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Branched pegylated linker-auristatin to control hydrophobicity for the production of homogeneous minibody-drug conjugate against HER2-positive breast cancer.
Douez, Emmanuel; Allard-Vannier, Emilie; Amar, Imène Ait Mohamed; Jolivet, Louis; Boursin, Fanny; Maisonial-Besset, Aurélie; Witkowski, Tiffany; Chezal, Jean-Michel; Colas, Cyril; Letast, Stéphanie; Auvert, Etienne; Denevault-Sabourin, Caroline; Aubrey, Nicolas; Joubert, Nicolas.
Afiliación
  • Douez E; UPR 4301 CBM, CNRS, University of Tours, University of Orléans, F-45071 Orléans, France; Pharmacy Department, Tours University Hospital, F-37200 Tours, France.
  • Allard-Vannier E; UPR 4301 CBM, CNRS, University of Tours, University of Orléans, F-45071 Orléans, France. Electronic address: emilie.allard@univ-tours.fr.
  • Amar IAM; UMR 1100 CEPR, INSERM, University of Tours, F-37200 Tours, France.
  • Jolivet L; UMR 1282 ISP, INRAE, University of Tours, Team BioMAP, F-37200 Tours, France.
  • Boursin F; UMR 1282 ISP, INRAE, University of Tours, Team BioMAP, F-37200 Tours, France.
  • Maisonial-Besset A; Université Clermont Auvergne, Inserm, Imagerie Moléculaire et Stratégies Théranostiques, UMR 1240, F-63000 Clermont-Ferrand, France.
  • Witkowski T; Université Clermont Auvergne, Inserm, Imagerie Moléculaire et Stratégies Théranostiques, UMR 1240, F-63000 Clermont-Ferrand, France.
  • Chezal JM; Université Clermont Auvergne, Inserm, Imagerie Moléculaire et Stratégies Théranostiques, UMR 1240, F-63000 Clermont-Ferrand, France.
  • Colas C; UPR 4301 CBM, CNRS, University of Tours, University of Orléans, F-45071 Orléans, France; UMR 7311 ICOA, CNRS, University of Orléans, F-45067 Orléans, France.
  • Letast S; UMR 1100 CEPR, INSERM, University of Tours, F-37200 Tours, France.
  • Auvert E; UMR 1100 CEPR, INSERM, University of Tours, F-37200 Tours, France.
  • Denevault-Sabourin C; UMR 1100 CEPR, INSERM, University of Tours, F-37200 Tours, France.
  • Aubrey N; UMR 1282 ISP, INRAE, University of Tours, Team BioMAP, F-37200 Tours, France.
  • Joubert N; UMR 1100 CEPR, INSERM, University of Tours, F-37200 Tours, France. Electronic address: nicolas.joubert@univ-tours.fr.
J Control Release ; 366: 567-584, 2024 Feb.
Article en En | MEDLINE | ID: mdl-38215985
ABSTRACT
Trastuzumab emtansine (Kadcyla®) was the first antibody-drug conjugate (ADC) approved by the Food and Drug Administration in 2013 against a solid tumor, and the first ADC to treat human epidermal growth factor receptor 2 positive (HER2+) breast cancer. However, this second generation ADC is burden by several limitations included heterogeneity, limited activity against heterogeneous tumor (regarding antigen expression) and suboptimal tumor penetration. To address this, different development strategies are oriented towards homogeneous conjugation, new drugs, optimized linkers and/or smaller antibody formats. To reach better developed next generation ADCs, a key parameter to consider is the management of the hydrophobicity associated with the linker-drug, increasing with and limiting the drug-to-antibody ratio (DAR) of the ADC. Here, an innovative branched pegylated linker was developed, to control the hydrophobicity of the monomethyl auristatin E (MMAE) and its cathepsin B-sensitive trigger. This branched pegylated linker-MMAE was then used for the efficient generation of internalizing homogeneous ADC of DAR 8 and minibody-drug conjugate of DAR 4, targeting HER2. Both immunoconjugates were then evaluated in vitro and in vivo on breast cancer models. Interestingly, this study highlighted that the minibody-MMAE conjugate of DAR 4 was the best immunoconjugate regarding in vitro cellular internalization and cytotoxicity, gamma imaging, ex vivo biodistribution profile in mice and efficient reduction of tumor size in vivo. These results are very promising and encourage us to explore further fragment-drug conjugate development.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligopéptidos / Neoplasias de la Mama / Inmunoconjugados / Aminobenzoatos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans País/Región como asunto: America do norte Idioma: En Revista: J Control Release Asunto de la revista: FARMACOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligopéptidos / Neoplasias de la Mama / Inmunoconjugados / Aminobenzoatos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans País/Región como asunto: America do norte Idioma: En Revista: J Control Release Asunto de la revista: FARMACOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Países Bajos