CLIO-8221 (Callio Therapeutics)

**CLIO-8221** is an investigational, first-in-class **HER2-targeted dual-payload antibody-drug conjugate** being developed by Callio Therapeutics for advanced HER2-expressing solid tumors. It uses an Fc-engineered trastuzumab-based anti-HER2 antibody, site-specifically conjugated through a hydrophilic, protease-cleavable branched linker to deliver the topoisomerase I inhibitor **exatecan** and the ATR inhibitor **berzosertib**. Following HER2 binding and tumor-cell internalization, the conjugate releases both payloads to induce DNA damage and impair the ATR-mediated DNA-damage response, with the aim of overcoming resistance to Topo1 inhibitor-based ADCs. CLIO-8221 entered Phase 1 clinical development in March 2026 and is administered by intravenous infusion in an ongoing study in advanced HER2-expressing solid tumors. ([ascopubs.org](https://ascopubs.org/doi/pdf/10.1200/JCO.2026.44.16_suppl.TPS3162))