ZELVARA
Full PI

Indication: ZELVARA® (celdatuzumab-mkrz) is indicated, in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative, claudin 18.2 (CLDN18.2)-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Mechanism of Action

ZELVARA (celdatuzumab-mkrz) is a humanized IgG1 monoclonal antibody that specifically targets claudin 18.2 (CLDN18.2) on the surface of gastric and GEJ tumor cells, engaging the immune system through dual mechanisms of tumor cell destruction.

Tumor CellGastric / GEJ AdenocarcinomaCLDNCLDNCLDNCLDNCLDNCLDNCLDN18.2 Expressed on Tumor SurfaceCeldatuzumabNKCellADCCC1qCDCMAC Formation
Step 1 of 4

CLDN18.2 Expression

Claudin 18.2 (CLDN18.2) is a tight junction protein normally expressed in gastric epithelial cells. In gastric and GEJ adenocarcinomas, CLDN18.2 becomes exposed on the tumor cell surface due to disrupted cell polarity, making it accessible for therapeutic targeting.

About CLDN18.2

Claudin 18.2 is a tight junction protein normally expressed in differentiated gastric epithelial cells but hidden within intact tight junctions. In gastric and GEJ adenocarcinomas, loss of cell polarity exposes CLDN18.2 on the tumor cell surface, creating a highly selective therapeutic target with limited expression in normal tissues.

Target Selectivity

CLDN18.2 expression has been detected in approximately 60% of gastric adenocarcinomas and 18% of GEJ tumors. In the BEACON-1 and BEACON-2 trials, CLDN18.2 positivity was defined as ≥75% of tumor cells showing moderate-to-strong membranous staining by immunohistochemistry (IHC 2+/3+).

Dual Mechanism of Tumor Cell Destruction

Antibody-Dependent Cellular Cytotoxicity (ADCC)

Upon binding CLDN18.2, the Fc region of celdatuzumab engages FcγRIIIa (CD16) on natural killer (NK) cells, triggering degranulation and release of cytotoxic mediators (perforin and granzymes) that directly lyse the target tumor cell.

Complement-Dependent Cytotoxicity (CDC)

The Fc region simultaneously activates the classical complement cascade by binding C1q, initiating a proteolytic cascade that culminates in assembly of the membrane attack complex (MAC, C5b-9), forming pores in the tumor cell membrane and inducing osmotic lysis.

Important Safety Information

The most common adverse reactions (≥20%) with ZELVARA plus chemotherapy were nausea, vomiting, decreased appetite, fatigue, diarrhea, and peripheral neuropathy. Severe nausea and vomiting can occur; administer antiemetic prophylaxis prior to and during treatment. See Full Prescribing Information.