Engineering, Characterization, and Biological Evaluation of an Antibody Targeting the HGF Receptor
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 a...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:7fa4ce6435b044b2be29090950ec838a2021-12-03T13:57:48ZEngineering, Characterization, and Biological Evaluation of an Antibody Targeting the HGF Receptor1664-322410.3389/fimmu.2021.775151https://doaj.org/article/7fa4ce6435b044b2be29090950ec838a2021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.775151/fullhttps://doaj.org/toc/1664-3224The 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. In vivo administration of RDO24 in the murine model of MS, represented by experimental autoimmune encephalomyelitis (EAE), delays the EAE onset, mitigates the early clinical symptoms, and reduces inflammatory infiltrates. Altogether, these results suggest that engineered RDO24 antibody may be beneficial in multiple sclerosis and possibly other types of inflammatory disorders.Claudia DesoleSimona GalloSimona GalloAnnapia VitacolonnaAnnapia VitacolonnaElisa VignaElisa VignaCristina BasilicoFrancesca MontaroloFrancesca MontaroloFrancesca ZuppiniElena CasanovaRiccardo MiggianoRiccardo MiggianoDavide Maria FerrarisDavide Maria FerrarisAntonio BertolottoPaolo Maria ComoglioTiziana CrepaldiTiziana CrepaldiFrontiers Media S.A.articleHGFMETPSI domainsantibody engineeringregenerative medicineanti-cancer therapyImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
HGF MET PSI domains antibody engineering regenerative medicine anti-cancer therapy Immunologic diseases. Allergy RC581-607 |
| spellingShingle |
HGF MET PSI domains antibody engineering regenerative medicine anti-cancer therapy Immunologic diseases. Allergy RC581-607 Claudia Desole Simona Gallo Simona Gallo Annapia Vitacolonna Annapia Vitacolonna Elisa Vigna Elisa Vigna Cristina Basilico Francesca Montarolo Francesca Montarolo Francesca Zuppini Elena Casanova Riccardo Miggiano Riccardo Miggiano Davide Maria Ferraris Davide Maria Ferraris Antonio Bertolotto Paolo Maria Comoglio Tiziana Crepaldi Tiziana Crepaldi Engineering, Characterization, and Biological Evaluation of an Antibody Targeting the HGF Receptor |
| description |
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. In vivo administration of RDO24 in the murine model of MS, represented by experimental autoimmune encephalomyelitis (EAE), delays the EAE onset, mitigates the early clinical symptoms, and reduces inflammatory infiltrates. Altogether, these results suggest that engineered RDO24 antibody may be beneficial in multiple sclerosis and possibly other types of inflammatory disorders. |
| format |
article |
| author |
Claudia Desole Simona Gallo Simona Gallo Annapia Vitacolonna Annapia Vitacolonna Elisa Vigna Elisa Vigna Cristina Basilico Francesca Montarolo Francesca Montarolo Francesca Zuppini Elena Casanova Riccardo Miggiano Riccardo Miggiano Davide Maria Ferraris Davide Maria Ferraris Antonio Bertolotto Paolo Maria Comoglio Tiziana Crepaldi Tiziana Crepaldi |
| author_facet |
Claudia Desole Simona Gallo Simona Gallo Annapia Vitacolonna Annapia Vitacolonna Elisa Vigna Elisa Vigna Cristina Basilico Francesca Montarolo Francesca Montarolo Francesca Zuppini Elena Casanova Riccardo Miggiano Riccardo Miggiano Davide Maria Ferraris Davide Maria Ferraris Antonio Bertolotto Paolo Maria Comoglio Tiziana Crepaldi Tiziana Crepaldi |
| author_sort |
Claudia Desole |
| title |
Engineering, Characterization, and Biological Evaluation of an Antibody Targeting the HGF Receptor |
| title_short |
Engineering, Characterization, and Biological Evaluation of an Antibody Targeting the HGF Receptor |
| title_full |
Engineering, Characterization, and Biological Evaluation of an Antibody Targeting the HGF Receptor |
| title_fullStr |
Engineering, Characterization, and Biological Evaluation of an Antibody Targeting the HGF Receptor |
| title_full_unstemmed |
Engineering, Characterization, and Biological Evaluation of an Antibody Targeting the HGF Receptor |
| title_sort |
engineering, characterization, and biological evaluation of an antibody targeting the hgf receptor |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/7fa4ce6435b044b2be29090950ec838a |
| work_keys_str_mv |
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| _version_ |
1718373213262577664 |