Claudin 18.2 Immunotherapy Pipeline Centers on Next-Generation Candidates After Zolbetuximab

VYLOY (zolbetuximab-clzb) is the only CLDN18.2 targeted therapy to be approved in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma whose tumors are claudin 18.2 positive. Zolbetuximab has been approved in Japan, the UK, Korea, the US, Canada, Brazil and China, and has received marketing authorization from the European Commission valid in all 27 EU member states as well as Iceland, Liechtenstein, and Norway.

Claudin 18.2 is a transmembrane, tight junction protein exclusively expressed in normal gastric mucosa cells and is retained in most gastric or gastroesophageal junction adenocarcinomas. In normal gastric mucosa, CLDN18.2 is typically buried within tight junctions, and during malignant transformation, loss of gastric mucosa cell polarity may result in CLDN18.2 becoming more exposed and thus accessible to therapeutic antibodies.

Zolbetuximab is a first-in-class immunoglobulin G1 monoclonal antibody that targets CLDN18.2 and mediates antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma cells. Zolbetuximab has become the current gold standard and benchmark for follow-on anti-CLDN18.2 immunotherapy candidates as it is the only candidate that has been evaluated in controlled pivotal clinical studies so far.

The clinical profile of zolbetuximab showed statistically significant and clinically relevant improvements in progression-free survival by 1.94 or 1.41 months and in overall survival of 2.69 or 2.23 months in the SPOTLIGHT or GLOW phase III trials, respectively. Major adverse events were gastrointestinal symptoms including nausea, vomiting and decreased appetite. Only 39.1% of gastric cancer patients were eligible to treatment with zolbetuximab; one inclusion criterion was expression of CLDN18.2 in tumor tissue defined by moderate to strong staining in 75% of cancer cells.

As zolbetuximab is a chimeric naked monoclonal antibody with limited effector function, numerous next-generation CLDN18.2-targeted immunotherapy candidates are being evaluated in clinical studies around the globe. The main market opportunities in the CLDN18.2-targeted immunotherapy space include:

• next-generation monoclonal antibodies with enhanced efficacy
• antibody-drug conjugates with improved linker and conjugation technology and payloads
• chimeric antigen receptor T-cells and natural killer cells with improved constructs
• bispecific T-cell engaging antibodies for recruitment of cytotoxic T-cells
• bispecific immune-oncology antibodies including PD-L1, 4-1BB, CD47/SIRP-a or CD8

Active CLDN18.2-targeted research and development programs are being pursued across drug modalities, including naked monoclonal antibodies with enhanced target affinity and increased ADCC, CDC and ADCP, as well as advanced CAR-T, NK-cell and bispecific antibody approaches.