Anti-Claudin Treatments in Gastroesophageal Adenocarcinoma: Mainstream and Upcoming Strategies

Abstract

Claudins (CLDNs) are a multigene family of proteins and the principal components of tight junctions (TJs), which normally mediate cell–cell adhesion and selectively allow the paracellular flux of ions and small molecules between cells. Downregulation of claudin proteins increases the paracellular permeability of nutrients and growth stimuli to malignant cells, which aids the epithelial transition. Claudin 18.2 (CLDN18.2) was identified as a promising target for the treatment of advanced gastroesophageal adenocarcinoma (GEAC), with high levels found in almost 30% of metastatic cases. CLDN18.2 aberrations, enriched in the genomically stable subgroup of GEAC and the diffuse histological subtype, are ideal candidates for monoclonal antibodies and CAR-T cells. Zolbetuximab, a highly specific anti-CLDN18.2 monoclonal antibody, demonstrated efficacy in phase II studies and, more recently, in the phase III SPOTLIGHT trial, with improvements in both PFS and OS with respect to standard chemotherapy. Anti-CLDN18.2 chimeric antigen receptor (CAR)-T cells showed a safety profile with a prevalence of hematologic toxicity in early phase clinical trials. The aim of this review is to present new findings in the treatment of CLDN18.2-positive GEAC, with a particular focus on the monoclonal antibody zolbetuximab and on the use of engineered anti-CLDN18.2 CAR-T cells.

Detection of driver mutations and genomic signatures in endometrial cancers using artificial intelligence algorithms

“…The antibody is effective in promoting antibody- and complement-dependent cytotoxicity as reported in recent phase II clinical studies [ 39 , 40 ]. CLDN18 isoform 2 CAR T-cell immunotherapy is another promising therapy for gastric cancers and also in clinical studies [ 41 ]. The finding that CLDN18 is also over-expressed in endometrial cancers highlight the importance of this gene and should be considered for similar targeted therapeutics.…”

cCPE Fusion Proteins as Molecular Probes to Detect Claudins and Tight Junction Dysregulation in Gastrointestinal Cell Lines, Tissue Explants and Patient-Derived Organoids

“…In contrast, several antibodies were described to be specific for a particular claudin subtype (e.g., CLDN1, −4, −5 or −18.2) [ 67 , 68 , 69 , 70 ]. For most applications, narrow specificity is desirable, for instance, to reduce potential side effects of anti-CLDN18.2 antibodies that are in clinical trials to treat gastric or gastroesophageal junction cancer [ 71 , 72 , 73 , 74 ]. However, in some cases, it is advantageous to address multiple claudins by cCPE variants in order to increase the number of targeted protein molecules and thus the efficacy of target-mediated effects, and to avoid target claudins escaping from a single specific claudin antibody [ 44 ].…”

“…Here, we used GST- and YFP-cCPE variants for simultaneous microscopic detection of the multiple cCPE variant-binding claudins expressed in the cells of interest (HT29-B6: CLDN1 to −5, −7, −8 [ 83 ]; colon tissue: CLDN1, −3 to −5, −7, −8 [ 11 ]; gastric tissue and organoids CLDN1 to −4, −6, −7 [ 12 , 74 ], this study).…”

“…CLDN18.2 is strongly expressed in the stomach but not in other tissues and is dysregulated in gastric cancer, and CLDN18.2-antibody-mediated targeting has been tested in clinical trials for cancer treatment [ 73 , 74 ]. However, this non-classic claudin is not recognized by any cCPE variant [ 35 ].…”

A consolidated working classification of gastric cancer for histopathologists (Review)

“…Claudin18.2 . Part of a large family of transmembrane proteins involved in tight junctions, claudin18.2 arises from differential splicing of mRNA and is overexpressed is some GC cases, particularly those of diffuse Laurén type ( 59 , 60 ). It is targeted by antibody-drug conjugates, bispecific antibodies (zolbetuximab) and cell therapies such as chimeric antigen receptor T-cells ( 61 ).…”