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

Journal of medicinal chemistry 2022 May 12

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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.

Citation

Héloïse Cahuzac, Antoine Sallustrau, Carole Malgorn, Fabrice Beau, Peggy Barbe, Victor Babin, Steven Dubois, Alberto Palazzolo, Robert Thai, Isabelle Correia, Ki Baek Lee, Sébastien Garcia-Argote, Olivier Lequin, Mathilde Keck, Hervé Nozach, Sophie Feuillastre, Xin Ge, Gregory Pieters, Davide Audisio, Laurent Devel. Monitoring In Vivo Performances of Protein-Drug Conjugates Using Site-Selective Dual Radiolabeling and Ex Vivo Digital Imaging. Journal of medicinal chemistry. 2022 May 12;65(9):6953-6968