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


METHODS
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.
Sahin
Ugur
U
Ganymed Pharmaceuticals, Johannes Gutenberg University, Mainz, Germany. sahin@uni-mainz.de
Koslowski
Michael
M
Dhaene
Karl
K
Usener
Dirk
D
Brandenburg
Gunda
G
Seitz
Gerhard
G
Huber
Christoph
C
Türeci
Ozlem
O
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D001483:Base Sequence; D057167:Claudins; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D016233:Immunotherapy, Active / Q000379:methods; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D020033:Protein Isoforms / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000911:Antibodies, Monoclonal; C486683:CLDN18 protein, human; D057167:Claudins; D008565:Membrane Proteins; D020033:Protein Isoforms