Development of ZW418, a biparatopic PTK7-targeting antibody-drug conjugate incorporating a novel pan-RAS inhibitor payload for the treatment of non-small cell lung cancer
Presenter: Vincent Fung, BS Session: Antibody-Drug Conjugates and Linker Engineering 1 Time: 4/20/2026 9:00:00 AM → 4/20/2026 12:00:00 PM
Authors
Luying Yang , Alex Wu , Vincent Fung , Kaylee J. Wu , Sara Weeres , Katina Mak , Taixiang Wang , Victoria Harman-McKenna , Allysha Bissessur , Jesse Leblanc , Vidhi Khanna , Matthew Bonderud , Jodi Wong , Rehan Higgins , Linglan Fu , Dunja Urosev , Raffaele Colombo , Graham A. E. Garnett , Jamie R. Rich , Stuart D. Barnscher Zymeworks Inc., Vancouver, BC, Canada
Abstract
Mutations in the RAS oncogene family occur in approximately 25-30% of lung adenocarcinomas and represent one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC). These alterations lead to constitutive activation of downstream MAPK signaling, promoting tumor growth and therapeutic resistance. Protein tyrosine kinase 7 (PTK7) is prevalently overexpressed in NSCLC but has limited expression in normal tissue, making it an attractive therapeutic target for NSCLC. Existing mutant-specific and pan-RAS inhibitors (RASi) have demonstrated clinical benefit in NSCLC but patients often experience on-target off-tumor toxicities and acquire resistance. These challenges may be improved upon by enhancing delivery of a RASi via an antibody drug conjugate (ADC) mechanism. We have developed ZW418, a biparatopic PTK7-targeting ADC that leverages a cleavable linker designed to deliver a novel pan-RASi payload with optimized stability and bystander effect for the treatment of NSCLC. A biparatopic antibody recognizing two non-overlapping epitopes on PTK7 was engineered and conjugated to a cleavable pan-RASi drug-linker. Binding affinity, internalization, spheroid penetration, and in vitro cytotoxicity were characterized across a panel of PTK7-expressing RAS-mutated cancer cell lines. Additional mechanistic evaluation of RAS inhibition was also performed in vitro. Pharmacokinetic properties were evaluated in non-tumor bearing mice, and antitumor activity was investigated in RAS-mutated cancer xenograft models. Across RAS-mutated cancer cell lines with varying PTK7 expression level, the biparatopic antibody demonstrated greater cell surface decoration, internalization, and spheroid penetration compared to cofetuzumab and other PTK7-targeted clinical benchmark antibodies. ZW418 exhibited potent target-dependent cytotoxicity in vitro and demonstrated strong anti-tumor activity in multiple RAS-mutated cancer cell line derived xenograft models. The pan-RASi ADC platform showed encouraging tolerability in mice with no significant toxicity observed up to a dose of 200 mg/kg. Overall, the data supports the potential of ZW418 as a novel, highly differentiated therapeutic agent against PTK7-expressing RAS mutant cancers.
Disclosure
L. Yang, Zymeworks Employment, Stock, Stock Option, Patent. A. Wu, Zymeworks Employment, Stock, Stock Option. V. Fung, Zymeworks Employment, Stock, Stock Option, Patent. K. J. Wu, Zymeworks Employment, Stock, Stock Option. S. Weeres, Zymeworks Employment, Stock, Stock Option. K. Mak, Zymeworks Employment, Stock, Stock Option. T. Wang, Zymeworks Employment, Stock, Stock Option. V. Harman-McKenna, Zymeworks Employment, Stock, Stock Option. A. Bissessur, Zymeworks Employment, Stock, Stock Option. J. Leblanc, Zymeworks Employment, Stock, Stock Option. V. Khanna, Zymeworks Employment, Stock, Stock Option. M. Bonderud, Zymeworks Employment, Stock, Stock Option. J. Wong, Zymeworks Employment, Stock, Stock Option, Patent. R. Higgins, Zymeworks Employment, Stock, Stock Option. L. Fu, Zymeworks Employment, Stock, Stock Option. D. Urosev, Zymeworks Employment, Stock, Stock Option, Patent. R. Colombo, Zymeworks Inc. Employment, Stock, Stock Option, Patent. AstraZeneca Stock. G. A. E. Garnett, Zymeworks Employment, Stock, Stock Option, Patent. J. R. Rich, Zymeworks Employment, Stock, Stock Option, Patent. S. D. Barnscher, Zymeworks Employment, Stock, Stock Option, Patent.
Cited in
Control: 4944 · Presentation Id: 5358 · Meeting 21436