The preclinical discovery and development of zolbetuximab for the treatment of gastric cancer

ABSTRACT

Introduction

Gastric cancer remains a formidable challenge in oncology with high mortality rates and few advancements in treatment. Claudin-18.2 (CLDN18.2) is a tight junction protein primarily expressed in the stomach and is frequently overexpressed in certain subsets of gastric cancers. Targeting CLDN18.2 with monoclonal antibodies, such as zolbetuximab (IMAB362), has shown promising efficacy results in combination with chemotherapy.

Areas covered

The molecular cell biology of CLDN18.2 is discussed along with studies demonstrating the utility of CLDN18.2 expression as a biomarker and therapeutic target. Important clinical studies are reviewed, including Phase III trials, SPOTLIGHT and GLOW, which demonstrate the efficacy of zolbetuximab in combination with chemotherapy in patients with CLDN18.2-positive advanced gastric cancer.

Expert opinion

CLDN18.2 is involved in gastric differentiation through maintenance of epithelial barrier function and coordination of signaling pathways, and its expression in gastric cancers reflects a ‘gastric differentiation’ program. Targeting Claudin-18.2 represents the first gastric cancer specific ‘targeted’ treatment. Further studies are needed to determine its role within current gastric cancer treatment sequencing, including HER2-targeted therapies and immunotherapies. Management strategies will also be needed to better mitigate zolbetuximab-related treatment side effects, including gastrointestinal (GI) toxicities.

KEYWORDS:

• Antibody–drug conjugate
• tight junction
• cancer biomarker
• gastric differentiation

Article highlights

• Gastric cancer remains a deadly disease with limited “targeted” treatments that are safe and efficacious.

• Claudin-18 exhibits unique tissue expression based on alternative splicing with Claudin-18.1 and Claudin-18.2 expressed in the lungs and stomach, respectively.

• Claudin-18.2 is expressed in the normal gastric mucosa within the pit and base regions of the healthy gastric units, and in various cancers including gastric cancers that exhibit gastric differentiation.

• Claudin-18 is an important component of tight junctions and mediates growth and proliferation signals within the cell, and its expression has been shown in mouse models to be lost early during gastric oncogenesis.

• IMAB362 (zolbetuximab), a chimeric IgG1 anti-CLDN18.2 monoclonal antibody, was identified to specifically target gastric cancer cells with limited activity in normal tissues.

• Phases I, II, and III (“GLOW” and “SPOTLIGHT”) clinical trials have demonstrated the safety and clinical efficacy of IMAB362 (zolbetuximab) in combination with chemotherapy for advanced gastric and gastroesophageal junction adenocarcinomas.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Y Zeng is supported by a National Cancer Center (NCC) Post-doctoral fellowship, while RU Jin is supported by the U.S. Department of Defense through award W81XWH-20-PRCRP-CDA, the American Society of Clinical Oncology (ASCO) (Conquer Cancer Foundation) through award 2021YIA-8674301298, the U.S. National Institutes of Health (NIH) through awards U54CA163060 and P30DK056338, and via the Baylor College of Medicine Chao Physician-Scientist Award.