Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development

Ugur Sahin, Michael Koslowski, Karl Dhaene, Dirk Usener, Gunda Brandenburg, Gerhard Seitz, Christoph Huber, Ozlem Türeci

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)7624-7634
Number of pages11
JournalClinical Cancer Research
Volume14
Issue number23
DOIs
Publication statusPublished - 1 Dec 2008

Keywords

  • Animals
  • Antibodies, Monoclonal/immunology
  • Base Sequence
  • Claudins
  • Flow Cytometry
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • Immunotherapy, Active/methods
  • Membrane Proteins/genetics
  • Mice
  • Molecular Sequence Data
  • Neoplasms, Glandular and Epithelial/drug therapy
  • Protein Isoforms/immunology
  • Reverse Transcriptase Polymerase Chain Reaction

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