Abstract
BACKGROUND: Gastric cancer is one of the most lethal malignancies in the world, but effective therapeutic options for patients with this disease remain limited. Claudin-18.2 (CLDN18.2) has emerged as a promising therapeutic target, yet the functional role of CLDN18.2 and the mechanisms of CLDN18.2-directed immunotherapy remain poorly understood. This study aims to explore the antitumor effects and related mechanisms of the CLDN18.2-CD3 bispecific antibody. METHODS: The antitumor efficacy and immunological mechanisms of the CLDN18.2-CD3 bispecific antibody IBI389 were evaluated through two preclinical models: a human peripheral blood mononuclear cell (PBMC)-reconstituted AGS xenograft and a B-hCD3EDG murine KPC pancreatic cancer model. Stable CLDN18.2-overexpressing cell lines were established for in vitro functional assays. Tumor growth inhibition was assessed through volume and weight measurements. Immune modulation was analyzed via flow cytometry, multiplex immunofluorescence, cytokine profiling, and histopathology. Human gastric cancer tissue microarrays were further used to validate spatial findings. RESULTS: CLDN18.2 overexpression enhanced the proliferation and migration of gastric and pancreatic cancer cells in vitro. In vivo, IBI389 significantly suppressed tumor growth, with the greatest efficacy achieved when combined with programmed death-1 (PD-1) blockade. Mechanistically, IBI389 increased the abundance of tumor-infiltrating CD8(+) T cells; reshaped the cytokine milieu toward an antitumor profile characterized by elevated interleukin (IL)-2, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) levels with concomitant reductions in IL-4, IL-10, and IL-17A; and reduced the spatial distance between CLDN18.2(+) tumor cells and CD3(+) T cells. These spatial changes were consistent with observations of human gastric cancer tissues. Histopathological analysis of the liver, kidney, and spleen identified no overt drug-related toxicity. CONCLUSIONS: In this study, we demonstrated that IBI389 effectively redirects T cells to CLDN18.2-expressing tumors, suppresses tumor growth, and synergizes with PD-1 blockade and has a favorable safety profile. By virtue of its ability to enhance immune infiltration, remodel cytokine responses, and reduce tumor-immune spatial separation, IBI389 may have considerable potential as a novel therapeutic strategy for CLDN18.2-positive gastric cancer and related malignancies.