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.Gastroesophageal and pancreatic cancers are among the malignancies with the highest unmet medical needs (1). Gastric cancer is the second leading cause of cancer death worldwide. In 2002, f1.4 million people worldwide developed gastroesophageal cancers and 1.1 million died (2). Esophageal cancer incidence has increased in recent decades, coinciding with a shift in histologic type and primary tumor location. Adenocarcinoma of the esophagus is now more prevalent than squamous cell carcinoma in the United States and Western Europe, with most tumors located in the distal esophagus (3).The overall 5-year survival rates for gastroesophageal cancers are 20% to 25% despite the aggressiveness of established standard treatments associated with substantial side effects (4, 5). For pancreatic cancer, there is an even greater medical need. Due to the advanced state of the disease at the time of diagnosis, the prognosis is extremely poor, with median survival times of less than 6 months and a 5-year survival rate of <5.5%. The lack of a major benefit from the various newergeneration combination chemotherapy regimens for these cancers has stimulated research into the use of targeted agents, such as small molecule -based kinase inhibitors and monoclonal antibodies (mAb; ref. 6). However, mAbs, such as bevacizumab, cetuximab, and trastuzumab...

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