Bivalent Binding of HER2 Inhibits Proliferation

Example 8

Binding of trastuzumab to overexpressed HER2 in HER2 amplified cancer cells results in robust interference of constitutive ligand independent PI3K signaling initiated by the deregulated HER2-HER3 complex (Junttila et al. Cancer Res. 74(19): 5561-5571, 2014). The 1Fab-IgG TDB molecule binds to HER2 in bivalent form. In vitro treatment of SKBR3 cells with incubation with 1Fab-IgG TDB resulted in transient non-durable reduction of pAKT, without detectable effect on HER3 phosphorylation (FIG. 28A). In addition, neither monovalent high HER2 affinity IgG TDB, nor bivalent low HER2 affinity 1Fab-IgG TDB substantially affected the proliferation/viability of SKBR3 cells (FIG. 28B). In summary, bivalent low affinity binding to HER2 does not inhibit proliferation of HER2-amplified cells.