Monoclonal Antibodies against the MET/HGF Receptor and Its Ligand: Multitask Tools with Applications from Basic Research to Therapy

Abstract

Monoclonal antibodies can be seen as valuable tools for many aspects of basic as well as applied sciences. In the case of MET/HGFR, they allowed the identification of truncated isoforms of the receptor, as well as the dissection of different epitopes, establishing structure-function relationships. Antibodies directed against MET extracellular domain were found to be full or partial receptor agonists or antagonists. The agonists can mimic the effects of the different isoforms of the natural ligand, but with the advantage of being more stable than the latter. Thus, some agonist antibodies promote all the biological responses triggered by MET activation, including motility, proliferation, morphogenesis, and protection from apoptosis, while others can induce only a migratory response. On the other hand, antagonists can inhibit MET-driven biological functions either by competing with the ligand or by removing the receptor from the cell surface. Since MET/HGFR is often over-expressed and/or aberrantly activated in tumors, monoclonal antibodies can be used as probes for MET detection or as "bullets" to target MET-expressing tumor cells, thus pointing to their use in diagnosis and therapy.

Keywords: agonist monoclonal antibodies; antagonist monoclonal antibodies; tumor therapy; tyrosine kinase receptor.

Figure 1

Schematic representation of MET interactions with HGF or with anti-MET antibodies. Left: Hypothetical model of HGF/MET interactions. The mature form of HGF consists of an α (dark blue) and a β (light blue) chain held together by a disulphide bond. MET is a single-pass, multi-domain, disulphide-linked α/β heterodimer. Its extracellular portion consists of three domains: the SEMA domain, folded into a seven-bladed β propeller, which encompasses the whole α chain (dark pink) and part of the β-subunit (light pink); the cysteine-rich PSI domain (orange); and the four immunoglobulin-like IPT domains (green). The intracellular region consists of the kinase domain (dark grey) and a multifunctional docking site (bidentate, light grey). In this model, based on data from different independent studies [38,39,40,41,42,43], the α chain of HGF interacts on one side with blades 4–6 of the SEMA β-propeller and on the other with the IPT 2–3 regions, while the β chain interacts with blades 2–3 of the SEMA β propeller; Right: Epitope mapping of anti-MET antibodies. Antibodies directed against the MET ectodomain (ECD) recognize epitopes localized in many different areas of the receptor.