Modality-aware computational agent identifies ADAM17 as a novel therapeutic target in biliary tract cancer

Biliary tract cancer (BTC) lacks effective, broad-spectrum therapeutic targets. To overcome the limitations of conventional target discovery, we developed ACT-Target, a modality-aware computational agent, to systematically identify therapeutic candidates and preclinically validate ADAM17-directed antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR) T cells. We constructed the ACT-Target framework by integrating multi-omics evidence, surface-antigen gating, safety profiling, and structural developability to prioritize therapeutic candidates. Following the omics-driven nomination of ADAM17, we assessed its clinical expression via immunohistochemistry in BTC tissues. Novel murine anti-human ADAM17 monoclonal antibodies (mAbs) were generated, characterized, and engineered into MMAE-conjugated ADCs and CAR-T cells to evaluate specific cytotoxicity in vitro and anti-tumor efficacy in vivo. Time-split benchmarking demonstrated that ACT-Target prospectively recovered 12 of 18 future solid-tumor ADC/CAR-T targets without introducing unsafe false positives. Application to a tumor-only multi-omics cohort prioritized ADAM17 as the top-ranked candidate due to its balanced omics support, surface accessibility, and dual-modality compatibility. Histological analysis confirmed significant ADAM17 upregulation in BTC tissues compared to normal controls. Three lead mAbs exhibited sub-nanomolar affinities and strict target specificity without cross-reactivity. The ADAM17-ADCs and CAR-T cells induced potent, specific in vitro cytotoxicity against BTC cells and profoundly inhibited in vivo tumor growth while demonstrating preclinical tolerability [1]. Integrating advanced computational target discovery with targeted immunotherapeutics establishes ADAM17 as a highly prevalent and actionable target in BTC. The ADAM17-ADCs and CAR-T cells exhibit robust preclinical efficacy and a potentially manageable safety profile, offering a versatile dual-modality strategy that warrants further translational evaluation for advanced disease.