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Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs)
Antibody–drug conjugates (ADCs) derived from a full immunoglobulin-G (IgG) are associated with suboptimal solid-tumor penetration and Fc-mediated toxicities. Antibody fragment–drug conjugates (FDCs) could be an alternative. Nevertheless, innovative solutions are needed to implant cysteines as conjug...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331466/ https://www.ncbi.nlm.nih.gov/pubmed/35893780 http://dx.doi.org/10.3390/pharmaceutics14081524 |
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author | Jolivet, Louis Ait Mohamed Amar, Imène Horiot, Catherine Boursin, Fanny Colas, Cyril Letast, Stéphanie Denevault-Sabourin, Caroline Allard-Vannier, Emilie Joubert, Nicolas Aubrey, Nicolas |
author_facet | Jolivet, Louis Ait Mohamed Amar, Imène Horiot, Catherine Boursin, Fanny Colas, Cyril Letast, Stéphanie Denevault-Sabourin, Caroline Allard-Vannier, Emilie Joubert, Nicolas Aubrey, Nicolas |
author_sort | Jolivet, Louis |
collection | PubMed |
description | Antibody–drug conjugates (ADCs) derived from a full immunoglobulin-G (IgG) are associated with suboptimal solid-tumor penetration and Fc-mediated toxicities. Antibody fragment–drug conjugates (FDCs) could be an alternative. Nevertheless, innovative solutions are needed to implant cysteines as conjugation sites in the single-chain fragment variable (scFv) format, which is the backbone from which many other antibody formats are built. In addition, the bioconjugation site has the utmost importance to optimize the safety and efficacy of bioconjugates. Our previous intra-tag cysteine (ITC) strategy consisted of introducing a bioconjugation motif at the C-terminal position of the 4D5.2 scFv, but this motif was subjected to proteolysis when the scFv was produced in CHO cells. Considering these data, using three intra-domain cysteine (IDC) strategies, several parameters were studied to assess the impact of different locations of a site-specific bioconjugation motif in the variable domains of an anti-HER2 scFv. In comparison to the ITC strategy, our new IDC strategy allowed us to identify new fragment–drug conjugates (FDCs) devoid of proteolysis and exhibiting enhanced stability profiles, better affinity, and better ability to kill selectively HER2-positive SK-BR-3 cells in vitro at picomolar concentrations. Thus, this work represents an important optimization step in the design of more complex and effective conjugates. |
format | Online Article Text |
id | pubmed-9331466 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-93314662022-07-29 Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs) Jolivet, Louis Ait Mohamed Amar, Imène Horiot, Catherine Boursin, Fanny Colas, Cyril Letast, Stéphanie Denevault-Sabourin, Caroline Allard-Vannier, Emilie Joubert, Nicolas Aubrey, Nicolas Pharmaceutics Article Antibody–drug conjugates (ADCs) derived from a full immunoglobulin-G (IgG) are associated with suboptimal solid-tumor penetration and Fc-mediated toxicities. Antibody fragment–drug conjugates (FDCs) could be an alternative. Nevertheless, innovative solutions are needed to implant cysteines as conjugation sites in the single-chain fragment variable (scFv) format, which is the backbone from which many other antibody formats are built. In addition, the bioconjugation site has the utmost importance to optimize the safety and efficacy of bioconjugates. Our previous intra-tag cysteine (ITC) strategy consisted of introducing a bioconjugation motif at the C-terminal position of the 4D5.2 scFv, but this motif was subjected to proteolysis when the scFv was produced in CHO cells. Considering these data, using three intra-domain cysteine (IDC) strategies, several parameters were studied to assess the impact of different locations of a site-specific bioconjugation motif in the variable domains of an anti-HER2 scFv. In comparison to the ITC strategy, our new IDC strategy allowed us to identify new fragment–drug conjugates (FDCs) devoid of proteolysis and exhibiting enhanced stability profiles, better affinity, and better ability to kill selectively HER2-positive SK-BR-3 cells in vitro at picomolar concentrations. Thus, this work represents an important optimization step in the design of more complex and effective conjugates. MDPI 2022-07-22 /pmc/articles/PMC9331466/ /pubmed/35893780 http://dx.doi.org/10.3390/pharmaceutics14081524 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Jolivet, Louis Ait Mohamed Amar, Imène Horiot, Catherine Boursin, Fanny Colas, Cyril Letast, Stéphanie Denevault-Sabourin, Caroline Allard-Vannier, Emilie Joubert, Nicolas Aubrey, Nicolas Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs) |
title | Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs) |
title_full | Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs) |
title_fullStr | Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs) |
title_full_unstemmed | Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs) |
title_short | Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs) |
title_sort | intra-domain cysteines (idc), a new strategy for the development of original antibody fragment–drug conjugates (fdcs) |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331466/ https://www.ncbi.nlm.nih.gov/pubmed/35893780 http://dx.doi.org/10.3390/pharmaceutics14081524 |
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