ZW220

ZW220 is a novel antibody-drug conjugate (ADC) developed by Zymeworks that targets the human sodium-dependent phosphate transporter 2b (NaPi2b). It consists of a fully humanized IgG1 monoclonal antibody, engineered with Fc-silencing mutations to minimize off-target toxicity, covalently linked via a maleimidocaproyl-GGFG-aminomethyl protease-cleavable linker to a proprietary moderate-potency topoisomerase I inhibitor payload (ZD06519), which is a camptothecin derivative. The drug-to-antibody ratio (DAR) has been optimized at four for clinical development. Upon binding NaPi2b and internalization into tumor cells, the ADC releases its cytotoxic payload intracellularly, inducing cell death in NaPi2b-positive cells and exerting strong bystander killing effects on neighboring tumor cells regardless of NaPi2b expression. Preclinical studies have demonstrated robust anti-tumor activity in ovarian carcinoma and non-small cell lung cancer models with both high and low NaPi2b expression, as well as favorable tolerability profiles in animal models. As of early 2025, clinical development has been paused at IND-ready status while the company prioritizes other assets[1][3][4][5][6][7].