A receptor-antibody hybrid hampering MET-driven metastatic spread.
A549 Cells
Animals
Binding Sites, Antibody
Cell Line, Tumor
Cell Proliferation
/ drug effects
Female
Hepatocyte Growth Factor
/ antagonists & inhibitors
Humans
Immunoconjugates
/ immunology
Immunoglobulin Fab Fragments
/ immunology
Mice
Mice, SCID
Neoplasm Metastasis
Neoplasms
/ drug therapy
Proto-Oncogene Proteins c-met
/ antagonists & inhibitors
Rats
Rats, Sprague-Dawley
Recombinant Proteins
/ pharmacology
Xenograft Model Antitumor Assays
Fusion proteins
HGF
MET
Metastasis
Targeted therapy
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
14 Jan 2021
14 Jan 2021
Historique:
received:
27
08
2020
accepted:
22
12
2020
entrez:
15
1
2021
pubmed:
16
1
2021
medline:
1
9
2021
Statut:
epublish
Résumé
The receptor encoded by the MET oncogene and its ligand Hepatocyte Growth Factor (HGF) are at the core of the invasive-metastatic behavior. In a number of instances genetic alterations result in ligand-independent onset of malignancy (MET addiction). More frequently, ligand stimulation of wild-type MET contributes to progression toward metastasis (MET expedience). Thus, while MET inhibitors alone are effective in the first case, combination therapy with ligand inhibitors is required in the second condition. In this paper, we generated hybrid molecules gathering HGF and MET inhibitory properties. This has been achieved by 'head-to-tail' or 'tail-to-head' fusion of a single chain Fab derived from the DN30 MET antibody with a recombinant 'ad-hoc' engineered MET extracellular domain (decoyMET), encompassing the HGF binding site but lacking the DN30 epitope. The hybrid molecules correctly bind MET and HGF, inhibit HGF-induced MET downstream signaling, and quench HGF-driven biological responses, such as growth, motility and invasion, in cancer cells of different origin. Two metastatic models were generated in mice knocked-in by the human HGF gene: (i) orthotopic transplantation of pancreatic cancer cells; (ii) subcutaneous injection of primary cells derived from a cancer of unknown primary. Treatment with hybrid molecules strongly affects time of onset, number, and size of metastatic lesions. These results provide a strategy to treat metastatic dissemination driven by the HGF/MET axis.
Sections du résumé
BACKGROUND
BACKGROUND
The receptor encoded by the MET oncogene and its ligand Hepatocyte Growth Factor (HGF) are at the core of the invasive-metastatic behavior. In a number of instances genetic alterations result in ligand-independent onset of malignancy (MET addiction). More frequently, ligand stimulation of wild-type MET contributes to progression toward metastasis (MET expedience). Thus, while MET inhibitors alone are effective in the first case, combination therapy with ligand inhibitors is required in the second condition.
METHODS
METHODS
In this paper, we generated hybrid molecules gathering HGF and MET inhibitory properties. This has been achieved by 'head-to-tail' or 'tail-to-head' fusion of a single chain Fab derived from the DN30 MET antibody with a recombinant 'ad-hoc' engineered MET extracellular domain (decoyMET), encompassing the HGF binding site but lacking the DN30 epitope.
RESULTS
RESULTS
The hybrid molecules correctly bind MET and HGF, inhibit HGF-induced MET downstream signaling, and quench HGF-driven biological responses, such as growth, motility and invasion, in cancer cells of different origin. Two metastatic models were generated in mice knocked-in by the human HGF gene: (i) orthotopic transplantation of pancreatic cancer cells; (ii) subcutaneous injection of primary cells derived from a cancer of unknown primary. Treatment with hybrid molecules strongly affects time of onset, number, and size of metastatic lesions.
CONCLUSION
CONCLUSIONS
These results provide a strategy to treat metastatic dissemination driven by the HGF/MET axis.
Identifiants
pubmed: 33446252
doi: 10.1186/s13046-020-01822-5
pii: 10.1186/s13046-020-01822-5
pmc: PMC7807714
doi:
Substances chimiques
HGF protein, human
0
Immunoconjugates
0
Immunoglobulin Fab Fragments
0
Recombinant Proteins
0
Hepatocyte Growth Factor
67256-21-7
MET protein, human
EC 2.7.10.1
Proto-Oncogene Proteins c-met
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
32Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : 21052
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : 21052
Organisme : Fondazione Piemontese per la Ricerca sul Cancro
ID : 5x1000 2014
Organisme : Ministero della Salute
ID : Ricerca Corrente 2019
Organisme : Metis Precision Medicine B-Corp
ID : Resource 2020
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