ZL-1211 Exhibits Robust Antitumor Activity by Enhancing ADCC and Activating NK Cell–mediated Inflammation in CLDN18.2-High and -Low Expressing Gastric Cancer Models

Abstract

CLDN18.2 (Claudin18.2)-targeting therapeutic antibodies have shown promising clinical efficacy in ~30% of gastric cancers expressing high levels of CLDN18.2 and less pronounced activity in low expressing malignancies. Here, we report that ZL-1211 is a monoclonal antibody targeting CLDN18.2 engineered to promote enhanced antibody-dependent cellular cytotoxicity (ADCC) with the goal of achieving more potent activity in a wider spectrum of high- and low-CLDN18.2 expressing tumors. ZL-1211 demonstrated more robust in vitro ADCC activity than clinical benchmark not only in CLDN18.2-high but also -low expressing gastric tumor cell lines. Greater anti-tumor efficacy was also observed in mouse xenograft models. Natural killer (NK) cell played critical roles in ZL-1211 efficacy and NK cell depletion abrogated ZL-1211-mediated ADCC activity in vitro. ZL-1211 efficacy in vivo was also dependent on the presence of an NK compartment. Strikingly, NK cells strongly induced an inflammatory response in response to ZL-1211 treatment, including increased IFNγ, TNFα, and IL-6 production, and were recruited into tumor microenvironment in patient-derived gastric tumors expressing CLDN18.2 upon ZL-1211 treatment to lyse the tumor cells. Taken together, our data suggest that ZL-1211 more effectively targets CLDN18.2-high gastric cancers as well as -low expressing malignancies that may not be eligible for treatment with the leading clinical benchmark by inducing enhanced ADCC response and activating NK cells with robust inflammation to enhance anti-tumor efficacy. Clinical activity of ZL-1211 is currently under evaluation in a Phase I clinical trial (NCT05065710).

Claudin18.2 in Advanced Gastric Cancer

“…This study was already discontinued. [52,53]. In the phase I/II trial with ZL-1211 plus CAPOX, 19 patients with CLDN18.2positive advanced solid tumors were enrolled in the dose-escalation phase to receive ZL-1211 at 1 mg/kg (n = 3), 5 mg/kg (n = 7), 10 mg/kg (n = 4), and 20 mg/kg (n = 5) (NCT05065710) [54].…”