Claudin-18 (CLDN18) is a member of a large family of four-span transmembrane proteins, claudins. These proteins are the essential components of the mammalian tight junctions (TJs) in the epithelial cells. Claudin-18 has two splice variants, 18.1 and 18.2. 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. The expression of CLDN18.2 is not only detected in primary tumors, but also in the metastatic sites. Therefore, CLDN18.2 is an ideal target for monoclonal antibody-based cancer therapies. Anti-CLDN18.2 monoclonal antibody claudiximab (IMAB362) demonstrated promising results in the phase II clinic trial for gastric cancer. CLDN18.2 specific antibodies are difficult to generate due to its high homology to CLDN18.1. There are only 7-8 amino acid differences between these two splice variants in the first extracellular loop. Using a combination of DNA, protein, and transfected cells as immunogens, coupled with high-throughput FACS-based hybridoma screening approach, we have generated a panel of mouse monoclonal antibodies that are highly specific for CLDN 18.2. These antibodies had high affinities for CLDN18.2 while they did not bind to CLDN18.1. The lead antibodies had similar or better binding affinity for CLDN18.2, compared to the IMAB362. The anti-CLDN18.2 antibodies bound to human gastric carcinoma cell line KATO III. Our IHC data showed that the antibody specifically bound to gastric and pancreatic cancer tissues. In addition, we demonstrated that anti-CLDN18.2 antibodies induced receptor internalization in CHO cell line expressing CLDN18.2. The humanized anti-CLDN18.2 antibodies have been generated and showed similar binding specificity as the mouse antibodies. Lead anti-CLDN18.2 antibodies have been selected for CMC optimization and preclinical studies for further development as cancer therapeutics.

Citation Format: Haishan Lin, Richard Zhang. Development of anti-human CLDN18.2 monoclonal antibody as cancer therapeutics [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B73.