An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity

Nina E. Weisser (), Mario Sanches, Eric Escobar-Cabrera, Jason O’Toole, Elizabeth Whalen, Peter W. Y. Chan, Grant Wickman, Libin Abraham, Kate Choi, Bryant Harbourne, Antonios Samiotakis, Andrea Hernández Rojas, Gesa Volkers, Jodi Wong, Claire E. Atkinson, Jason Baardsnes, Liam J. Worrall, Duncan Browman, Emma E. Smith, Priya Baichoo, Chi Wing Cheng, Joy Guedia, Sohyeong Kang, Abhishek Mukhopadhyay, Lisa Newhook, Anders Ohrn, Prajwal Raghunatha, Matteo Zago-Schmitt, Joseph D. Schrag, Joel Smith, Patricia Zwierzchowski, Joshua M. Scurll, Vincent Fung, Sonia Black, Natalie C. J. Strynadka, Michael R. Gold, Leonard G. Presta, Gordon Ng and Surjit Dixit
Additional contact information
Nina E. Weisser: Zymeworks BC Inc.
Mario Sanches: Zymeworks BC Inc.
Eric Escobar-Cabrera: Zymeworks BC Inc.
Jason O’Toole: Zymeworks BC Inc.
Elizabeth Whalen: Zymeworks BC Inc.
Peter W. Y. Chan: Zymeworks BC Inc.
Grant Wickman: Zymeworks BC Inc.
Libin Abraham: University of British Columbia
Kate Choi: University of British Columbia
Bryant Harbourne: Zymeworks BC Inc.
Antonios Samiotakis: Zymeworks BC Inc.
Andrea Hernández Rojas: Zymeworks BC Inc.
Gesa Volkers: Zymeworks BC Inc.
Jodi Wong: Zymeworks BC Inc.
Claire E. Atkinson: University of British Columbia
Jason Baardsnes: Human Health Therapeutics Portfolio, NRC-CNRC
Liam J. Worrall: University of British Columbia
Duncan Browman: Zymeworks BC Inc.
Emma E. Smith: Human Health Therapeutics Portfolio, NRC-CNRC
Priya Baichoo: Zymeworks BC Inc.
Chi Wing Cheng: Zymeworks BC Inc.
Joy Guedia: Zymeworks BC Inc.
Sohyeong Kang: Zymeworks BC Inc.
Abhishek Mukhopadhyay: Zymeworks BC Inc.
Lisa Newhook: Zymeworks BC Inc.
Anders Ohrn: Zymeworks BC Inc.
Prajwal Raghunatha: Zymeworks BC Inc.
Matteo Zago-Schmitt: Zymeworks BC Inc.
Joseph D. Schrag: Human Health Therapeutics Portfolio, NRC-CNRC
Joel Smith: Zymeworks BC Inc.
Patricia Zwierzchowski: Zymeworks BC Inc.
Joshua M. Scurll: University of British Columbia
Vincent Fung: Zymeworks BC Inc.
Sonia Black: Zymeworks BC Inc.
Natalie C. J. Strynadka: University of British Columbia
Michael R. Gold: University of British Columbia
Leonard G. Presta: Zymeworks BC Inc.
Gordon Ng: AbbVie
Surjit Dixit: Zymeworks BC Inc.

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combination of trastuzumab plus pertuzumab (tras + pert). Zanidatamab binds adjacent HER2 molecules in trans and initiates distinct HER2 reorganization, as shown by polarized cell surface HER2 caps and large HER2 clusters, not observed with trastuzumab or tras + pert. Moreover, zanidatamab, but not trastuzumab nor tras + pert, elicit potent complement-dependent cytotoxicity (CDC) against high HER2-expressing tumor cells in vitro. Zanidatamab also mediates HER2 internalization and downregulation, inhibition of both cell signaling and tumor growth, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), and also shows superior in vivo antitumor activity compared to tras + pert in a HER2-expressing xenograft model. Collectively, we show that zanidatamab has multiple and distinct mechanisms of action derived from the structural effects of biparatopic HER2 engagement.

Date: 2023
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DOI: 10.1038/s41467-023-37029-3

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