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Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody

The MET oncogene encodes a tyrosine kinase receptor involved in the control of a complex network of biological responses that include protection from apoptosis and stimulation of cell growth during embryogenesis, tissue regeneration, and cancer progression. We previously developed an antagonist anti...

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Autores principales: Modica, Chiara, Gallo, Simona, Chiriaco, Cristina, Spilinga, Martina, Comoglio, Paolo Maria, Crepaldi, Tiziana, Basilico, Cristina, Vigna, Elisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140090/
https://www.ncbi.nlm.nih.gov/pubmed/32245152
http://dx.doi.org/10.3390/cancers12030741
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author Modica, Chiara
Gallo, Simona
Chiriaco, Cristina
Spilinga, Martina
Comoglio, Paolo Maria
Crepaldi, Tiziana
Basilico, Cristina
Vigna, Elisa
author_facet Modica, Chiara
Gallo, Simona
Chiriaco, Cristina
Spilinga, Martina
Comoglio, Paolo Maria
Crepaldi, Tiziana
Basilico, Cristina
Vigna, Elisa
author_sort Modica, Chiara
collection PubMed
description The MET oncogene encodes a tyrosine kinase receptor involved in the control of a complex network of biological responses that include protection from apoptosis and stimulation of cell growth during embryogenesis, tissue regeneration, and cancer progression. We previously developed an antagonist antibody (DN30) inducing the physical removal of the receptor from the cell surface and resulting in suppression of the biological responses to MET. In its bivalent form, the antibody displayed a residual agonist activity, due to dimerization of the lingering receptors, and partial activation of the downstream signaling cascade. The balance between the two opposing activities is variable in different biological systems and is hardly predictable. In this study, we generated and characterized two single-chain antibody fragments derived from DN30, sharing the same variable regions but including linkers different in length and composition. The two engineered molecules bind MET with high affinity but induce different biological responses. One behaves as a MET-antagonist, promoting programmed cell death in MET “addicted” cancer cells. The other acts as a hepatocyte growth factor (HGF)-mimetic, protecting normal cells from doxorubicin-induced apoptosis. Thus, by engineering the same receptor antibody, it is possible to generate molecules enhancing or inhibiting apoptosis either to kill cancer cells or to protect healthy tissues from the injuries of chemotherapy.
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spelling pubmed-71400902020-04-13 Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody Modica, Chiara Gallo, Simona Chiriaco, Cristina Spilinga, Martina Comoglio, Paolo Maria Crepaldi, Tiziana Basilico, Cristina Vigna, Elisa Cancers (Basel) Article The MET oncogene encodes a tyrosine kinase receptor involved in the control of a complex network of biological responses that include protection from apoptosis and stimulation of cell growth during embryogenesis, tissue regeneration, and cancer progression. We previously developed an antagonist antibody (DN30) inducing the physical removal of the receptor from the cell surface and resulting in suppression of the biological responses to MET. In its bivalent form, the antibody displayed a residual agonist activity, due to dimerization of the lingering receptors, and partial activation of the downstream signaling cascade. The balance between the two opposing activities is variable in different biological systems and is hardly predictable. In this study, we generated and characterized two single-chain antibody fragments derived from DN30, sharing the same variable regions but including linkers different in length and composition. The two engineered molecules bind MET with high affinity but induce different biological responses. One behaves as a MET-antagonist, promoting programmed cell death in MET “addicted” cancer cells. The other acts as a hepatocyte growth factor (HGF)-mimetic, protecting normal cells from doxorubicin-induced apoptosis. Thus, by engineering the same receptor antibody, it is possible to generate molecules enhancing or inhibiting apoptosis either to kill cancer cells or to protect healthy tissues from the injuries of chemotherapy. MDPI 2020-03-21 /pmc/articles/PMC7140090/ /pubmed/32245152 http://dx.doi.org/10.3390/cancers12030741 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Modica, Chiara
Gallo, Simona
Chiriaco, Cristina
Spilinga, Martina
Comoglio, Paolo Maria
Crepaldi, Tiziana
Basilico, Cristina
Vigna, Elisa
Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody
title Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody
title_full Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody
title_fullStr Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody
title_full_unstemmed Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody
title_short Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody
title_sort molecular engineering strategies tailoring the apoptotic response to a met therapeutic antibody
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140090/
https://www.ncbi.nlm.nih.gov/pubmed/32245152
http://dx.doi.org/10.3390/cancers12030741
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