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 b...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)(^(89)Zr)labled-TST001 to detect the expression of in the human stomach cancer BGC823CLDN18.2 cell lines.The[^(89)Zr]Zr-desferrioxamine(DFO)-TST001 showed high radiochemical purity(RCP,>99%)and specific activity(24.15±1.34 GBq/mmol),and was stable in 5%human serum albumin,and phosphate buffer saline(>85%RCP at 96 h).The EC_(50) 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.).BGC823CLDN18.2 mice models showed high tumor/muscle ratios 96 h p.i.with[^(89)Zr]Zr-DFO-TST001 was much higher than those of the other imaging groups.Immunohistochemistry results showed that BGC823CLDN18.2 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 BGC823CLDN18.2 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[^(89)Zr]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.展开更多
Objective: Immunotherapeutic outcomes and clinical characteristics of claudin 18 isoform 2 positive(CLDN18.2-positive) gastric cancer(GC) vary in different clinical studies, making it difficult to optimize antiCLDN18....Objective: Immunotherapeutic outcomes and clinical characteristics of claudin 18 isoform 2 positive(CLDN18.2-positive) gastric cancer(GC) vary in different clinical studies, making it difficult to optimize antiCLDN18.2 therapy. We conducted a retrospective analysis to explore the association of CLDN18.2 expression with clinicopathological characteristics and immunotherapeutic outcomes in GC.Methods: A total of 536 advanced GC patients from 2019 to 2021 in the CT041-CG4006 and CT041-ST-01clinical trials were included in the analysis. CLDN18.2 expression on ≥40% of tumor cells(2+, 40%) and CLDN18.2 expression on ≥70% of tumor cells(2+, 70%) were considered the two levels of positively expressed GC. The clinicopathological characteristics and immunotherapy outcomes of GC patients were analyzed according to CLDN18.2 expression status.Results: CLDN18.2 was expressed in 57.6%(cut-off: 2+, 40%) and 48.9%(cut-off: 2+, 70%) of patients.Programmed death-ligand 1(PD-L1) and CLDN18.2 were co-expressed in 19.8% [combined positive score(CPS)≥1, CLDN18.2(cut-off: 2+, 40%)] and 17.2% [CPS≥5, CLDN18.2(cut-off: 2+, 70%)] of patients.CLDN18.2 expression positively correlated with younger age, female sex, non-gastroesophageal junction(nonGEJ), and diffuse phenotype(P<0.001). HER2 and PD-L1 expression were significantly lower in CLDN18.2-positive GC(both P<0.05). Uterine adnexa metastasis(P<0.001) was more frequent and liver metastasis(P<0.001)was less common in CLDN18.2-positive GC. Overall survival and immunotherapy-related progression-free survival(ir PFS) were inferior in the CLDN18.2-positive group.Conclusions: CLDN18.2-positive GC is associated with poor prognosis and worse immunotherapeutic outcomes. The combination of anti-CLDN18.2 therapy, anti-PD-L1/PD-1 therapy, and chemotherapy for GC requires further investigation.展开更多
中国临床肿瘤学会(Chinese Society of Clinical Oncology,CSCO)胃癌诊疗指南每年更新,融合国内外最新的临床研究进展,关注中国人群研究数据和新药在中国适应证的获批,以期临床诊疗更加符合我国胃癌国情和贴近本国临床实践,对中国临床...中国临床肿瘤学会(Chinese Society of Clinical Oncology,CSCO)胃癌诊疗指南每年更新,融合国内外最新的临床研究进展,关注中国人群研究数据和新药在中国适应证的获批,以期临床诊疗更加符合我国胃癌国情和贴近本国临床实践,对中国临床医师及广大胃癌患者有着重要意义。胃癌靶向治疗不断取得突破,包括新靶点的识别和开发、新型靶向药物的不断涌现以及以靶向药物为基础的联合治疗策略的不断拓展等。2023年CSCO指南针对转移性胃癌靶向治疗的更新主要体现在2个方面:(1)经典靶点的新型靶向药物取得突破,代表药物为人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)的抗体偶联药物(antibody-drug conjugate,ADC);(2)针对新靶点的靶向药物的兴起,代表药物为针对Claudin18.2的单克隆抗体。本文将对2023年指南的转移性胃癌靶向治疗部分的主要内容更新进行解读。展开更多
