Abstract 882: The anti-claudin 6 antibody, IMAB027, induces antibody-dependent cellular and complement-dependent cytotoxicity in claudin 6-expressing cancer cells

Abstract

Abstract Background Claudin 6 (CLDN6) is a tight junction membrane protein whose expression in normal tissue is confined to embryonic cells, but aberrantly expressed in various human cancer types, including some with a high medical need (eg, ovarian and uterine cancers). This tumor-specific expression in adult organs makes CLDN6 an attractive drug target; as such, IMAB027, an anti-CLDN6 monoclonal antibody (mAb), was developed. This report describes the preclinical characteristics of IMAB027. Methods IMAB027 was generated by hybridoma technology; the discovery process was set up so that mAbs that were good binders as well as inducers of the immune effector mechanisms of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activity would be detected. ADCC and CDC were assessed in vitro. Apoptosis of CLDN6+ cells was assessed by caspase 3/7, annexin V, and TUNEL assays. Xenografted mouse tumors with human CLDN6+ cells were generated to investigate the in vivo antitumor effects of IMAB027 both as a single agent and in combination with chemotherapeutic agents such as paclitaxel. Results: IMAB027 binds specifically to CLDN6 without cross-reactivity with other closely related family members, such as Claudins 3, 4, and 9. IMAB027 induced target-selective ADCC and CDC in a number of CLDN6+ ovarian and testicular cancer cell lines; median EC50 values for ADCC and CDC were of the order of ng/mL in representative cell lines. Direct induction of apoptosis did not appear to be a contributor to the antitumor effect of IMAB027. In cancer cell lines that heterogeneously expressed CLDN6, but not in those with high or homogeneous CLDN6 levels, pretreatment with chemotherapeutic agents upregulated CLDN6 expression. Increased CLDN6 expression sensitized the cells to IMAB027-induced ADCC, resulting in increased cell lysis. In vivo, treatment with IMAB027 was associated with reduced tumor growth and increased overall survival in different mouse tumor models. These potent antitumor effects were observed in both early and advanced ovarian cancer xenografts. IMAB027, in combination with paclitaxel administered to mice with CLDN6+ xenografts, also prolonged survival compared with paclitaxel alone. Conclusions In these preclinical studies, binding of IMAB027 was CLDN6 specific. IMAB027 as a single agent induced cell death in CLDN6+ cancer cells via ADCC and CDC, thereby exerting in vitro and in vivo antitumor activity. Further, in tumors that have heterogeneous CLDN6 expression, chemotherapy sensitizes cells to IMAB027-induced ADCC, and the combination of IMAB027 and chemotherapeutic agents may enhance the antitumor effect of chemotherapy. Citation Format: Özlem Türeci, Maria Kreuzberg, Korden Walter, Stefan Wöll, Ramona Schmitt, Rita Mitnacht-Kraus, Ikumi Nakajo, Tomohiro Yamada, Ugur Sahin. The anti-claudin 6 antibody, IMAB027, induces antibody-dependent cellular and complement-dependent cytotoxicity in claudin 6-expressing cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 882.