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

Author

Listed:
  • 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
    University of British Columbia
    University of British Columbia)

  • Jason Baardsnes

    (Human Health Therapeutics Portfolio, NRC-CNRC)

  • Liam J. Worrall

    (University of British Columbia
    University of British Columbia
    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
    University of British Columbia)

  • Vincent Fung

    (Zymeworks BC Inc.)

  • Sonia Black

    (Zymeworks BC Inc.)

  • Natalie C. J. Strynadka

    (University of British Columbia
    University of British Columbia
    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.)

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.

Suggested Citation

  • 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 & Andr, 2023. "An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37029-3
    DOI: 10.1038/s41467-023-37029-3
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    References listed on IDEAS

    as
    1. Florian Kast & Martin Schwill & Jakob C. Stüber & Svende Pfundstein & Gabriela Nagy-Davidescu & Josep M. Monné Rodríguez & Frauke Seehusen & Christian P. Richter & Annemarie Honegger & Karen Patricia , 2021. "Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    2. Thomas Nerreter & Sebastian Letschert & Ralph Götz & Sören Doose & Sophia Danhof & Hermann Einsele & Markus Sauer & Michael Hudecek, 2019. "Super-resolution microscopy reveals ultra-low CD19 expression on myeloma cells that triggers elimination by CD19 CAR-T," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    3. Rastislav Tamaskovic & Martin Schwill & Gabriela Nagy-Davidescu & Christian Jost & Dagmar C. Schaefer & Wouter P. R. Verdurmen & Jonas V. Schaefer & Annemarie Honegger & Andreas Plückthun, 2016. "Intermolecular biparatopic trapping of ErbB2 prevents compensatory activation of PI3K/AKT via RAS–p110 crosstalk," Nature Communications, Nature, vol. 7(1), pages 1-18, September.
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