In healthy tissue, the
tight junction protein Claudin 18.2 (CLDN18.2) is present only in the gastric mucosa. Upon malignant transformation of gastric epithelial tissue, perturbations in cell polarity lead to cell surface exposure of CLDN18.2
epitopes. Moreover, CLDN18.2 is aberrantly expressed in
malignancies of several other organs, such as
pancreatic cancer (PC). A
monoclonal antibody,
zolbetuximab (formerly known as
IMAB362), has been generated against CLDN18.2. In a phase 2 clinical trial (FAST: NCT01630083),
zolbetuximab in conjunction with
chemotherapy prolonged overall and progression-free survival over
chemotherapy alone and improved quality of life. In this study, the mechanism of action and antitumor activity of
zolbetuximab were investigated using nonclinical PC models.
Zolbetuximab bound specifically and with strong affinity to human PC cells that expressed CLDN18.2 on the cell surface. In ex vivo systems using immune effector cells and serum from healthy donors,
zolbetuximab induced antibody-dependent cellular cytotoxicity (ADCC) and
complement-dependent cytotoxicity (CDC), resulting in the lysis of cultured human PC cells. The amplitude of ADCC and CDC directly correlated with cell surface CLDN18.2 levels. The chemotherapeutic agent
gemcitabine upregulated CLDN18.2 expression in cultured human PC cells and enhanced
zolbetuximab-induced ADCC. In mouse xenograft
tumors derived from human PC cell lines, including
gemcitabine-refractory ones,
zolbetuximab slowed
tumor growth, benefited survival, and attenuated
metastases development. The results presented here validate CLDN18.2 as a targetable
biomarker in PC and support extension of the clinical development of
zolbetuximab to patients with CLDN18.2-expressing PC.