Abstract 342: Development and characterization of a novel anti-CLDN6 antibody drug conjugate for the treatment of CLDN6 positive cancers

Abstract Background: Claudin 6 (CLDN6), a member of the claudin family of tight junction proteins, is expressed at high levels in multiple human malignancies including ovarian and endometrial cancers. Conversely it has little or no expression in normal tissues. This expression profile makes CLDN6 an ideal target for development of potential therapeutic antibody-drug conjugates (ADCs). This study describes the generation and preclinical characterization of an anti-CLDN6 ADC consisting of a humanized anti-CLDN6 monoclonal antibody coupled to MMAE via a cleavable linker. Materials and Methods: A fully humanized anti-CLDN6 antibody was initially characterized for binding affinity, selectivity/specificity, internalization characteristics and in vivo efficacy. It was then conjugated to MMAE resulting in the potential therapeutic anti-CLDN6 ADC. The anti-tumor efficacy of the ADC was next assessed for anti-tumor efficacy in CLDN6 positive (CLDN6+) and negative (CLDN6-) xenografts and patient-derived xenograft (PDX) models of specific cancers including ovarian and endometrial cancer. Results: Selective binding of the ADC to CLDN6, without cross reactivity to other CLDN family members CLDN3, CLDN4 and CLDN9, was confirmed in human cancer cell lines and cells engineered to overexpress each protein. The ADC was also shown to rapidly internalize in CLDN6+ cells. Robust tumor regressions following treatment with the ADC were observed in CLDN6+ xenografts that were sustained beyond the treatment window. Conversely, there was limited to no activity of the ADC in CLDN6- xenografts models. In addition, the prevalence of CLDN6 expression in human ovarian and endometrial cancers was assessed by IHC in tissue microarrays and found to be 28% (ovarian epithelial carcinomas) and 11% (endometrial carcinomas), respectively. Discussion: Overall, these data suggest that our anti-CLDN6 ADC may be a promising treatment for patients with CLDN6+ tumors and it is currently in Phase I clinical testing. Citation Format: Martina S. McDermott, Ke Wei Gong, Neil A. O'Brien, Dylan Conklin, Benjamin Hoffstrom, Ming Lu, Jun Zhang, Tong Luo, Weiping Jia, Jenny J. Hong, Kevin Chau, Simon Davenport, Michael F. Press, Abram Handly-Santana, Joan S. Brugge, Ronny Drapkin, John A. Glaspy, Leonard Presta, Dennis J. Slamon. Development and characterization of a novel anti-CLDN6 antibody drug conjugate for the treatment of CLDN6 positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 342.