Oncolytic adenovirus-mediated delivery of anti-CLDN18.2 IgG3 for the treatment of solid tumors.

BACKGROUND

Claudin 18.2 (CLDN18.2) is a promising therapeutic target for gastric, pancreatic and ovarian cancers. The Food and Drug Administration-approved antibody, zolbetuximab (IgG1), induces tumor cell death via antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC). While the IgG3 subclass offers superior ADCC, ADCP and CDC effector functions compared with IgG1, its clinical application has been limited by a short plasma half-life due to reduced binding to the neonatal Fc receptor.

METHODS

To overcome this limitation, we engineered a conditionally replicating oncolytic adenovirus (OAd-aCLDN18.2) to deliver and locally express an anti-CLDN18.2 IgG3 antibody specifically within the tumor microenvironment. This strategy leverages the tumor-specific replication of the oncolytic virus (OVs) to achieve high local concentrations of the potent IgG3 antibody, minimizing systemic exposure and its associated half-life liability.

RESULTS

OAd-aCLDN18.2 effectively delivered and expressed the functional anti-CLDN18.2 IgG3 antibody. This localized antibody secretion induced robust ADCC, ADCP and CDC effects against CLDN18.2-positive tumor cells. In vitro, the virus-delivered antibody potently mediated natural killer (NK) cell activation and cytotoxicity. In murine tumor models, treatment with OAd-aCLDN18.2 resulted in significantly superior tumor control compared with systemic administration of zolbetuximab (IgG1), without notable toxicity or changes in body weight. The enhanced efficacy was attributed to the localized, intratumoral production of the highly active IgG3 antibody, combined with the OV’s ability to remodel the tumor microenvironment and potentiate a stronger local NK cell response. Viral replication was largely confined to the tumor, indicating a favorable safety profile.

CONCLUSIONS

This study presents the first report of an OV armed with an anti-CLDN18.2 IgG3 antibody. By combining the potent effector functions of the IgG3 subclass with the localized delivery capabilities of an OV, OAd-aCLDN18.2 overcomes the traditional pharmacokinetic drawbacks of IgG3. This approach elicits robust immune-mediated antitumor responses and demonstrates superior efficacy over the current standard-of-care IgG1 antibody in preclinical models. Our findings support OAd-aCLDN18.2 as a novel and promising therapeutic strategy for CLDN18.2-positive gastric, pancreatic, and ovarian cancers.