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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7140090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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