CLDN18.2蛋白在恶性肿瘤治疗中的研究进展
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摘要
随着分子生物学研究的进展,靶向治疗已成为除手术、放疗、化疗之外恶性肿瘤治疗中的第四种有效手段。与传统化疗药物不同,分子靶向治疗药物具有特异性强、疗效明显、不良反应较小等优点。CLDN18.2蛋白是新发现的一种跨膜蛋白,具有高选择性特点,稳定地过表达于多种恶性肿瘤中,尤其是消化系统肿瘤及其转移瘤。近年来,其特异性抗体claudiximab(zolbetuximab/IMAB362)在最新的临床试验中取得了显著的成功,CLDN18.2蛋白有望成为某些特定恶性肿瘤靶向治疗的分子靶点。
With the development of molecular biology research, targeted therapy has become the fourth effective method for the treatment of malignant tumors after surgery, radiotherapy, and chemotherapy. Unlike the traditional chemotherapeutic drugs, molecular targeted drugs possess the advantages of high specificity, definite curative effects, and less adverse effects. CLDN18.2 protein is a transmembrane protein that is highly selective and stably overexpressed during the development of various malignant tumors, especially gastrointestinal tumors, and metastases. A specific antibody against this protein, claudiximab(zolbetuximab/IMAB362), has achieved great success in recent clinical trials. Thus, CLDN18.2 protein is expected to be a safe and effective molecular target for targeted therapy in some malignancies.
With the development of molecular biology research, targeted therapy has become the fourth effective method for the treatment of malignant tumors after surgery, radiotherapy, and chemotherapy. Unlike the traditional chemotherapeutic drugs, molecular targeted drugs possess the advantages of high specificity, definite curative effects, and less adverse effects. CLDN18.2 protein is a transmembrane protein that is highly selective and stably overexpressed during the development of various malignant tumors, especially gastrointestinal tumors, and metastases. A specific antibody against this protein, claudiximab(zolbetuximab/IMAB362), has achieved great success in recent clinical trials. Thus, CLDN18.2 protein is expected to be a safe and effective molecular target for targeted therapy in some malignancies.
引文
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[17]Türeci O,Koslowski M,Helftenbein G,et al.Claudin-18 gene structure,regulation,and expression is evolutionary conserved in mammals[J].Gene,2011,481(2):83-92.
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[19]Ito T,Kojima T,Yamaguchi H,et al.Transcriptional regulation of claudin-18 via specific protein kinase C signaling pathways and modification of DNA methylation in human pancreatic cancer cells[J].JCell Biochem,2011,112(7):1761-1772.
[20]Wan YL,Dai HJ,Liu W,et al.miR-767-3p Inhibits Growth and Migration of Lung Adenocarcinoma Cells by Regulating CLDN18[J].Oncol Res,2018,26(4):637-644.
[21]Klamp T,Schumacher J,Huber G,et al.Highly specific auto-antibodies against claudin-18 isoform 2 induced by a chimeric HBcAg viruslike particle vaccine kill tumor cells and inhibit the growth of lung metastases[J].Cancer Res,2011,71(2):516-527.
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[24]Sahin U,Al-Batran S-E,Hozaeel W,et al.IMAB362 plus zoledronic acid(ZA)and interleukin-2(IL-2)in patients(pts)with advanced gastroesophageal cancer(GEC):clinical activity and safety data from the PILOT phase I trial[J].ASCO Meet,2015,33:e15079.
[25]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[J].Eur J Cancer,2018,100:17-26.
[26]Minacht-Kraus R,Kreuzberg M,Utsch M,et al.Preclinical characterization of IMAB362 for the treatment of gastric carcinoma[J].Ann Oncol,2017,28:126.
[27]Al-Batran S,Schuler M,Zvirbule Z,et al.FAST:an international,multicenter,randomized,phase II trial of epirubicin,oxaliplatin,and capecitabine(EOX)with or without IMAB362,a first-in-class antiCLDN18.2 antibody,as first-line therapy in patients with advanced CLDN18.2+gastric and gastroesophageal junction(GEJ)adenocarcinoma[J].J CO,2016,34:LBA4001.
[28]Trarbach T,Schuler M,Zvirbule Z,et al.Efficacy and safety of multiple doses of IMAB362 in patients with advanced gastroesophageal cancer:results of a phase II study[J].Ann Oncol,2014,25(4):iv218.
[29]Al-Batran S-E,Schuler M,Zvirbule Z,et al.LBA-06.IMAB362:a novel immunotherapeutic antibody targeting the tight-junction protein component CLAUDIN18.2 in gastric cancer.Ann Oncol,2016,27(2):ii141-142.
[30]Moran D,Maurus D,Rohde C,et al.Prevalence of CLDN18.2,HER2and PD-L1 in gastric cancer samples[J].Ann Oncol,2018,29(8):103.
[2]Lee YT,Tan YJ,Oon CE.Molecular targeted therapy:Treating cancer with specificity[J].Eur J Pharmacol,2018,834:188-196.
[3]Lyons TG,Ku GY.Systemic therapy for esophagogastric cancer:targeted therapies[J].Chin Clin Oncol,2017,6(5):48.
[4]Singh P,Toom S,Huang Y.Anti-claudin 18.2 antibody as new targeted therapy for advanced gastric cancer[J].J Hematol Oncol,2017,10(1):105.
[5]Günzel D.Claudins:vital partners in transcellular and paracellular transport coupling[J].Pflugers Arch,2017,469(1):35-44.
