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Pharmaceutics
Volume 14
Issue 8
10.3390/pharmaceutics14081524
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Article

Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs)

by
Louis Jolivet
1,†,
Imène Ait Mohamed Amar
2,†,
Catherine Horiot
1,
Fanny Boursin
1,
Cyril Colas
3,4,
Stéphanie Letast
2,
Caroline Denevault-Sabourin
2,
Emilie Allard-Vannier
5,
Nicolas Joubert
2,* and
Nicolas Aubrey
1
1
ISP UMR 1282, INRA, Team BioMAP, Université de Tours, 31 Avenue Monge, 37200 Tours, France
2
GICC EA7501, Team IMT, Université de Tours, UFR de Médecine, Bâtiment Vialle, 10 Boulevard Tonnelé, BP 3223, CEDEX 01, 37032 Tours, France
3
ICOA UMR 7311, Université d’Orléans, CNRS, Rue de Chartres, 45067 Orléans, France
4
CBM UPR 4301, CNRS, Université d’Orléans, Rue Charles Sadron, 45071 Orléans, France
5
NMNS EA 6295, Université de Tours, 31 Avenue Monge, 37200 Tours, France
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Pharmaceutics 2022, 14(8), 1524; https://doi.org/10.3390/pharmaceutics14081524
Submission received: 29 June 2022 / Revised: 20 July 2022 / Accepted: 20 July 2022 / Published: 22 July 2022
(This article belongs to the Special Issue Recent Advancements in Nanobiotechnology and Immunotherapy for the Treatment of Solid Tumors)
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Abstract

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.
Keywords: drug delivery; antibody–drug conjugate (ADC); fragment–drug conjugate (FDC); molecular engineering; conjugation motif; bioconjugation; cancer drug delivery; antibody–drug conjugate (ADC); fragment–drug conjugate (FDC); molecular engineering; conjugation motif; bioconjugation; cancer
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MDPI and ACS Style

Jolivet, L.; Ait Mohamed Amar, I.; Horiot, C.; Boursin, F.; Colas, C.; Letast, S.; Denevault-Sabourin, C.; Allard-Vannier, E.; Joubert, N.; Aubrey, N. Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs). Pharmaceutics 2022, 14, 1524. https://doi.org/10.3390/pharmaceutics14081524

AMA Style

Jolivet L, Ait Mohamed Amar I, Horiot C, Boursin F, Colas C, Letast S, Denevault-Sabourin C, Allard-Vannier E, Joubert N, Aubrey N. Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs). Pharmaceutics. 2022; 14(8):1524. https://doi.org/10.3390/pharmaceutics14081524

Chicago/Turabian Style

Jolivet, Louis, Imène Ait Mohamed Amar, Catherine Horiot, Fanny Boursin, Cyril Colas, Stéphanie Letast, Caroline Denevault-Sabourin, Emilie Allard-Vannier, Nicolas Joubert, and Nicolas Aubrey. 2022. "Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs)" Pharmaceutics 14, no. 8: 1524. https://doi.org/10.3390/pharmaceutics14081524

APA Style

Jolivet, L., Ait Mohamed Amar, I., Horiot, C., Boursin, F., Colas, C., Letast, S., Denevault-Sabourin, C., Allard-Vannier, E., Joubert, N., & Aubrey, N. (2022). Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment–Drug Conjugates (FDCs). Pharmaceutics, 14(8), 1524. https://doi.org/10.3390/pharmaceutics14081524

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