Overcoming claudin family homology: discovery of ARC101, a highly potent CLDN6-specific T-cell engager with a novel CD3 binder for ovarian adenocarcinoma.

Claudin-6 (CLDN6) is an oncofetal tight junction protein with minimal to no expression in healthy adult tissues but aberrant upregulation in ovarian malignancies, making it an attractive tumor-selective antigen for T cell-based immunotherapy. The development of CLDN6-targeting antibodies, however, has been challenged by its high homology to CLDN9, which is expressed in normal tissues and differs by only three amino acids within the extracellular domains. Here, we describe the discovery and preclinical development of ARC101, a bispecific CLDN6×CD3 antibody featuring a naturally derived, highly potent CLDN6 binder with no cross-reactivity to CLDN9 or other human membrane proteins. The stringent specificity of ARC101 eliminates off-target binding and distinguishes it from other CLDN6-targeting antibodies in development. The effector arm of ARC101 incorporates a novel conformational CD3 binder, enabling potent T cell-mediated cytotoxicity against CLDN6-expressing tumor cells in vitro and in vivo. ARC101 also demonstrated a favorable pharmacokinetic profile in cynomolgus monkeys, low immunostimulatory responses in ex vivo human donor assays, and robust biophysical properties compatible with standard antibody manufacturing. Collectively, these findings support the clinical advancement of ARC101 as a differentiated, CLDN6-specific bispecific immunotherapy with exceptional tumor selectivity and optimized T cell activity for the treatment of solid tumors.