BACKGROUND Claudin 18.2(CLDN18.2)is a cell surface protein expressed by gastric cancer cells.The monoclonal antibody zolbetuximab binds CLDN18.2-positive cancer cells and causes cancer cell death.A few studies researc...BACKGROUND Claudin 18.2(CLDN18.2)is a cell surface protein expressed by gastric cancer cells.The monoclonal antibody zolbetuximab binds CLDN18.2-positive cancer cells and causes cancer cell death.A few studies researched the prognostic effect of CLDN18.2 expression in metastatic gastric adenocarcinoma.AIM To identify the prognostic value of CLDN18.2 expression in patients with metastatic gastric adenocarcinoma.METHODS This study was conducted with 65 patients over the age of 18 who were diagnosed with metastatic gastric adenocarcinoma.We investigated the effect of CLDN18.2 expression on clinicopathological characteristics(age,sex,histological grade,Lauren classification,family history,metastatic site,HER2 expression)and prognosis for patients with metastatic gastric adenocarcinoma.RESULTS CLDN18.2 expression was positive in 73.8%(48)of the patients.During the median 17.7-mo follow-up period,89.2%(58)of the patients died.Median progression-free survival and overall survival(OS)were 6 mo(95%confidence interval:1.6-10.4)and 12 mo(95%confidence interval:7.5-16.5).There was no statistically significant correlation between CLDN18.2 expression and clinicopathological characteristics of the patients.In univariate and multivariate Cox regression analysis,there was no correlation between clinicopathological characteristics of patients and progression-free survival or OS.CONCLUSION CLDN18.2 expression was quite high in patients with gastric adenocarcinoma,identifying the proportion of the patients in whom zolbetuximab would be efficacious.There is no statistically significant correlation with clinicopathological characteristics and OS.CLDN18.2 is not a prognostic marker in patients with gastric adenocarcinoma,although it is predictive.展开更多
Claudin 18.2(CLDN18.2)is a tight-junction protein.CLDN18.2-targeting strategy has cut a striking figure in CLDN18.2 positive patients with advanced gastric cancer.Zolbetuximab,the CLDN18.2 antibody,obtained a better c...Claudin 18.2(CLDN18.2)is a tight-junction protein.CLDN18.2-targeting strategy has cut a striking figure in CLDN18.2 positive patients with advanced gastric cancer.Zolbetuximab,the CLDN18.2 antibody,obtained a better clinical benefit in patients compared with the controlled.In phase II trials,combination treatment of epirubicin,oxaliplatin and capecitabine(EOX)+zolbetuximab achieved the optimal effects of overall survival which extended to 13.2 months with tolerable safety events,indicating its greater potential playing the second promising target in gastric cancer.This review will reveal the definitive clinical benefit CLDN18.2-targeting therapies have achieved and update the highlighting development(like chimeric antigen receptor T-cell immunotherapy)to CLDN18.2 positive patients.We then focus on 10 questions arisen from recent progress and anticipate to provide a future perspective for novel cancer treatment.展开更多
BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is frequently diagnosed and treated in advanced tumor stages with poor prognosis.More effective screening programs and novel therapeutic means are urgently needed.Recen...BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is frequently diagnosed and treated in advanced tumor stages with poor prognosis.More effective screening programs and novel therapeutic means are urgently needed.Recent studies have regarded tight junction protein claudin 18.2(CLDN18.2)as a candidate target for cancer treatment,and zolbetuximab(formerly known as IMAB362)has been developed against CLDN18.2.However,there are few data reported thus far related to the clinicopathological characteristics of CLDN18.2 expression for PDAC.AIM To investigate the expression of CLDN18.2 in PDAC patients and subsequently propose a new target for the treatment of PDAC.METHODS The Cancer Genome Atlas,Genotype-Tissue Expression,Gene Expression Omnibus,and European Genome-phenome Archive databases were first employed to analyze the CLDN18 gene expression in normal pancreatic tissue compared to that in pancreatic cancer tissue.Second,we analyzed the expression of CLDN18.2 in 93 primary PDACs,86 para-cancer