Monitoring In Vivo Performances of Protein–Drug Conjugates Using Site-Selective Dual Radiolabeling and Ex Vivo Digital Imaging - CEA - Commissariat à l’énergie atomique et aux énergies alternatives Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2022

Monitoring In Vivo Performances of Protein–Drug Conjugates Using Site-Selective Dual Radiolabeling and Ex Vivo Digital Imaging

Olivier Lequin

Résumé

In preclinical models, the development and optimization of protein−drug conjugates require accurate determination of the plasma and tissue profiles of both the protein and its conjugated drug. To this aim, we developed a bioanalytical strategy based on dual radiolabeling and ex vivo digital imaging. By combining enzymatic and chemical reactions, we obtained homogeneous dual-labeled anti-MMP-14 Fabs (antigen-binding fragments) conjugated to monomethyl auristatin E where the protein scaffold was labeled with carbon-14 (14C) and the conjugated drug with tritium (3H). These antibody−drug conjugates with either a noncleavable or a cleavable linker were then evaluated in vivo. By combining liquid scintillation counting and ex vivo dual-isotope radio-imaging, it was possible not only to monitor both components simultaneously during their circulation phase but also to quantify accurately their amount accumulated within the different organs.

Dates et versions

cea-03834302 , version 1 (04-11-2022)

Identifiants

Citer

Héloïse Cahuzac, Antoine Sallustrau, Carole Malgorn, Fabrice Beau, Peggy Barbe, et al.. Monitoring In Vivo Performances of Protein–Drug Conjugates Using Site-Selective Dual Radiolabeling and Ex Vivo Digital Imaging. Journal of Medicinal Chemistry, 2022, 65 (9), pp.6953 - 6968. ⟨10.1021/acs.jmedchem.2c00401⟩. ⟨cea-03834302⟩
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