Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development
| Autor: | Michael Koslowski, Karl Dhaene, Gunda Brandenburg, Ugur Sahin, Christoph Huber, Dirk Usener, Özlem Türeci, Gerhard Seitz |
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| Přispěvatelé: | Supporting clinical sciences, Experimental Pathology |
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty mice medicine.drug_class Molecular Sequence Data Gene Expression Biology Monoclonal antibody Malignant transformation Antigen medicine Protein Isoforms Animals Humans Neoplasms Glandular and Epithelial Membrane Proteins/genetics Antibodies Monoclonal/immunology Protein Isoforms/immunology Base Sequence Reverse Transcriptase Polymerase Chain Reaction Neoplasms Glandular and Epithelial/drug therapy Antibodies Monoclonal Immunotherapy Active Membrane Proteins Cancer medicine.disease Flow Cytometry Immunohistochemistry Immunotherapy Active/methods Oncology Cancer cell Claudins biology.protein Cancer research Antibody Stem cell |
| Popis: | Purpose: Antibody-based cancer therapies have emerged as the most promising therapeutics in oncology. The purpose of this study was to discover novel targets for therapeutic antibodies in solid cancer. Experimental Design: We combined data mining and wet-bench experiments to identify strictly gastrocyte lineage–specific cell surface molecules and to validate them as therapeutic antibody targets. Results: We identified isoform 2 of the tight junction molecule claudin-18 (CLDN18.2) as a highly selective cell lineage marker. Its expression in normal tissues is strictly confined to differentiated epithelial cells of the gastric mucosa, but it is absent from the gastric stem cell zone. CLDN18.2 is retained on malignant transformation and is expressed in a significant proportion of primary gastric cancers and the metastases thereof. In addition to its orthotopic expression, we found frequent ectopic activation of CLDN18.2 in pancreatic, esophageal, ovarian, and lung tumors, correlating with distinct histologic subtypes. The activation of CLDN18.2 depends on the binding of the transcription factor cyclic AMP–responsive element binding protein to its unmethylated consensus site. Most importantly, we were able to raise monoclonal antibodies that bind to CLDN18.2 but not to its lung-specific splice variant and recognize the antigen on the surface of cancer cells. Conclusions: Its highly restricted expression pattern in normal tissues, its frequent ectopic activation in a diversity of human cancers, and the ability to specifically target this molecule at the cell surface of tumor cells qualify CLDN18.2 as a novel, highly attractive pan-cancer target for the antibody therapy of epithelial tumors. |
| Databáze: | OpenAIRE |
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