Targeting HER3 using mono- and bispecific antibodies or alternative scaffolds

Abstract

The human epidermal growth factor receptor 3 (HER3) has in recent years been recognized as a key node in the complex signaling network of many different cancers. It is implicated in de novo and acquired resistance against therapies targeting other growth factor receptors, e.g., EGFR, HER2, and it is a major activator of the PI3K/Akt signaling pathway. Consequently, HER3 has attracted substantial attention, and is today a key target for drugs in clinical development. Sophisticated protein engineering approaches have enabled the generation of a range of different affinity proteins targeting this receptor, including antibodies and alternative scaffolds that are either mono- or bispecific. Here, we describe HER3 and its role as a key tumor target, and give a comprehensive review of HER3-targeted proteins currently in development, including discussions on the opportunities and challenges of targeting this receptor.

Keywords: Affibody molecules; ErbB3; HER3; alternative scaffolds; bispecific antibodies; monoclonal antibodies; protein therapeutics; tumor targeting.

Figure 1.

Schematic illustration of the epidermal growth factor receptors EGFR, HER2, HER3 and HER4. The receptors consist of an extracellular unit, divided into 4 domains (I-IV), a transmembrane region, a cytoplasmic tyrosine kinase domain as well as a C-terminal tail with phosphotyrosine residues. Whereas inactive EGFR, HER3 and HER4 adopt a tethered extracellular conformation, HER2 is constantly in an untethered conformation available for dimerization. Binding of the ligands NRG1 or NRG2 to the catalytically inactive HER3 results in exposure of a dimerization arm on domain II and subsequent receptor dimerization, here exemplified by the HER2/HER3 heterodimer. Extracellular dimerization induces intracellular signaling pathways such as the MAPK and PtdIns-3K pathways, mainly resulting in increased proliferation and survival.

Figure 2.

Schematic description of an antibody (IgG), antibody derivatives (scFv, Fab and VHL/VHH) and structural representation of the Affibody molecule (PDB entry 2B89).