[6]Colpitts CC,Baumert TF.Claudins in viral infection:from entry to spread[J].Pflugers Arch,2017,469(1):27-34.
[7]Hayashi D,Tamura A,Tanaka H,et al.Deficiency of claudin-18causes paracellular H+leakage,up-regulation of interleukin-1β,and atrophic gastritis in mice[J].Gastroenterology,2012,142(2):292-304.
[8]Li G,Flodby P,Luo J,et al.Knockout mice reveal key roles for claudin 18 in alveolar barrier properties and fluid homeostasis[J].Am JRespir Cell Mol Biol,2014,51(2):210-222.
[9]Türeci?,Mitnacht-Kraus R,W?ll S,et al.Characterization of zolbetuximab in pancreatic cancer models[J].Oncoimmunology,2019,8(1):e1523096.
[10]Sentani K,Oue N,Tashiro T,et al.Immunohistochemical staining of Reg IV and claudin-18 is useful in the diagnosis of gastrointestinal signet ring cell carcinoma[J].Am J Surg Pathol,2008,32(8):1182-1189.
[11]Kumar V,Soni P,Garg M,et al.Emerging Therapies in the Management of Advanced-Stage Gastric Cancer[J].Front Pharmacol,2018,9:404.
[12]W?ll S,Schlitter AM,Dhaene K,et al.Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms[J].Int J Cancer,2014,134(3):731-739.
[13]Micke P,Mattsson Johanna SM,Edlund K,et al.Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer[J].Int J Cancer,2014,135(9):2206-2214.
[14]Jovov B,Van Itallie CM,Shaheen N,et al.Claudin-18:a dominant tight junction protein in Barrett's esophagus and likely contributor to its acid resistance[J].Am J Physiol Gastrointest Liver Physiol,2007,293(6):G1106-1113.
[15]Jiang H,Shi Z,Wang P,et al.Claudin18.2-Specific Chimeric Antigen Receptor Engineered T Cells for the Treatment of Gastric Cancer[J].J Natl Cancer Inst,2018,111(4):1-10.
[16]Tabariès S,Siegel PM.The role of claudins in cancer metastasis[J].Oncogene,2017,36(9):1176-1190.
[17]Türeci O,Koslowski M,Helftenbein G,et al.Claudin-18 gene structure,regulation,and expression is evolutionary conserved in mammals[J].Gene,2011,481(2):83-92.
[18]Zhang X,Odom DT,Koo SH,et al.Genome-wide analysis of cAMP-response element binding protein occupancy,phosphorylation,and target gene activation in human tissues[J].Proc Natl Acad Sci U S A,2005,102(12):4459-4464.
[19]Ito T,Kojima T,Yamaguchi H,et al.Transcriptional regulation of claudin-18 via specific protein kinase C signaling pathways and modification of DNA methylation in human pancreatic cancer cells[J].JCell Biochem,2011,112(7):1761-1772.
[20]Wan YL,Dai HJ,Liu W,et al.miR-767-3p Inhibits Growth and Migration of Lung Adenocarcinoma Cells by Regulating CLDN18[J].Oncol Res,2018,26(4):637-644.
[21]Klamp T,Schumacher J,Huber G,et al.Highly specific auto-antibodies against claudin-18 isoform 2 induced by a chimeric HBcAg viruslike particle vaccine kill tumor cells and inhibit the growth of lung metastases[J].Cancer Res,2011,71(2):516-527.
[22]Maron SB,Catenacci Daniel VT.Novel Targeted Therapies for Esophagogastric Cancer[J].Surg Oncol Clin N Am,2017,26(2):293-312.
[23]Schuler MH,Zvirbule Z,Lordick F,et al.Safety,tolerability,and efficacy of the first-in-class antibody IMAB362 targeting claudin 18.2in patients with metastatic gastroesophageal adenocarcinomas[J].ASCO Meet Abstr,2013,31:4080.
[24]Sahin U,Al-Batran S-E,Hozaeel W,et al.IMAB362 plus zoledronic acid(ZA)and interleukin-2(IL-2)in patients(pts)with advanced gastroesophageal cancer(GEC):clinical activity and safety data from the PILOT phase I trial[J].ASCO Meet,2015,33:e15079.
[25]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[J].Eur J Cancer,2018,100:17-26.
[26]Minacht-Kraus R,Kreuzberg M,Utsch M,et al.Preclinical characterization of IMAB362 for the treatment of gastric carcinoma[J].Ann Oncol,2017,28:126.
[27]Al-Batran S,Schuler M,Zvirbule Z,et al.FAST:an international,multicenter,randomized,phase II trial of epirubicin,oxaliplatin,and capecitabine(EOX)with or without IMAB362,a first-in-class antiCLDN18.2 antibody,as first-line therapy in patients with advanced CLDN18.2+gastric and gastroesophageal junction(GEJ)adenocarcinoma[J].J CO,2016,34:LBA4001.
[28]Trarbach T,Schuler M,Zvirbule Z,et al.Efficacy and safety of multiple doses of IMAB362 in patients with advanced gastroesophageal cancer:results of a phase II study[J].Ann Oncol,2014,25(4):iv218.
[29]Al-Batran S-E,Schuler M,Zvirbule Z,et al.LBA-06.IMAB362:a novel immunotherapeutic antibody targeting the tight-junction protein component CLAUDIN18.2 in gastric cancer.Ann Oncol,2016,27(2):ii141-142.
[30]Moran D,Maurus D,Rohde C,et al.Prevalence of CLDN18.2,HER2and PD-L1 in gastric cancer samples[J].Ann Oncol,2018,29(8):103.