Abstract 7325: Pharmacologic characterization of a highly specific and potent CLDN6xCD3 T cell engager (TCE), ARC101, for the treatment of CLDN6+ cancers

Abstract Claudin 6 (CLDN6) is an oncofetal protein involved in tight junction formation and is responsible for regulating cell polarity, adhesion and permeability. CLDN6 has recently emerged as an ideal target for novel oncology therapeutics, given the expression in various solid tumors, with limited normal tissue expression. High-levels of CLDN6 cell-surface protein expression are commonly detected in testicular cancer and epithelial ovarian cancer (EOC), with lower frequency expression in additional solid tumors such as gastric-, cervical-, endometrial-, and lung cancer. Using normal human tissue microarrays (TMA) and a highly selective commercially available CLDN6 antibody, minimal staining of CLDN6 was confirmed across a large panel of normal tissues by IHC, where sparse and limited apical staining of CLND6 was detected in pancreas, stomach, salivary gland, kidney and uterine tissues. High CLDN6 expression in ovarian tumors was demonstrated with the same selective antibody, confirming CLDN6 as a unique solid tumor target with limited normal tissue expression. ARC101 is a bispecific antibody that targets CLDN6 on tumor cells and CD3 on T cells, leading to T-cell-mediated tumor cell lysis. Generation of CLDN6-specific therapeutic antibodies has been challenging given the high degree of homology that exists between CLDN6 and CLN9, and to a lesser extent CLDN4. ARC101 was selected as a therapeutic candidate, due to the high degree of specificity obtained with this molecule. ARC101 bound to and induced cytotoxicity of a CLDN6 overexpressing SKOV3 ovarian cell line. No significant binding or cytotoxicity was observed for CLDN9 or CLDN4 overexpressing SKOV3 cell lines, underscoring the high specificity of ARC101 for CLDN6 over other highly homologous claudins. ARC101 bound to CLDN6-positive human ovarian cancer cell lines OVCAR3, PA1, and OV90, while binding to OVCAR3 cells was completely abolished when CLDN6 expression was deleted via knock out. ARC101 induced potent T cell activation and cytotoxicity at low effector to target (E:T) cell ratios across the panel of CLDN6-positive cells (2D and 3D models), with no activity observed on the CLDN6-negative OVCAR3 knock out cell line. In vivo, ARC101 demonstrated potent and dose-dependent anti-tumor activity in an ovarian tumor xenograft model. Overall, ARC101 is a highly specific CLDN6-directed T-cell engager with significant therapeutic potential for CLDN6-positive solid tumors. A Phase 1 first-in-human (FIH) clinical trial of ARC101 (NCT06672185) is planned to commence in 2025. Citation Format: Sanjaya Singh, Danlin Yang, Joseph Erhardt, Theresa McDevitt, Scott R. Brodeur, Bridget Larkin, Cassandra Lowenstein, Desmond Lewis, Tabitha Soto, Brinda Shah. Pharmacologic characterization of a highly specific and potent CLDN6xCD3 T cell engager (TCE), ARC101, for the treatment of CLDN6+ cancers [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 7325.