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High-Content Screening Assay for the Identification of Antibody-Dependent Cellular Cytotoxicity Modifying Compounds
Published on: August 18, 2023
An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity
Nina E Weisser1, Mario Sanches2, Eric Escobar-Cabrera2
1Zymeworks BC Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, Canada. nweisser@zymeworks.com.
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.
Insights
Zanidatamab, a novel bispecific antibody, demonstrates superior efficacy against HER2-positive cancers by engaging HER2 differently than existing therapies. It triggers enhanced cell killing mechanisms and tumor growth inhibition.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Human epidermal growth factor receptor 2 (HER2) is a key driver in various cancers, including breast and gastric.
- Current anti-HER2 therapies face limitations due to treatment resistance.
- There is a need for novel therapeutic strategies targeting HER2.
Purpose of the Study:
- To engineer and characterize zanidatamab, a biparatopic anti-HER2 antibody.
- To compare zanidatamab's functionalities and mechanisms of action against established anti-HER2 agents.
- To evaluate zanidatamab's in vitro and in vivo antitumor activity.
Main Methods:
- Engineering of an IgG1 bispecific, biparatopic antibody (zanidatamab).
- Assessment of HER2 reorganization, internalization, and downregulation.
- Evaluation of complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and phagocytosis (ADCP).
- In vivo efficacy studies in HER2-expressing xenograft models.
Main Results:
- Zanidatamab induces unique HER2 clustering and cell surface reorganization.
- Zanidatamab elicits potent CDC against HER2-high tumor cells.
- Zanidatamab mediates HER2 internalization, signaling inhibition, and tumor growth suppression.
- Zanidatamab demonstrates superior in vivo antitumor activity compared to trastuzumab plus pertuzumab.
Conclusions:
- Zanidatamab possesses distinct mechanisms of action driven by biparatopic HER2 engagement.
- Zanidatamab exhibits enhanced anti-tumor functions including CDC, ADCC, and ADCP.
- Zanidatamab represents a promising therapeutic candidate for HER2-driven cancers.
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