8FFJ

Structure of Zanidatamab bound to HER2

Summary for 8FFJ

• Entry DOI: 10.2210/pdb8ffj/pdb
• EMDB information: 29044
• Descriptor: Receptor tyrosine-protein kinase erbB-2, Zanidatamab Heavy Chain A, Zanidatamab Light Chain A, ... (4 entities in total)
• Functional Keywords: antibody, biparatopic, transferase-immune system complex, transferase/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 194044.89

Authors

Worrall, L.J.,Atkinson, C.E.,Sanches, M.,Dixit, S.,Strynadka, N.C.J. (deposition date: 2022-12-08, release date: 2023-02-22, Last modification date: 2024-09-04)

Primary citation

Weisser, N.E.,Sanches, M.,Escobar-Cabrera, E.,O'Toole, J.,Whalen, E.,Chan, P.W.Y.,Wickman, G.,Abraham, L.,Choi, K.,Harbourne, B.,Samiotakis, A.,Rojas, A.H.,Volkers, G.,Wong, J.,Atkinson, C.E.,Baardsnes, J.,Worrall, L.J.,Browman, D.,Smith, E.E.,Baichoo, P.,Cheng, C.W.,Guedia, J.,Kang, S.,Mukhopadhyay, A.,Newhook, L.,Ohrn, A.,Raghunatha, P.,Zago-Schmitt, M.,Schrag, J.D.,Smith, J.,Zwierzchowski, P.,Scurll, J.M.,Fung, V.,Black, S.,Strynadka, N.C.J.,Gold, M.R.,Presta, L.G.,Ng, G.,Dixit, S.
An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity.
Nat Commun, 14:1394-1394, 2023

PubMed 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.

PubMed: 36914633
DOI: 10.1038/s41467-023-37029-3

Experimental method

ELECTRON MICROSCOPY (7.5 Å)