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Dual intra- and extracellular release of monomethyl auristatin E from a neutrophil elastase-sensitive antibody-drug conjugate.
Mohamed Amar, Imene Ait; Huvelle, Steve; Douez, Emmanuel; Letast, Stéphanie; Henrion, Sylvain; Viaud-Massuard, Marie-Claude; Aubrey, Nicolas; Allard-Vannier, Emilie; Joubert, Nicolas; Denevault-Sabourin, Caroline.
Afiliación
  • Mohamed Amar IA; EA 7501 GICC, Team IMT, University of Tours, F-37032, Tours, France.
  • Huvelle S; EA 7501 GICC, Team IMT, University of Tours, F-37032, Tours, France.
  • Douez E; EA 6295 NMNS, University of Tours, F-37200, Tours, France.
  • Letast S; EA 7501 GICC, Team IMT, University of Tours, F-37032, Tours, France.
  • Henrion S; EA 7501 GICC, Team IMT, University of Tours, F-37032, Tours, France.
  • Viaud-Massuard MC; EA 7501 GICC, Team IMT, University of Tours, F-37032, Tours, France.
  • Aubrey N; UMR 1282 ISP, Team BioMAP, University of Tours-INRAE, F-37200, Tours, France.
  • Allard-Vannier E; EA 6295 NMNS, University of Tours, F-37200, Tours, France.
  • Joubert N; EA 7501 GICC, Team IMT, University of Tours, F-37032, Tours, France. Electronic address: nicolas.joubert@univ-tours.fr.
  • Denevault-Sabourin C; EA 7501 GICC, Team IMT, University of Tours, F-37032, Tours, France. Electronic address: caroline.sabourin@univ-tours.fr.
Eur J Med Chem ; 229: 114063, 2022 Feb 05.
Article en En | MEDLINE | ID: mdl-34974337
Antibody-drug conjugates (ADCs) are targeted therapies, mainly used in oncology, consisting in a three-component molecular architecture combining a highly potent drug conjugated via a linker onto a monoclonal antibody (mAb), designed for the selective delivery of the drug to the tumor site. The linker is a key component, defining the ADC stability and mechanism of action, and particularly the drug release strategy. In this study, we have developed and synthesized a cleavable linker, which possesses an Asn-Pro-Val (NPV) sequence sensitive to the human neutrophil elastase (HNE), overexpressed in the tumor microenvironment. This linker permitted the site-specific conjugation of the cell-permeable drug, monomethyl auristatin E (MMAE), onto trastuzumab, using a disulfide re-bridging technology. The resulting ADC was then evaluated in vitro. This conjugate demonstrated retained antigen (Ag) binding affinity and exhibited high subnanomolar potency against Ag-positive tumor cells after internalization, suggesting an intracellular mechanism of linker cleavage. While no internalization and cytotoxic activity of this ADC was observed on Ag-negative cells in classical conditions, the supplementation of exogenous HNE permitted to restore a nanomolar activity on these cells, suggesting an extracellular mechanism of drug release in these conditions. This in vitro proof of concept tends to prove that the NPV sequence could allow a dual intra- and extracellular mechanism of drug release. This work represents a first step in the design of original ADCs with a new dual intra- and extracellular drug delivery system and opens the way to further experimentations to evaluate their full potential in vivo.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligopéptidos / Inmunoconjugados / Elastasa de Leucocito / Trastuzumab / Antineoplásicos Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: Eur J Med Chem Año: 2022 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Francia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligopéptidos / Inmunoconjugados / Elastasa de Leucocito / Trastuzumab / Antineoplásicos Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: Eur J Med Chem Año: 2022 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Francia