CLDN18.2 and 4-1BB bispecific antibody givastomig exerts antitumor activity through CLDN18.2-expressing tumor-directed T-cell activation

作者：Jing Gao, Zhengyi Wang, Wenqing Jiang, Yanni Zhang, Zhen Meng, Yan-Ling Niu, Zhen Sheng, Chan Chen, Xuejun Liu, Xi Chen, Chanjuan Liu, Keren Jia, Cheng Zhang, Haiyan Liao, Jaeho Jung, Eun-Sil Sung, Hyejin Chung, Jingwu Z. Zhang, Andrew X. Zhu, Lin Shen · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2023 · DOI：10.1136/jitc-2023-006704 · 被引用次数：45 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Cancer Immunotherapy and Biomarkers、CAR-T cell therapy research

Background Claudin18.2 (CLDN18.2) is a tight junction protein that has been identified as a clinically proven target in gastric cancer. Stimulation of 4-1BB with agonistic antibodies is also a promising strategy for immunotherapy and 4-1BB + T cells were reported to be present within the tumor microenvironment of patients with gastric cancer. However, hepatotoxicity-mediated by 4-1BB activation was observed in clinical trials of agonistic anti-4-1BB monoclonal antibodies. Methods To specifically activate the 4-1BB + T cells in tumor and avoid the on-target liver toxicity, we developed a novel CLDN18.2×4-1BB bispecific antibody (termed ‘givastomig’ or ‘ABL111’; also known as TJ-CD4B or TJ033721) that was designed to activate 4-1BB signaling in a CLDN18.2 engagement-dependent manner. Results 4-1BB + T cells were observed to be coexisted with CLDN18.2 + tumor cells in proximity by multiplex immunohistochemical staining of tumor tissues from patients with gastric cancer (n=60). Givastomig/ABL111 could bind to cell lines expressing various levels of CLDN18.2 with a high affinity and induce 4-1BB activation in vitro only in the context of CLDN18.2 binding. The magnitude of T-cell activation by givastomig/ABL111 treatment was closely correlated with the CLDN18.2 expression level of tumor cells from gastric cancer patient-derived xenograft model. Mechanistically, givastomig/ABL111 treatment could upregulate the expression of a panel of pro-inflammatory and interferon-γ-responsive gen...