tissues,and 13 normal pancreatic tissues by immunohistochemistry.Immunostained tissues were assessed applying the histoscore.subsequently,they fell into two groups according to the expression state of CLDN18.2.Furthermore,the correlations between CLDN18.2 expression and diverse clinicopathological characteristics,including survival,were investigated.RESULTS The gene expression of CLDN18 was statistically higher(P<0.01)in pancreatic tumors than in normal tissues.However,there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients.CLDN18.2 was expressed in 88(94.6%)of the reported PDACs.Among these tumors,50(56.8%)cases showed strong immunostaining.The para-cancer tissues were positive in 81(94.2%)cases,among which 32(39.5%)of cases were characterized for strong staining intensities.Normal pancreatic tissue was identified solely via weak immunostaining.Finally,CLDN18.2 expression significantly correlated with lymph node metastasis,distant metastasis,nerve invasion,stage,and survival of PDAC patients,while there was no correlation between CLDN18.2 expression and localization,tumor size,patient age and sex,nor any other clinicopathological characteristic.CONCLUSION CLDN18.2 expression is frequently increased in PDAC patients.Thus,it may act as a potential therapeutic target for zolbetuximab in PDAC.展开更多
The treatment of gastrointestinal cancer has always been a crucial research area,and targeted therapy has been receiving increasing attention.At present,the effect of targeted therapy is unsatisfactory for gastric can...The treatment of gastrointestinal cancer has always been a crucial research area,and targeted therapy has been receiving increasing attention.At present,the effect of targeted therapy is unsatisfactory for gastric cancer.Thus,the discovery of new targets is crucial.Claudin 18.2(CLDN18.2),a member of the claudin family,belongs to the tight junction protein family that controls the flow of molecules between cell layers.CLDN18.2 expression has been discussed in many studies.In recent years,there have been many studies on targeted therapy with CLDN18.2-ideal monoclonal antibody 362.Furthermore,CLDN18.2-specific chimeric antigen receptor T therapy has been used for CLDN18.2-positive tumors,such as gastric and pancreatic cancers.Considerable research has been focused on CLDN18.2.CLDN18.2,a newly discovered marker for precise targeted therapy of gastric cancer,could offer new hope for the treatment of gastric cancer.展开更多
基金The research was funded by the National Natural Science Foundation of China(Grant Nos.:82171973,82171980,and 82102092)Beijing Millions of Talent Projects A Level Funding(Grant No.:2019A38)+2 种基金The study was also supported by Beijing Hospitals Authority Dengfeng Project(Grant No.:DFL20191102)the Pilot Project(4th Round)to Reform Public Development of Beijing Municipal Medical Research Institute(20211)the Third Foster Plan in 2019“Molecular Imaging Probe Preparation and Characterization of Key Technologies and Equipment”for the Development of Key Technologies and Equipment in Major Science and Technology Infrastructure in Shenzhen,China.
文摘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)(^(89)Zr)labled-TST001 to detect the expression of in the human stomach cancer BGC823CLDN18.2 cell lines.The[^(89)Zr]Zr-desferrioxamine(DFO)-TST001 showed high radiochemical purity(RCP,>99%)and specific activity(24.15±1.34 GBq/mmol),and was stable in 5%human serum albumin,and phosphate buffer saline(>85%RCP at 96 h).The EC_(50) 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.).BGC823CLDN18.2 mice models showed high tumor/muscle ratios 96 h p.i.with[^(89)Zr]Zr-DFO-TST001 was much higher than those of the other imaging groups.Immunohistochemistry results showed that BGC823CLDN18.2 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 BGC823CLDN18.2 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[^(89)Zr]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.
