cohort study[J].Virchows Arch,2019, 475 (5): 563-571.
[20] TŐKÉS AM,SZÁSZ AM,JUHÁSZ E,et al.Expression of tight junction molecules in breast carcinomas analysed by array PCR and immunohistochemistry[J].Pathol Oncol Res,2012, 18 (3):593-606.
[21] KWAK Y,KIM TY,NAM SK,et al.Clinicopathologic and mo-lecular characterization of stages II~IV gastric cancer with Clau-din 18.2 expression[J].Oncologist,2025,30 (2):oyae238.
[22] BAEK JH,PARK DJ,KIM GY,et al.Clinical implications of Claudin18.2 expression in patients with gastric cancer[J].Anti-cancer Res,2019,39 (12):6973-6979.
[23] SHAH MA,SHITARA K,AJANI JA,et al.Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junc-tion adenocarcinoma:the randomized,phase 3 GLOW trial[J]. Nat Med,2023,29 (8):2133-2141.
[24] XU Y,FU J,HENDERSON M,et al.CLDN18. 2 BiTE engages effector and regulatory T cells for antitumor immune response in preclinical models of pancreatic cancer[J].Gastroenterology, 2023,165 (5):1219-1232.
[25] MENG QH,HAO YM,YANG M,et al.Development and vali-dation of ELISA method for quantification of Q-1802 in serum and its application to pharmacokinetic study in ICR Mouse[J].J Pharm Biomed Anal,2024,245: 116138.
[26] QI CS,XIE T,ZHOU J,et al.CT041 CAR T cell therapy for Claudin18.2-positive metastatic pancreatic cancer[J].J Hematol Oncol,2023,16 (1): 102.
[27] WU J,CHEN J,ZHAO YT,et al.Molecular SPECT/CT profi-ling of Claudin18. 2 expression in vivo:implication for patients with gastric cancer[J].Mol Pharm,2024, 21 (7): 3447-3458.
[28] WANG Y,HE SH,MA L,et al.Targeted radionuclide therapy of CLDN18.2-positive gastric cancer with [¹³¹I] I-zolbetuximab: an in vitro and in vivo study[J].Mol Pharm,2025, 22 (5): 2535-2544.
[29] WANG Y,MA L,KUANG ZJ,et al.Preparation of radiolabeled zolbetuximab targeting CLDN18.2 and its preliminary evaluation for potential clinical applications[J].Mol Pharm,2024, 21 (8):3838-3847.
[30] CHEN Y,HOU XG,LI DP,et al.Development of a CLDN18. 2-targeting immuno-PET probe for non-invasive imaging in gastro-intestinal tumors[J].J Pharm Anal,2023,13 (4):367-375.
[31] ZENG ZQ,LI LQ,TAO JP,et al.¹⁷⁷Lu Lu-labeled anti-clau-din-18.2 antibody demonstrated radioimmunotherapy potential in gastric cancer mouse xenograft models[J].Eur J Nucl Med Mol Imaging,2024,51 (5):1221-1232.
[32] WANG SJ,QI CS,DING J,et al.First-in-human CLDN18. 2 functional diagnostic pet imaging of digestive system neoplasms enables whole-body target mapping and lesion detection[J].Eur J Nucl Med Mol Imaging,2023,50 (9):2802-2817.
[33] ZHAO CK,RONG ZN,DING J,et al.Targeting claudin 18.2 using a highly specific antibody enables cancer diagnosis and guided surgery[J].Mol Pharm,2022,19 (10):3530-3541.
[34] WANG ZL,ZHAO CK,DING J,et al.Screening,construction, and preliminary evaluation of CLDN18.2-specific peptides for noninvasive molecular imaging[J].ACS Pharmacol Transl Sci, 2023,6 (12):1829-1840.
[35] HAMERS-CASTERMAN C,ATARHOUCH T,MUYLDERMANS S, et al.Naturally occurring antibodies devoid of light chains[J]. Nature,1993,363 (6428):446-448.
[36] INGRAM JR,SCHMIDT FI,PLOEGH HL.Exploiting nanobodies＇ singular traits[J].Annu Rev Immunol,2018,36:695-715.
[37] WEI WJ,ZHANG D,ZHANG Y,et al.Development and com-parison of ⁶⁸Ga/¹⁸F/⁶⁴Cu-labeled nanobody tracers probing Clau-din18.2[J].Mol Ther Oncolytics,2022,27:305-314.
[38] ZHONG WX,LU YM,MA Z,et al.Development of a human-ized VHH based recombinant antibody targeting claudin 18. 2 positive cancers[J].Front Immunol,2022,13: 885424.
[39] HU GL,ZHU WJ,LIU Y,et al.Development and comparison of three ⁸⁹Zr-labeled anti-CLDN18. 2 antibodies to noninvasively evaluate CLDN18. 2 expression in gastric cancer:a preclinical study[J].Eur J Nucl Med Mol Imaging,2022,49 (8): 2634-2644.
[40] WANG RX,BAI ZD,ZHONG WT,et al.Synthesis,preclinical evaluation and pilot clinical translation of [⁶⁸Ga] Ga-PMD22,a novel nanobody PET probe targeting CLDN18.2 of gastrointestinal cancer[J].Eur J Nucl Med Mol Imag,2024, 51 (12): 3731-3743.
[41] QI CS,GUO R,CHEN Y,et al.⁶⁸Ga-NC-BCH whole-body PET imaging rapidly targets Claudin18.2 in lesions in gastrointes-tinal cancer patients[J].J Nucl Med,2024, 65 (6): 856-863.
[42] KUBOTA Y,SHITARA K.Zolbetuximab for Claudin18.2-posi-tive gastric or gastroesophageal junction cancer[J].Ther Adv Med Oncol,2024,16: 17588359231217967.
[43] SHITARA K,LORDICK F,BANG YJ,et al.Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive,HER2-nega-tive,untreated,locally advanced unresectable or metastatic gas-tric or gastro-oesophageal junction adenocarcinoma (SPOT-LIGHT):a multicentre,randomised,double-blind,phase 3 trial[J].Lancet,2023,401 (10389):1655-1668.
[44] JARDIM DL,SCHWAEDERLE M,HONG DS,et al.An ap-praisal of drug development timelines in the Era of precision on-cology[J].Oncotarget,2016,7 (33):53037-53046.

基金资助

国家自然科学基金区域重点资助项目(U24A20765);苏州市"科教兴卫"青年科技项目(KJXW2023004)