Fig. 8: Zanidatamab has multiple mechanisms of action.

We hypothesize that the trans biparatopic HER2 binding properties of zanidatamab forms the foundation of its multiple mechanisms of action. Zanidatamab binding leads to approximately 1.5-fold increased cell surface Ab saturation as well as to receptor crosslinking. The large cell surface HER2 clusters mediated by zanidatamab engagement facilitate C1q binding, likely by promoting hexamerization, and elicit potent CDC in HER2-high cell lines. In all HER2-expressing cells, including HER2-low tumors, ADCC and ADCP activities were also observed. It is also likely that receptor crosslinking and clustering prevent HER2 homodimerization and heterodimerization with other signaling partners, leading to the ligand-independent and ligand-dependent signal inhibition observed. Additionally, large receptor clusters are not efficiently recycled from early endosomes, culminating in increased receptor internalization and degradation. Together, these mechanisms contribute to the overall effect of tumor cell death and growth inhibition of zanidatamab in vitro and in vivo.