Bispecific HER2 and HER3 antigen binding constructs

An isolated bi-specific antigen binding construct comprising:

• a first antigen-binding polypeptide construct which monovalently and specifically binds to an extracellular domain 4 (ECD4) of HER2 (human epidermal growth factor receptor 2), the first antigen-binding polypeptide construct comprising three variable heavy chain CDRs comprising the sequences set forth in SEQ ID NOs:49, 50, and 51, and three variable light chain CDRs comprising the sequences set forth in SEQ ID NOs:52, 53, and 54;
• a second antigen-binding polypeptide construct which monovalently and specifically binds to an extracellular domain (ECD) of HER3 (human epidermal growth factor receptor 3), the antigen-binding polypeptide construct comprising three variable heavy chain CDRs comprising the sequences set forth in SEQ ID NOs:
• 58, 59, and 60, and three variable light chain CDRs comprising the sequences DVS and as set forth in SEQ ID NOs:62 and 63;
• and
• an Fc comprising a first Fc polypeptide comprising a first CH3 domain and a second Fc polypeptide comprising a second CH3 domain, the first Fc polypeptide linked to the C-terminus of the first antigen-binding polypeptide construct with or without a linker and the second Fc polypeptide linked to the C-terminus of the second antigen-binding polypeptide construct with or without a linker;
• wherein the first antigen-binding polypeptide construct is a Fab format and the second antigen-binding polypeptide construct is an scFv format;
• and
• wherein the isolated bi-specific antigen binding construct has a geometry that allows the first antigen-binding polypeptide construct and the second antigen-binding polypeptide construct to each bind its respective extracellular domain and exhibit greater inhibition of heregulin-stimulated growth of BT-474 cells in vitro as compared to a control, wherein the control is v880 as described in FIG. 10.