ZW191——一种差异化的FRalpha靶向拓扑异构酶I抗体药物偶联物，与标准治疗药物联用具有活性

ZW191 is a clinical stage differentiated FRalpha-targeted ADC under ongoing investigation for tolerability and efficacy in patients with advanced cancers, including ovarian, endometrial, and NSCLC (NCT06555744). ZW191 markedly improves on the FDA-approved FRalpha-targeted ADC mirvetuximab soravtansine in its efficacy in patient-derived xenograft tumors with both high and low level of FRalpha by virtue of its novel and highly effective FRalpha-targeted antibody and its novel ZD06519 TOPO1i payload. The by-design moderate potency of ZW191's payload confers a best-in-class nonclinical tolerability profile, with an HNSTD of 60 mg/kg in NHP, potentially enabling its clinical application in combination with multiple other clinically relevant drug modalities and in various lines of treatment. Here, we demonstrate ZW191's strong antitumor activity in a xenograft model of ovarian cancer when dosed in combination with each of the platinum-based drug carboplatin, the microtubule inhibitor paclitaxel, and the anti-angiogenic antibody bevacizumab. In multiple 3D spheroid tumor cell models in vitro, ZW191 demonstrates combination effects with poly (ADP-ribose) polymerase (PARP) inhibitor and platinum-based drugs as determined by the Bliss independence model of drug interactions. Mechanistically, ZW191's TOPO1i payload and platins both drive DNA strand breaks in tumor cells, and we show the enhanced target-dependent cytotoxic activity of these drugs in combination is associated with greater levels of the DNA damage marker gamma H2AX (gammaH2AX). A clinical landscape analysis demonstrates that moderate potency ADC payloads facilitate higher dosing levels in the clinic. Together with encouraging early clinical data that highlight ZW191's single agent activity and differentiated safety profile, these data reinforce its potential to achieve meaningful efficacy gains through combination with other agents.