基金supported by Beijing Natural Science Foundation (No. Z20J00105)the National Natural Science Foundation of China (No. 82272627)。
文摘Objective: Immunotherapeutic outcomes and clinical characteristics of claudin 18 isoform 2 positive(CLDN18.2-positive) gastric cancer(GC) vary in different clinical studies, making it difficult to optimize antiCLDN18.2 therapy. We conducted a retrospective analysis to explore the association of CLDN18.2 expression with clinicopathological characteristics and immunotherapeutic outcomes in GC.Methods: A total of 536 advanced GC patients from 2019 to 2021 in the CT041-CG4006 and CT041-ST-01clinical trials were included in the analysis. CLDN18.2 expression on ≥40% of tumor cells(2+, 40%) and CLDN18.2 expression on ≥70% of tumor cells(2+, 70%) were considered the two levels of positively expressed GC. The clinicopathological characteristics and immunotherapy outcomes of GC patients were analyzed according to CLDN18.2 expression status.Results: CLDN18.2 was expressed in 57.6%(cut-off: 2+, 40%) and 48.9%(cut-off: 2+, 70%) of patients.Programmed death-ligand 1(PD-L1) and CLDN18.2 were co-expressed in 19.8% [combined positive score(CPS)≥1, CLDN18.2(cut-off: 2+, 40%)] and 17.2% [CPS≥5, CLDN18.2(cut-off: 2+, 70%)] of patients.CLDN18.2 expression positively correlated with younger age, female sex, non-gastroesophageal junction(nonGEJ), and diffuse phenotype(P<0.001). HER2 and PD-L1 expression were significantly lower in CLDN18.2-positive GC(both P<0.05). Uterine adnexa metastasis(P<0.001) was more frequent and liver metastasis(P<0.001)was less common in CLDN18.2-positive GC. Overall survival and immunotherapy-related progression-free survival(ir PFS) were inferior in the CLDN18.2-positive group.Conclusions: CLDN18.2-positive GC is associated with poor prognosis and worse immunotherapeutic outcomes. The combination of anti-CLDN18.2 therapy, anti-PD-L1/PD-1 therapy, and chemotherapy for GC requires further investigation.
文摘BACKGROUND Claudin 18.2(CLDN18.2)is a cell surface protein expressed by gastric cancer cells.The monoclonal antibody zolbetuximab binds CLDN18.2-positive cancer cells and causes cancer cell death.A few studies researched the prognostic effect of CLDN18.2 expression in metastatic gastric adenocarcinoma.AIM To identify the prognostic value of CLDN18.2 expression in patients with metastatic gastric adenocarcinoma.METHODS This study was conducted with 65 patients over the age of 18 who were diagnosed with metastatic gastric adenocarcinoma.We investigated the effect of CLDN18.2 expression on clinicopathological characteristics(age,sex,histological grade,Lauren classification,family history,metastatic site,HER2 expression)and prognosis for patients with metastatic gastric adenocarcinoma.RESULTS CLDN18.2 expression was positive in 73.8%(48)of the patients.During the median 17.7-mo follow-up period,89.2%(58)of the patients died.Median progression-free survival and overall survival(OS)were 6 mo(95%confidence interval:1.6-10.4)and 12 mo(95%confidence interval:7.5-16.5).There was no statistically significant correlation between CLDN18.2 expression and clinicopathological characteristics of the patients.In univariate and multivariate Cox regression analysis,there was no correlation between clinicopathological characteristics of patients and progression-free survival or OS.CONCLUSION CLDN18.2 expression was quite high in patients with gastric adenocarcinoma,identifying the proportion of the patients in whom zolbetuximab would be efficacious.There is no statistically significant correlation with clinicopathological characteristics and OS.CLDN18.2 is not a prognostic marker in patients with gastric adenocarcinoma,although it is predictive.
