CLDN18.2

Claudin (CLDN) family consist of at least 23 different members in humans. CLDNs are transmembrane proteins, a major component of the tight-junction complex regulating cellular barrier permeability and membrane polarity. CLDN is composed of four transmembrane segments with two extracellular loops, and the N- and C- termini localized in the cytoplasm of cells. CLDN-18 has two isoforms, CLDN-18.1 and CLDN-18.2, that are expressed mainly in normal lung and gastric tissues, respectively.

CLDN-18 is expressed in many neoplasias, such as gastric and gastroesophageal junction (G/GEJ) cancer, pancreatic cancer, head and neck cancer and non-small cell lung cancer. Different therapeutic drugs targeting CLDN-18.2 for cancer immunotherapy have now been developed and IHC for CLDN-18.2 to be used for the selection of patients to be offered anti-CLDN18.2 treatment. The distinction and scoring criteria separating CLDN-18.2 positive cancers versus negative cancers depend on tumour type and therapeutic agent. For G/GEJ cancer a moderate to strong (2+/3+) positive membrane staining in ≥75% of tumor cells should be considered as the standard cut-off for a CLDN18.2-positive tumor to be treated with zolbetuximab (VYLOY™, Astellas)

Identification of G/GEJ cancers positive for CLDN-18.2 and eligible for zolbetuximab treatment. 

CLDN-18.2 has a very limited expression in normal tissues and is exclusively expressed in the mucosal membrane of differentiated gastric epithelial cells complicating the design of guidelines for composition of control material for CLDN-18.2 IHC. The gastric epithelial cells will typically show a moderate to strong membranous staining reaction and thus mainly applicable to confirm “right IHC assay” being applied. No staining reaction should be seen in e.g. smooth muscle cells, lymphocytes and endothelial cells enabling these structures to be used as negative tissue controls. Gastric intestinal metaplasia is reported and shown to have a reduced CLDN-18.2 expression and potential to be used as immunohistochemical critical assay performance control (iCAPC) with emphasis on low level demonstration of CLDN-18.2. Gastric intestinal metaplastic epithelial cells (either as external tissue control or internally in patient sample) will typically show a weak to moderate staining reaction. At present internal NordiQC testing has revealed that the presence of gastric intestinal metaplasia is very focal and heterogeneously observed compromising the use for iCAPC in external tissue controls.