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

Maria Prat,Cristina Basilico,Francesca Oltolina

doi:10.3390/biomedicines2040359

Maria Prat, Cristina Basilico + Show 1 more

Open Access

https://doi.org/10.3390/biomedicines2040359

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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.

Highlights

Monoclonal antibodies have been revealed to be extremely useful reagents, because of their high specificity, affinity, and robust structure
One of the best examples in cancer therapy is Trastuzumab (Herceptin®: Genentech Inc.), which was approved by the FDA in 2006 for patients with invasive breast cancers over-expressing the tyrosine kinase orphan receptor HER2, generally in a combined therapy with chemotherapeutics [2]
Two antibodies (DO-24 and DN-31 [50]) that behave as reciprocal cross-competitors for binding to the receptor were found to act as full agonists, being able to trigger all the biological effects elicited by the natural ligand hepatocyte growth factor/scatter factor (HGF), e.g., motility, proliferation, cell survival, invasion, tubulogenesis, and in vivo angiogenesis [47,80]

Summary

Introduction

Monoclonal antibodies (mAbs) have been revealed to be extremely useful reagents, because of their high specificity, affinity, and robust structure. While in the case of some tumors MET-mediated cellular activities may be independent from the ligand, all the physiological activities mediated by this receptor are strictly dependent on and regulated by HGF stimulation. Antibodies may act as agonists, mimicking the natural ligands and promoting useful biological responses—for example, stimulating the survival and proliferation of cells in injured tissues. MET-mediated uncontrolled excessive responses of tumor cells In the latter scenario, antibodies against the ligand could represent valuable tools for hampering the ligand–receptor interaction. A brief summary of the structures of the two partners, instrumental for elucidating their interaction with the mAbs, is presented

HGF and MET

Agonist MET mAbs

Antagonist MET mAbs

Conclusions and Future Perspectives