基金supported by the National Key Research and Development Program of China(No.2017YFC1308900)。
文摘Claudin 18.2(CLDN18.2)is a tight-junction protein.CLDN18.2-targeting strategy has cut a striking figure in CLDN18.2 positive patients with advanced gastric cancer.Zolbetuximab,the CLDN18.2 antibody,obtained a better clinical benefit in patients compared with the controlled.In phase II trials,combination treatment of epirubicin,oxaliplatin and capecitabine(EOX)+zolbetuximab achieved the optimal effects of overall survival which extended to 13.2 months with tolerable safety events,indicating its greater potential playing the second promising target in gastric cancer.This review will reveal the definitive clinical benefit CLDN18.2-targeting therapies have achieved and update the highlighting development(like chimeric antigen receptor T-cell immunotherapy)to CLDN18.2 positive patients.We then focus on 10 questions arisen from recent progress and anticipate to provide a future perspective for novel cancer treatment.
基金Supported by the Basic Research Project of Natural Science of Shaanxi Province,No.2020JQ-943,2021JQ-916 and 2021JQ-914Research Project of Chinese Society of Clinical Oncology-Sai Sheng Fund,No.Y-2020Sciclone/qn-0181+2 种基金Science and Technology Support Program of Shaanxi Provincial People’s Hospital,No.2021JY-26,2021JY-38,2021JY-50 and 2021BJ-13Research Fund Project of Shaanxi Provincial People’s Hospital,No.2021YJY-18China Postdoctoral Science Foundation,No.2021M702607.
文摘BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is frequently diagnosed and treated in advanced tumor stages with poor prognosis.More effective screening programs and novel therapeutic means are urgently needed.Recent studies have regarded tight junction protein claudin 18.2(CLDN18.2)as a candidate target for cancer treatment,and zolbetuximab(formerly known as IMAB362)has been developed against CLDN18.2.However,there are few data reported thus far related to the clinicopathological characteristics of CLDN18.2 expression for PDAC.AIM To investigate the expression of CLDN18.2 in PDAC patients and subsequently propose a new target for the treatment of PDAC.METHODS The Cancer Genome Atlas,Genotype-Tissue Expression,Gene Expression Omnibus,and European Genome-phenome Archive databases were first employed to analyze the CLDN18 gene expression in normal pancreatic tissue compared to that in pancreatic cancer tissue.Second,we analyzed the expression of CLDN18.2 in 93 primary PDACs,86 para-cancer tissues,and 13 normal pancreatic tissues by immunohistochemistry.Immunostained tissues were assessed applying the histoscore.subsequently,they fell into two groups according to the expression state of CLDN18.2.Furthermore,the correlations between CLDN18.2 expression and diverse clinicopathological characteristics,including survival,were investigated.RESULTS The gene expression of CLDN18 was statistically higher(P<0.01)in pancreatic tumors than in normal tissues.However,there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients.CLDN18.2 was expressed in 88(94.6%)of the reported PDACs.Among these tumors,50(56.8%)cases showed strong immunostaining.The para-cancer tissues were positive in 81(94.2%)cases,among which 32(39.5%)of cases were characterized for strong staining intensities.Normal pancreatic tissue was identified solely via weak immunostaining.Finally,CLDN18.2 expression significantly correlated with lymph node metastasis,distant metastasis,nerve invasion,stage,and survival of PDAC patients,while there was no correlation between CLDN18.2 expression and localization,tumor size,patient age and sex,nor any other clinicopathological characteristic.CONCLUSION CLDN18.2 expression is frequently increased in PDAC patients.Thus,it may act as a potential therapeutic target for zolbetuximab in PDAC.
文摘The treatment of gastrointestinal cancer has always been a crucial research area,and targeted therapy has been receiving increasing attention.At present,the effect of targeted therapy is unsatisfactory for gastric cancer.Thus,the discovery of new targets is crucial.Claudin 18.2(CLDN18.2),a member of the claudin family,belongs to the tight junction protein family that controls the flow of molecules between cell layers.CLDN18.2 expression has been discussed in many studies.In recent years,there have been many studies on targeted therapy with CLDN18.2-ideal monoclonal antibody 362.Furthermore,CLDN18.2-specific chimeric antigen receptor T therapy has been used for CLDN18.2-positive tumors,such as gastric and pancreatic cancers.Considerable research has been focused on CLDN18.2.CLDN18.2,a newly discovered marker for precise targeted therapy of gastric cancer,could offer new hope for the treatment of gastric cancer.
