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TitleAn anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 1394, Year 2023
Publish dateMar 13, 2023
AuthorsNina 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 / Surjit Dixit /
PubMed AbstractHuman 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 ...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.
External linksNat Commun / PubMed:36914633 / PubMed Central
MethodsEM (single particle)
Resolution7.5 Å
Structure data

29044

8ffj

EMDB-29044, PDB-8ffj:
Structure of Zanidatamab bound to HER2
Method: EM (single particle) / Resolution: 7.5 Å

Source
  • homo sapiens (human)
KeywordsTRANSFERASE/IMMUNE SYSTEM / Antibody / biparatopic / TRANSFERASE-IMMUNE SYSTEM complex

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