ZW191, an FRα-Targeted Topoisomerase 1 Inhibitor ADC with a Differentiated Antitumor Efficacy and Tolerability Profile

PURPOSE: Multiple antibody-drug conjugates (ADC) are approved for the treatment of human cancers, yet there remains significant potential for design improvements through iterative learnings from nonclinical and clinical experience. ZW191 is a clinical-stage ADC bearing a novel topoisomerase I inhibitor payload and targeted to the clinically validated tumor antigen folate receptor α (FRα). EXPERIMENTAL DESIGN: The nonclinical activity and tolerability profiles of ZW191 were assessed in vitro and in vivo, focusing on properties of its antibody and payload components. RESULTS: ZW191 has a highly differentiated efficacy and tolerability profile, markedly improving on the FDA-approved FRα-targeted ADC mirvetuximab soravtansine in its activity in tumors with both high and low levels of FRα in multiple patient-derived xenograft models of ovarian cancer, endometrial cancer, non-small cell lung cancer, and triple-negative breast cancer. ZW191's novel FRα-targeting antibody demonstrates unique binding properties and is superior to multiple other clinical-stage ADC antibodies in its internalization, payload delivery, and penetration through 3D tumor spheroids. ZW191's novel payload drives strong antitumor activity in vitro, including bystander activity. Furthermore, ZW191 is effective in vivo in combination with clinically relevant standard-of-care drugs carboplatin, bevacizumab, and paclitaxel. ZW191's best-in-class tolerability profile in Good Laboratory Practice nonhuman primate toxicity studies is owing to its payload's moderate potency-an ADC feature that we show from a clinical landscape analysis allows for higher dosing in humans. CONCLUSIONS: ZW191 demonstrates favorable preclinical efficacy and tolerability. This differentiated profile is supported by initial clinical data, potentially positioning ZW191 to meaningfully improve responses and substantially widen the targetable patient population over standard-of-care treatment.