A phase I dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer

Şahin, Uğur; Schüler, Martin; Richly, Heike; Bauer, Sebastian; Крилова, А.С.; Dechow, Tobias; Jerling, Markus; Utsch, Magdalena; Rohde, Christoph; Dhaene, Karl; Huber, Christoph; Türeci, Özlem

doi:10.1016/j.ejca.2018.05.007

Cited by 103 publications

(114 citation statements)

References 13 publications

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“…To best of our knowledge, the present study is the largest systematic investigation of claudin 18.2 protein expression in EAC (n=485) in addition to the first study to detect claudin 18.2 expression in corresponding regional lymph node metastases using a commercially available monoclonal antibody, which was also used in other studies on gastric cancer (18)(19)(20)30). The present study demonstrated detectable claudin 18.2 expression in up to 18.4% of EAC cases.…”

Section: Discussionmentioning

confidence: 50%

“…Claudin 18.2 is an interesting tight-junction protein that may be therapeutically modifiable and whose relevance is currently being tested in studies on gastric cancer (16,(18)(19)(20)(21)28). In these studies, the response to therapy is associated with the measurable presence of the protein in the tumor (16,(18)(19)(20)(21)30). This may make claudin 18.2 a relevant biomarker, as we have known for years with programmed death-ligand 1, HER2/neu or hormone receptors in breast carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…Regarding claudin 18.2 as a potential target for immunotherapy, the present results have an impact on potential future therapeutic strategies. IMAB362, a novel antibody targeting claudin 18.2, has been investigated in various phase I and phase II studies for patients with gastric and/or gastro-esophageal junction cancer and has exhibited anti-tumor activity (16,(18)(19)(20)(21)28). Gastrointestinal toxicities were the most commonly observed treatment-associated adverse events (18)(19)(20)30).…”

Section: Discussionmentioning

confidence: 99%

“…IMAB362 is currently undergoing a number of phase I and IIb trials, which have revealed that IMAB362 is well-tolerated, exhibits anti-tumor activity and improves the disease control rate and progression-free survival time when administered as a monotherapy or in combination with chemotherapy. The most frequently observed treatment-associated adverse events include nausea and vomiting (18)(19)(20)(21).…”

Section: Claudin 182 Expression In Esophageal Adenocarcinoma and Itsmentioning

confidence: 99%

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Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies

et al. 2020

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The incidence of esophageal adenocarcinoma (EAC) has rapidly increased, particularly in the Western world. Despite improvements in perioperative treatments, the overall survival of patients remains low. Claudin 18.2 is a tight junction protein that is exclusively expressed in the gastric epithelia. However, following malignant transformation, gastric cancer metastases maintain this expression. Therefore, claudin 18.2 is a promising target for immunotherapy. Previous clinical trials have revealed improved anti-tumor activity in patients treated with an anti-claudin antibody by investigating the expression of claudin 18.2 in tumor cells. However, there is currently very limited data on the importance of claudin 18.2 expression in EAC. The present study analyzed the distribution of claudin 18.2 using immunohistochemistry in 485 patients with EAC, including their lymph node metastases. Additionally, these results were associated with clinical and molecular data. Claudin 18.2 was detected in 89/485 patients (18.4%). No correlations between expression and clinicopathological data (sex, age, pT stage, lymph node metastasis and grading) were observed. However, significantly decreased claudin 18.2 expression was observed in tumor types with upregulated human epidermal growth factor receptor 2 expression (P=0.036). Additionally, neoadjuvant treatment did not have any significant impact on claudin 18.2 expression (P= 0.331). To the best of our knowledge, the present study is the largest systematic investigation of claudin 18.2 protein expression in EAC. The results obtained suggested that claudin 18.2 may serve as a promising therapeutic target in a substantial number of patients with EAC.

