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.
Type 1 von Willebrand disease (VWD) is associated with a reduction in qualitatively normal von Willebrand factor (VWF). Current diagnostic guidelines only take into consideration the contribution of basal VWF levels, despite a lack of correlation with bleeding severity. Defects in stimulated VWF release, which occurs following hemostatic challenge, may contribute to bleeding in Type 1 VWD, but the pathogenic mechanisms are poorly defined. In the present study, a layered multiomic approach including mRNA and miRNA sequencing was used to evaluate transcriptome-wide differences between Type 1 VWD- and control-derived endothelial colony forming cells (ECFCs) during basal and stimulated VWF release. ECFCs from eight Type 1 VWD patients and four controls were included in this study. VWF protein analysis revealed heterogenous responses to stimulation amongst Type 1 VWD and control ECFCs. During basal VWF release, 64 mRNAs and 7 miRNAs were differentially regulated between Type 1 VWD and control ECFCs and 65 putatively pathogenic miRNA-mRNA interactions were identified. During stimulated VWF release, 190 mRNAs and five mRNAs were differentially regulated between Type 1 VWD and control ECFCs and 110 putatively pathogenic miRNA-mRNA interactions were identified. Five gene ontology terms including coagulation, regulation of cell shape, and regulation of cell signalling were also differentially regulated in Type 1 VWD ECFCs during stimulated release. We have shown for the first time that transcriptome-wide differences exist between Type 1 VWD and control ECFCs. These differences may contribute to bleeding in Type 1 VWD, and further investigation may reveal novel biomarkers and therapeutic targets.
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