Weisser et al. engineered and evaluated zanidatamab – a biparatopic antibody with an Fc region, a scFv that binds to ECD4 on HER2 (like trastuzumab), and a Fab that binds to ECD2 on HER2 (like pertuzumab) – and found that it binds in trans, cross-linking adjacent HER2 molecules and forming large HER2 clusters that trigger CDC in HER2hi tumor cell lines – an effect not observed with the combination of parental antibodies. Compared to tras + pert, zanidatamab showed similar or superior ADCC; ADCP; HER2 internalization and downregulation; inhibition of ligand-independent and EGF-driven signal transduction; and antitumor activity in PDX models of HER2+ human gastric cancer.
Contributed by Lauren Hitchings
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.
Author Info: (1) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. nweisser@zymeworks.com. (2) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada.
Author Info: (1) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. nweisser@zymeworks.com. (2) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (3) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (4) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (5) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (6) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (7) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (8) Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada. (9) Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada. (10) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (11) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (12) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (13) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (14) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (15) Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada. Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada. HRMEM Facility, University of British Columbia, Vancouver, BC, Canada. (16) Human Health Therapeutics Portfolio, NRC-CNRC, Montreal, QC, Canada. (17) Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada. Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada. HRMEM Facility, University of British Columbia, Vancouver, BC, Canada. (18) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (19) Human Health Therapeutics Portfolio, NRC-CNRC, Montreal, QC, Canada. (20) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (21) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (22) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (23) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (24) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (25) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (26) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (27) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (28) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (29) Human Health Therapeutics Portfolio, NRC-CNRC, Montreal, QC, Canada. (30) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (31) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (32) Department of Mathematics and Institute of Applied Mathematics, University of British Columbia, Vancouver, BC, V6T 1Z2, Canada. Department of Urologic Sciences (Vancouver Prostate Centre) and the Institute of Applied Mathematics, University of British Columbia, Vancouver, BC, Canada. (33) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (34) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (35) Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada. Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada. HRMEM Facility, University of British Columbia, Vancouver, BC, Canada. (36) Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada. (37) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. (38) AbbVie, 1N. Waukegan Road, North Chicago, IL, 60064, USA. (39) Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada.
