Antigen-binding constructs targeting HER2

An antigen-binding construct comprising a variant first antigen-binding polypeptide construct which monovalently binds a first HER2 ECD2 (human epidermal growth factor receptor 2 extracellular domain 2) antigen, the variant first antigen-binding polypeptide construct comprising a heavy chain variable (VH) domain as set forth in SEQ ID NO:2 and a light chain variable (VL) domain as set forth in SEQ ID NO:11 and comprising an amino acid modification at position 75 in the VH domain (Kabat numbering) wherein the lysine at position 75 has been substituted with a tryptophan (H_K75W), glutamic acid (H_K75E), or tyrosine (H_K75Y),

• optionally wherein the variant first antigen-binding polypeptide construct comprises H_K75W and further comprises the following substitutions or set of substitutions, numbering according to Kabat numbering system:
• H_T30Q;
• or
• H_T30Y;
• or
• H_G56Y;
• or
• H_S99W;
• or
• L_Y49W;
• or
• L_Y96G;
• or
• H_S99W and L_Y49W;
• or
• L_Y49W and L_Y96G;
• or
• H_T30Q and L_Y49W;
• or
• H_T30Q and H_S99W;
• or
• H_T30Q and L_Y96G;
• or
• H_T30Y and L_Y49W;
• or
• H_S99W and L_Y49W and L_Y96G;
• or
• H_T3000 and H_S99W and L_Y96G or
• H_T3000 and H_S99W and L_Y49W;
• or
• H_T3000 and L_Y49W and L_Y96G;
• or
• H_T30Y and L_Y49W and L_Y96G, and
• optionally wherein the variant first antigen-binding polypeptide construct comprises H_K75E and further comprises the following substitutions or set of substitutions, numbering according to Kabat numbering system
• L_Y49W;
• or
• H_T30Q;
• or
• H_S74W;
• or
• H_S99W.