Described herein are high affinity antigen binding constructs, e.g.,antibodies, directed to the ECD2 domain ofHER2. The antigen-binding constructs comprise at least one antigen- bindingpolypeptide construct that binds to ECD2 of HER2(HER2 ECD2) with increased affinity compared to a wild-type 2C4 antibody. Suchantigen-binding polypeptide constructs compriseone or more amino acid modifications in the framework region and/or CDRscompared to the amino acid sequence of a wild-type2C4 antibody that increase affinity of the antigen- binding polypeptideconstruct for ECD2 by 2-fold or greater. The antigen-bindingconstructs can inhibit the growth of HER2-expressing breast cancer cells andgastric cancer cells. Antigen- binding constructs inbi-paratopic format are internalized in HER2-expressing cells.
