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Characterization of zolbetuximab in pancreatic cancer models
In healthy tissue, the tight junction protein Claudin 18.2 (CLDN18.2) is present only in the gastric mucosa. Upon malignant transformation of gastric epithelial tissue, perturbations in cell polarity lead to cell surface exposure of CLDN18.2 epitopes. Moreover, CLDN18.2 is aberrantly expressed in ma...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287799/ https://www.ncbi.nlm.nih.gov/pubmed/30546962 http://dx.doi.org/10.1080/2162402X.2018.1523096 |
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author | Türeci, Ӧzlem Mitnacht-Kraus, Rita Wöll, Stefan Yamada, Tomohiro Sahin, Ugur |
author_facet | Türeci, Ӧzlem Mitnacht-Kraus, Rita Wöll, Stefan Yamada, Tomohiro Sahin, Ugur |
author_sort | Türeci, Ӧzlem |
collection | PubMed |
description | In healthy tissue, the tight junction protein Claudin 18.2 (CLDN18.2) is present only in the gastric mucosa. Upon malignant transformation of gastric epithelial tissue, perturbations in cell polarity lead to cell surface exposure of CLDN18.2 epitopes. Moreover, CLDN18.2 is aberrantly expressed in malignancies of several other organs, such as pancreatic cancer (PC). A monoclonal antibody, zolbetuximab (formerly known as IMAB362), has been generated against CLDN18.2. In a phase 2 clinical trial (FAST: NCT01630083), zolbetuximab in conjunction with chemotherapy prolonged overall and progression-free survival over chemotherapy alone and improved quality of life. In this study, the mechanism of action and antitumor activity of zolbetuximab were investigated using nonclinical PC models. Zolbetuximab bound specifically and with strong affinity to human PC cells that expressed CLDN18.2 on the cell surface. In ex vivo systems using immune effector cells and serum from healthy donors, zolbetuximab induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), resulting in the lysis of cultured human PC cells. The amplitude of ADCC and CDC directly correlated with cell surface CLDN18.2 levels. The chemotherapeutic agent gemcitabine upregulated CLDN18.2 expression in cultured human PC cells and enhanced zolbetuximab-induced ADCC. In mouse xenograft tumors derived from human PC cell lines, including gemcitabine-refractory ones, zolbetuximab slowed tumor growth, benefited survival, and attenuated metastases development. The results presented here validate CLDN18.2 as a targetable biomarker in PC and support extension of the clinical development of zolbetuximab to patients with CLDN18.2-expressing PC. |
format | Online Article Text |
id | pubmed-6287799 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-62877992019-05-01 Characterization of zolbetuximab in pancreatic cancer models Türeci, Ӧzlem Mitnacht-Kraus, Rita Wöll, Stefan Yamada, Tomohiro Sahin, Ugur Oncoimmunology Original Research In healthy tissue, the tight junction protein Claudin 18.2 (CLDN18.2) is present only in the gastric mucosa. Upon malignant transformation of gastric epithelial tissue, perturbations in cell polarity lead to cell surface exposure of CLDN18.2 epitopes. Moreover, CLDN18.2 is aberrantly expressed in malignancies of several other organs, such as pancreatic cancer (PC). A monoclonal antibody, zolbetuximab (formerly known as IMAB362), has been generated against CLDN18.2. In a phase 2 clinical trial (FAST: NCT01630083), zolbetuximab in conjunction with chemotherapy prolonged overall and progression-free survival over chemotherapy alone and improved quality of life. In this study, the mechanism of action and antitumor activity of zolbetuximab were investigated using nonclinical PC models. Zolbetuximab bound specifically and with strong affinity to human PC cells that expressed CLDN18.2 on the cell surface. In ex vivo systems using immune effector cells and serum from healthy donors, zolbetuximab induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), resulting in the lysis of cultured human PC cells. The amplitude of ADCC and CDC directly correlated with cell surface CLDN18.2 levels. The chemotherapeutic agent gemcitabine upregulated CLDN18.2 expression in cultured human PC cells and enhanced zolbetuximab-induced ADCC. In mouse xenograft tumors derived from human PC cell lines, including gemcitabine-refractory ones, zolbetuximab slowed tumor growth, benefited survival, and attenuated metastases development. The results presented here validate CLDN18.2 as a targetable biomarker in PC and support extension of the clinical development of zolbetuximab to patients with CLDN18.2-expressing PC. Taylor & Francis 2018-11-10 /pmc/articles/PMC6287799/ /pubmed/30546962 http://dx.doi.org/10.1080/2162402X.2018.1523096 Text en © 2019 The Author(s). Published with license by Taylor & Francis Group, LLC. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. |
spellingShingle | Original Research Türeci, Ӧzlem Mitnacht-Kraus, Rita Wöll, Stefan Yamada, Tomohiro Sahin, Ugur Characterization of zolbetuximab in pancreatic cancer models |
title | Characterization of zolbetuximab in pancreatic cancer models |
title_full | Characterization of zolbetuximab in pancreatic cancer models |
title_fullStr | Characterization of zolbetuximab in pancreatic cancer models |
title_full_unstemmed | Characterization of zolbetuximab in pancreatic cancer models |
title_short | Characterization of zolbetuximab in pancreatic cancer models |
title_sort | characterization of zolbetuximab in pancreatic cancer models |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287799/ https://www.ncbi.nlm.nih.gov/pubmed/30546962 http://dx.doi.org/10.1080/2162402X.2018.1523096 |
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