Abstract 1833: Development of anti-CLDN18.2-anti-CD3 bispecific antibody as cancer therapeutics

Abstract

Abstract Claudin-18 (CLDN18) is a member of the large Claudin family of four-span transmembrane proteins, which are essential components of the mammalian tight junctions (TJs) in the epithelial cells. Claudin-18 has two splice variants, CLDN18.1 and CLDN18.2. While CLDN18.1 is specifically expressed in the lung tissue, CLDN18.2 expression in normal tissue is more restricted and is only detected in small patches of stomach mucosal. CLDN18.2 expression is elevated in many types of epithelial cancers including stomach, esophagus, pancreatic and ovarian cancers. Anti-CLDN18.2 monoclonal antibody Claudiximab (IMAB362) demonstrated promising results in clinical trials for gastric cancers. Using a combination of DNA, protein, and transfected cells as immunogens, we have generated a panel of mouse monoclonal antibodies which are highly specific for CLDN18.2 but do not cross-react to CLDN18.1. The lead antibody E9 had higher binding affinity for CLDN18.2, compared to the IMAB362. The humanized anti-CLDN18.2 antibody showed a strong antibody dependent cytotoxicity (ADCC) activity against Mia PaCa-2 cells overexpressing CLDN18.2. To redirect T-cell-mediated lysis toward CLDN18.2-overexpressed tumor cells, we generated an anti-CLDN18.2/anti-CD3 bispecific antibody. We demonstrated that the bispecific antibody binds to both human T cells and CLDN18.2-expressing tumor cells. Furthermore, the anti-CLDN18.2/anti-CD3 bispecific antibody had robust activity in killing Mia PaCa-2 cells overexpressing CLDN18.2 in the in vitro T cell-dependent cellular cytotoxicity (TDCC) assay. In addition, the bispecific antibody retained the in vitro ADCC activity against Mia PaCa-2 cells overexpressing CLDN18.2. Taken together, our data suggest that the anti-CLDN18.2/anti-CD3 bispecific antibody is a promising cancer therapeutic candidate utilizing multiple anti-tumor mechanisms of action, including ADCC and TDCC. Citation Format: Haishan Lin, Huey Li, Hunter Drobenaire, Veronica Pizzarella, Richard Zhang. Development of anti-CLDN18.2-anti-CD3 bispecific antibody as cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1833.