Claudin 18.2 (CLDN18.2) is a gastric-specific membrane protein. In the healthy tissue, CLDN18.2 expression is restricted to the short-lived differentiated cells of gastric mucosa as a component of tight junction with limited accessibility of antibody treatment. However, it was ectopically expressed at significant levels in a variety of primary lesion and metastases of epithelial tumor entities, including gastric, pancreatic, esophageal, and lung adenocarcinoma cells. Taken together, CLDN18.2 was believed to be an ideal tumor antigen for immunotherapy. Here, we generated and described a bispecific antibody TJ-CD4B which could redirect and activate T cells to CLDN18.2 positive tumor cells by engaging 4-1BB antigen, thus positioned as a potential novel therapy for gastric cancer and other CLDN18.2 positive tumors.
TJ-CD4B was evaluated for its antigen binding through protein-based binding and cell based binding assay. The cell-based function of TJ-CD4B was further evaluated in a 4-1BB signaling reporter assay and primary human T cell assay. The in vivo efficacy was validated in 4-1BB humanized C57BL/6 mice transferred with colon cancer cell line MC38 overexpressed with human CLDN18.2. Percentage of tumor infiltrating and peripheral CD8+ T cells was evaluated by FACS analysis.
TJ-CD4B showed stronger binding capability to CLDN18.2 when compared with benchmark monoclonal antibody against CLDN18.2 (IMAB362). Functional evaluation of TJ-CD4B indicated the activation of 4-1BB signaling was solely dependent on CLDN18.2 expression on the cell. Furthermore, TJ-CD4B showed superior 4-1BB activity than benchmark 4-1BB monoclonal antibody (Urelumab) in the presence of cells expressing a wide range of CLDN18.2 level including CLDN18.2-low cells. Using a humanized 4-1BB mouse model, TJ-CD4B showed strong tumor growth inhibition (TGI) of CLDN18.2 expressing tumor cells. Meanwhile, we also observed TJ-CD4B increased tumor infiltrating lymphocytes while it had no impact on peripheral lymphocytes. Drug developability assessment indicated that TJ-CD4B was a reasonably developable molecule to be taken forward.
Our data showed that CLDN18.2-targeted 4-1BB bispecific antibody, TJ-CD4B, displayed potent anti-tumor activity only in tumor microenvironment, possibly minimizing the risk of peripheral toxicity. These compelling data supported the further development of TJ-CD4B, which aims to enter clinical phase in early 2021.
Citation Format: Wenqing Jiang, Lei Fang, Zhengyi Wang, Taylor B. Guo, Eunyoung Park, Eunsil Sung, Jaeho Jung. Claudin 18.2 X 4-1BB bispecific antibody induced potent tumor inhibition through tumor-specific 4-1BB activation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5644.