ZW-191: A Folate Receptor Alpha-Targeting Antibody-Drug Conjugate for Oncological Applications

1. Executive Summary

ZW-191 is an investigational antibody-drug conjugate (ADC) engineered by Zymeworks Inc., targeting Folate Receptor alpha (FRα), a validated cell-surface antigen overexpressed in various solid tumors with high unmet medical need. The molecular architecture of ZW-191 comprises a novel humanized IgG1 antibody, a proprietary potent topoisomerase I inhibitor (TOPO1i) payload designated ZD06519, and a protease-cleavable linker system (maleimidocaproyl anchor with a GGFG-aminomethyl sequence), achieving a drug-to-antibody ratio (DAR) of 8.[1] This design reflects a strategic approach to optimize therapeutic efficacy, particularly in tumor microenvironments characterized by heterogeneous antigen expression, leveraging superior antibody internalization and a potent bystander-active payload.

Preclinical evaluations have demonstrated ZW-191's potent and selective anti-tumor activity. In vitro, the ADC exhibited sub-nanomolar binding affinity to FRα, superior cellular internalization, and efficient payload delivery, leading to cytotoxicity in FRα-expressing cancer cell lines and 3D tumor spheroids.[1] A significant bystander effect, mediated by the cell-permeable ZD06519 payload, was observed, enabling the killing of adjacent FRα-negative tumor cells.[1] In vivo, ZW-191 induced substantial tumor regressions in patient-derived xenograft (PDX) models of ovarian cancer, non-small cell lung cancer (NSCLC), endometrial cancer, and triple-negative breast cancer (TNBC), critically, across a spectrum of FRα expression levels (high, mid, and low).[1] Comparative studies indicated superior or comparable activity to mirvetuximab soravtansine, especially in models with lower FRα expression.[2]