Review Highlights Potential for CLDN18.2 as a Therapeutic Target in Various Cancers

Claudins (CLDNs), a group of proteins that control molecule flow between cells, have been linked to prognosis in several cancer types. A recent review published in Biomarker Research highlights a specific CLDN, claudin18.2 (CLDN18.2), as a particularly useful marker that has led to the development of targeted immunotherapy strategies in recent years.

CLDN18.2 is an isoform of claudin18, which is a member of the tight junction family of proteins and plays roles in the proliferation, differentiation, and migration of cancer cells. Abnormal CLDN18.2 expression often occurs with cancer development across a variety of tumor types, including gastric cancer (GC) and gastroesophageal junction (GEJ) cancer. It is very specific and has very limited expression in normal tissues, but very stable expression in tissues that have become malignant.

Recently, immunotherapy options, including monoclonal antibodies (mAbs), bispecific antibodies, redirected chimeric antigen receptor (CAR) T cells, and antibody-drug conjugates (ADCs) have been developed to target CLDN18.2. None are approved yet, but as of the end of January 2022, 15 clinical trials related to CLDN18.2 were listed on the National Medical Products Administration website and 28 were listed on the National Clinical Trial website, the review notes. Of those trials, 22 involved mAbs, 3 included bispecific mAbs, 9 involved CAR T-cell therapy, and 9 involved ADCs. Most of the trials involved solid tumors, and 4 were phase 3, 4 were phase 2, 8 were phase 1/2, and 27 were phase 1 trials.

Potential CLDN18.2-Targeted Therapies

The mAb zolbetuximab was developed to target CLDN18.2 and has undergone studies largely focused on GC and GEJ. It has been shown to positively impact progression-free survival (PFS) and overall survival in conjunction with chemotherapy in GEJ cancer. Studies have also found zolbetuximab to boost T-cell infiltration and induce cytokine release, adding to the curative effect of first-line chemotherapy. Further advanced research is needed before zolbetuximab is added to the cancer treatment armamentarium, but studies are underway, including phase 3 trials to assess PFS in advanced GC and GEJ.

Another mAb, TST001, has been found comparable to zolbetuximab in preclinical research, potentially with more potent antitumor activity, and is currently being assessed in phase 1 trials on patients with advanced solid tumors. Preliminary data has found it safe thus far.

In addition to mAbs, research is now focusing on bispecific and trispecific mAbs, which may improve T-cell cytotoxicity with low overall toxicity. Studies have shown that using a CDLN18.2-targeted bispecific agent or ADC may have potential in the GC and pancreatic cancer settings. The bispecific T-cell engager (BiTE) AMG-910 is in preclinical and early clinical studies. The safety and efficacy of BiTEs in humans is not confirmed, but a phase 1 trial involving patients with advanced CLDN18.2-positive GC and GEJ adenocarcinoma is ongoing.

Q-1802, a bispecific antibody, targets both programmed death-ligand 1 (PD-L1) and CLDN18.2, and animal studies have shown it effective at killing malignant cells. A phase 1 trial of Q-1802 is underway for patients with advanced solid tumors.

Early studies have also explored potential CLDN18.2-targeted CAR T-cell therapy in GC and other cancers, with mouse models showing promising results. Early clinical trials are assessing safety and dose-limiting toxicity, although more research is needed to confirm safety and efficacy. As with CAR T-cell therapy in general, cytokine release syndrome is a potential adverse effect that may make clinical application challenging.

Other agents, including ADCs, are also being tested in preliminary research but are pending results. Overall, further research on CLDN18.2-targeted therapies is needed to confirm efficacy and safety.

“Although no drug targeting CLDN18 has been approved for clinical application worldwide yet, global research and development have demonstrated that CLDN18.2 targeting candidates may become an important alternative for GC targeted treatment after HER-2-targeted agents,” study authors wrote. Considering the specificity and stability of CLDN18.2 as a marker in various cancer types, study authors are optimistic about utilizing it as a therapeutic target as further research provides insight on the efficacy and safety of novel agents.

Reference

Cao W, Xing H, Li Y, et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark Res. Published online May 31, 2022. doi:10.1186/s40364-022-00385-1