Claudin 18.2 His Tag Protein, Human (Detergent)

CLDN18.2 is a splice variant of the tight junction protein Claudin 18, encoded by the CLDN18 gene located on human chromosome 3q22. The protein consists of 261 amino acids with a molecular weight of approximately 27 kDa. In normal tissues, its expression is strictly confined to differentiated epithelial cells of the gastric mucosa, localized at the apical side of tight junctions, and notably absent from the gastric stem cell zone. Another splice variant, CLDN18.1, is predominantly expressed in the lung.

Structural Characteristics and Functional Mechanisms: CLDN18.2 is a four-transmembrane protein with two extracellular loops, where the first extracellular loop differs from CLDN18.1 by only 8 out of 51 amino acids. In normal gastric epithelium, CLDN18.2 forms tight junction complexes that maintain cellular polarity and serve as a barrier against paracellular H⁺ leakage. Its expression is epigenetically regulated by promoter CpG island methylation, with the transcription factor CREB playing a central role in transcriptional activation.

Aberrant Expression in Malignancies: During malignant transformation, loss of cellular polarity exposes CLDN18.2 epitopes on the tumor cell surface, making it accessible for antibody targeting. CLDN18.2 is retained in approximately 77% of primary gastric adenocarcinomas (56% with significant expression) and is frequently ectopically activated in pancreatic ductal adenocarcinoma (60-90%), esophageal adenocarcinoma, non-small cell lung cancer, and mucinous ovarian cancer. Overall, approximately 38.4% of advanced gastric/gastroesophageal junction adenocarcinomas are CLDN18.2-positive (defined as ≥75% tumor cells with ≥2+ staining intensity).

Therapeutic Development: Zolbetuximab (IMAB362) is a first-in-class chimeric IgG1 monoclonal antibody that specifically binds to CLDN18.2 without cross-reacting with CLDN18.1. It exerts antitumor activity primarily through ADCC and CDC, with efficacy correlating with cell surface CLDN18.2 density. In preclinical pancreatic cancer models, zolbetuximab demonstrated tumor growth inhibition and reduced metastasis, with gemcitabine shown to upregulate CLDN18.2 expression and enhance ADCC. Pivotal Phase III trials (SPOTLIGHT and GLOW) established zolbetuximab plus chemotherapy as a standard-of-care for CLDN18.2-positive advanced gastric cancer, significantly improving both PFS and OS. Beyond monoclonal antibodies, a diverse pipeline of CLDN18.2-targeted therapies is under development, including high-affinity antibodies, bispecific antibodies (CLDN18.2/CD3, CLDN18.2/PD-L1), antibody-drug conjugates (CMG901/AZD0901, SYSA1801), and CAR-T cell therapies (CT041), with potential expansion to pancreatic, esophageal, ovarian, and other CLDN18.2-expressing solid tumors.