A receptor-antibody hybrid hampering MET-driven metastatic spread

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The HGF/MET signaling pathway drives cancer invasion and metastasis.
• MET addiction (ligand-independent) and MET expedience (ligand-dependent) are key mechanisms in malignancy.
• Combination therapy is often needed for ligand-dependent MET-driven cancers.

Purpose of the Study:

• To create hybrid molecules with dual HGF and MET inhibitory functions.
• To develop a novel therapeutic strategy against HGF/MET-driven metastasis.

Main Methods:

• Engineered hybrid molecules by fusing a MET-targeting antibody fragment (DN30 Fab) with a MET-binding decoy domain.
• Tested hybrid molecules in vitro for inhibition of HGF-induced MET signaling and cancer cell responses.
• Evaluated efficacy in preclinical mouse models of pancreatic and unknown primary cancers with human HGF knock-in.

Main Results:

• Hybrid molecules effectively bind MET and HGF, inhibiting downstream signaling and HGF-driven cancer cell growth, motility, and invasion.
• Treatment with hybrid molecules significantly reduced the onset, number, and size of metastatic lesions in mouse models.
• Demonstrated potent anti-metastatic activity in vivo.

Conclusions:

• The developed hybrid molecules represent a promising strategy for treating cancers driven by the HGF/MET axis.
• This approach offers a potential new avenue for managing metastatic dissemination.