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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Claudin 182 Expression In Esophageal Adenocarcinoma and Itsmentioning

confidence: 99%

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Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies

et al. 2020

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“…This antibody was demonstrated to mediate cancer cell death through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In several early clinical trials for the treatment of advanced gastric cancer (GC), zolbetuximab alone or in combination with standard chemotherapy significantly prolonged survival with acceptable safety and tolerability [8,9].…”

Section: Introductionmentioning

confidence: 99%

Identification of CLDN18 as a potential diagnostic biomarker and therapeutic target for pancreatic cancer based on multiomic analysis

Li¹,

Zhang²,

Hu³

2020

Preprint

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Background Claudin 18 (CLDN18) is a transmembrane protein localized in the apical regions to form a tight-junction complex. The expression of CLDN18 was restricted to normal lung and stomach tissues but was aberrantly activated in some types of cancers, and this molecule can serve as a promising target for targeted treatment. Methods The mRNA expression, genetic variations and prognostic values of CLDN18 in pancreatic cancer (PC) were analyzed using public data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Human Protein Atlas (HPA) databases and multiple online tools. The role of cyclic AMP-responsive element binding protein (CREB) and DNA methylation in regulating the expression of CLDN18 was determined by correlation analysis. Results The expression of CLDN18 was restricted to the lung and stomach in normal tissues, but was ectopically overexpressed in PC. CLDN18 mRNA expression was higher in cancers with advanced local invasion, later clinical stage, infiltrating duct or mucinous carcinoma types. Genetic variations of CLDN18 are rarely observed in PC. Correlation analysis revealed that CREB3L1, CREB3L3, and CREB3L4 were significantly positively coexpressed with CLDN18, and CLDN18 expression increased as methylation gradually decreased. The expression of CLDN18 was not observed to plays a role in predicting the survival of PC patients. Conclusions This data-driven study summarizes the expression features of CLDN18 in PC and demonstrates that it may serve as an ideal biomarker and therapy target for PC.

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Membranous and nuclear staining of CLDN18 in HPV‐independent and HPV‐associated endocervical adenocarcinomas

et al. 2022

Cancer Medicine

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Objectives: A classification system for endocervical adenocarcinoma (ECA) based on high-risk human papillomavirus (HPV) status has been established; however, the immunohistochemical markers distinguishing HPV-independent and HPV-associated ECAs have not been fully described. Here, we aimed to characterize ECA immunopathological features. Methods:We evaluated the immunohistochemical profile of CLDN18, CDX2, PAX8, p16, p53, and CEA in 60 ECAs comprising 10 HPV-independent ECAs and 50 HPV-associated ECAs. Both the membranous and nuclear expression levels of CLDN18 were analyzed. Results: Membranous CLDN18 (CLDN18 [M]) was found to be expressed in the mucinous epithelium of all HPV-independent ECAs, including eight gastric-type ECAs (G-ECAs), one endometrioid ECA, and one clear cell ECA, but no nuclear CLDN18 (CLDN18 [N]) expression was detected in HPV-independent ECAs. Among HPV-associated ECAs, CLDN18 (M) expression levels in intestinal-type (I-ECAs) and usual-type ECAs (U-ECAs) were significantly different from those in invasive stratified mucin-producing (iSMILE) carcinomas (p = 0.036). Positive CLDN18 (M) staining was present in 55.6% (5/9) of intestinal-type and 39.4% (13/33) of usual-type ECAs and was not present in iSMILE ECAs. Silva pattern C cancers expressed higher levels of CLDN18 (M) than Silva pattern A and B cancers (p = 0.004), whereas the CLDN18 (N) expression levels in cancers showing Silva pattern A were significantly higher than those in cancers exhibiting Silva patterns B and C (p < 0.001). Conclusion:Membranous CLDN18 is expressed in ECAs and is particularly frequently expressed in HPV-independent ECAs, and membranous CLDN18 expression has potential as a therapeutic target. Nuclear staining of CLDN18 is a new

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A phase I dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer

Abstract: ClinicalTrials.gov, Identifier NCT00909025.

Cited by 103 publications

References 13 publications

Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies

Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies

Identification of CLDN18 as a potential diagnostic biomarker and therapeutic target for pancreatic cancer based on multiomic analysis

Membranous and nuclear staining of CLDN18 in HPV‐independent and HPV‐associated endocervical adenocarcinomas

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