Engineering, Characterization, and Biological Evaluation of an Antibody Targeting the HGF Receptor.
Animals
Antibodies, Monoclonal
/ genetics
Antibody Affinity
Antineoplastic Agents, Immunological
Cell Line
Cloning, Molecular
Drug Development
/ methods
Encephalomyelitis, Autoimmune, Experimental
/ drug therapy
Gene Expression
Genetic Vectors
/ genetics
Hepatocyte Growth Factor
/ antagonists & inhibitors
Humans
Mice
Models, Molecular
Mutagenesis
Protein Engineering
/ methods
Recombinant Proteins
/ genetics
Structure-Activity Relationship
Treatment Outcome
HGF
MET
PSI domains
anti-cancer therapy
antibody engineering
experimental autoimmune encephalomyelitis
multiple sclerosis
regenerative medicine
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2021
2021
Historique:
received:
15
09
2021
accepted:
08
11
2021
entrez:
20
12
2021
pubmed:
21
12
2021
medline:
11
2
2022
Statut:
epublish
Résumé
The Hepatocyte growth factor (HGF) and its receptor (MET) promote several physiological activities such as tissue regeneration and protection from cell injury of epithelial, endothelial, neuronal and muscle cells. The therapeutic potential of MET activation has been scrutinized in the treatment of acute tissue injury, chronic inflammation, such as renal fibrosis and multiple sclerosis (MS), cardiovascular and neurodegenerative diseases. On the other hand, the HGF-MET signaling pathway may be caught by cancer cells and turned to work for invasion, metastasis, and drug resistance in the tumor microenvironment. Here, we engineered a recombinant antibody (RDO24) and two derived fragments, binding the extracellular domain (ECD) of the MET protein. The antibody binds with high affinity (8 nM) to MET ECD and does not cross-react with the closely related receptors RON nor with Semaphorin 4D. Deletion mapping studies and computational modeling show that RDO24 binds to the structure bent on the Plexin-Semaphorin-Integrin (PSI) domain, implicating the PSI domain in its binding to MET. The intact RDO24 antibody and the bivalent Fab2, but not the monovalent Fab induce MET auto-phosphorylation, mimicking the mechanism of action of HGF that activates the receptor by dimerization. Accordingly, the bivalent recombinant molecules induce HGF biological responses, such as cell migration and wound healing, behaving as MET agonists of therapeutic interest in regenerative medicine.
Identifiants
pubmed: 34925346
doi: 10.3389/fimmu.2021.775151
pmc: PMC8679783
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antineoplastic Agents, Immunological
0
HGF protein, human
0
Recombinant Proteins
0
Hepatocyte Growth Factor
67256-21-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
775151Informations de copyright
Copyright © 2021 Desole, Gallo, Vitacolonna, Vigna, Basilico, Montarolo, Zuppini, Casanova, Miggiano, Ferraris, Bertolotto, Comoglio and Crepaldi.
Déclaration de conflit d'intérêts
EV and PMC own shares in Metis BeCorp. RM and DMF are co-founders of the academic spin-off IXTAL, in which they hold shares (www.ixtal.it). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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