Abstract 6715: CLDN6: Biological insight into therapeutic potency of SAIL66, a next generation of T-cell engager targeting CLDN6
Authors: Kimura Naoki , Taniguchi Kenji , Kamikawa Takayuki , Yoshimoto Moe , Ishii Shinya , Muraoka Masaru , Shimada Mei , Kamata-Sakurai Mika , Kitazawa Takehisa , Igawa Tomoyuki 
Published: March 2024

Abstract
Background: Because of high recurrence rate, ovarian cancer continues to demand new treatments. Recently, we have developed a next-generation T-cell engager SAIL66, which is a tri-specific monoclonal antibody designed to bind to CLDN6 on cancer cells with one Fab arm and to both CD3 and CD137 with the other Fab arm. By boosting T cell activation through both CD3 and CD137 binding, SAIL66 shows potent anti tumor efficacy against CLDN6-positive cancers and are currently being evaluated in patients with CLDN6-positive solid cancers including ovarian cancer (NCT05735366). CLDN6 is upregulated in many solid tumors but shows minimal or no expression in healthy adult tissues. Due to its cancer specific expression profile, CLDN6 has been utilized as a target for cancer immune therapies. Here, we demonstrate that CLDN6 is an attractive therapeutic target from its biological perspective in ovarian cancer.
Methods and Results: In a HuNOG tumor-bearing mouse model transplanted with CLDN6-positive ovarian cancer cells (OV90, OVCAR3), SAIL66 showed potent antitumor activity as a single agent. Surprisingly, CLDN6 expression in transplanted tumors was significantly lower compared to in vitro cultured cells, suggesting that CLDN6 expression is highly variable. In vitro, CLDN6 expression reversibly fluctuated depending on cell density, and its expression was consistent with the expression of epithelial-mesenchymal transition (EMT) and stemness-related genes. Furthermore, FACS and qPCR revealed that chemotherapeutic agents increased CLDN6-positive cells, and this fluctuation was accompanied by the expression of EMT and stemness-related genes. Based on this biology, we tested the combination effect of SAIL66 and chemotherapies in a non-clinical tumor-bearing mouse model. As a result, significant tumor regression was observed in mice treated with SAIL66 in combination with carboplatin.
Conclusion and Discussion: Ovarian cancer is characterized by significant tumor heterogeneity. The presence of cancer stem/stem-like cells or EMT has been proposed to elucidate the underlying mechanisms of the heterogeneity. Our study potentially could offer valuable insights into the biology of CLDN6-positive cells and the causes of ovarian cancer heterogeneity. Furthermore, it could help in patient selection, the development of combination strategies, and future clinical validation of SAIL66.
Citation Format: Naoki Kimura, Kenji Taniguchi, Takayuki Kamikawa, Moe Yoshimoto, Shinya Ishii, Masaru Muraoka, Mei Shimada, Mika Kamata-Sakurai, Takehisa Kitazawa, Tomoyuki Igawa. CLDN6: Biological insight into therapeutic potency of SAIL66, a next generation of T-cell engager targeting CLDN6 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6715.