Abstract 3407: Development of bispecific antibodies targeting claudin-6 for precision cancer therapy

Abstract Background: Claudin 6 (CLDN6), a tight junction protein, is an oncofetal antigen with limited expression in adult tissues but aberrantly overexpressed in several cancers, including ovarian, testicular, and gastric tumors. Its tumor-specific expression and critical role in maintaining cell adhesion make CLDN6 a compelling target for cancer therapy. Recent studies have linked CLDN6 to tumor progression, metastasis, and chemoresistance, highlighting its potential as both a biomarker and a therapeutic target in precision oncology. This study presents the development of bispecific antibodies for the treatment of CLDN6-positive tumors. Methods: Monoclonal antibodies specific to CLDN6 were generated using virus-like particles (VLPs) displaying CLDN6 as immunogens. Chickens were selected for immunization due to their ability to produce antibodies against highly conserved, multi-transmembrane proteins. Antibody discovery was performed using HybriFree B cell cloning technology and phage display platforms. Results: Bispecific antibodies that specifically recognize CLDN6 and CD3 were developed and evaluated for their effectiveness in killing CLDN6-positive cells while sparing CLDN6-negative cells. Various bispecific antibody formats were assessed, showing differences in non-specific T-cell activation. These findings underscore the importance of selecting appropriate bispecific antibody modalities to achieve maximum therapeutic potency while ensuring a favorable safety profile. The functionality and potency of these novel bispecific antibodies were further demonstrated in vivo using ovarian cancer xenograft models. Conclusions: This study highlights the development of novel bispecific antibodies targeting CLDN6 and CD3, emphasizing their superior safety profile. The use of specifically engineered antibody modalities and highly selective CLDN6 binders ensures minimal cross-reactivity with other homologous family members. These findings support the potential of these bispecific antibodies as a promising therapeutic approach for CLDN6-positive cancers. Citation Format: Siret Tahk, Paule Hermet, Anu Ustav, Robin Pau, Ana Shahpazir, Mario Plaas, Gaily Kivi, Andres Männik, Joan Teyra, Tanel Mahlakōiv, Mart Ustav. Development of bispecific antibodies targeting claudin-6 for precision cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3407.