10D1F, an Anti-HER3 Antibody that Uniquely Blocks the Receptor Heterodimerization Interface, Potently Inhibits Tumor Growth Across a Broad Panel of Tumor Models.

In recent years, HER3 has increasingly been implicated in the progression of a variety of tumor types and in acquired resistance to EGFR and HER2 therapies. Whereas EGFR and HER2 primarily signal through the MAPK pathway, HER3, as a heterodimer with EGFR or HER2, potently activates the PI3K pathway. Despite its critical role, previous attempts to target HER3 with neutralizing antibodies have shown disappointing efficacy in the clinic, most likely due to suboptimal and indirect mechanisms of action that fail to completely block heterodimerization; for example, tumors can escape inhibition of ligand binding by upregulating ligand-independent mechanisms of HER3 activation.