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Scientific result | Pharmacology | Cell and molecular imaging
A team from SIMoS, in collaboration with the SCBM (DMTS), has developed an original bioanalytical approach based on the double 14C-3H isotopic labeling of an antibody-drug conjugate. By enabling the in vivo monitoring of both components in mouse models as well as their accurate quantification in organs, this study constitutes a significant advance for the identification and development of protein-drug conjugates with high potential for future clinical evaluations.
Over the past decade, protein-drug conjugates and more specifically antibody-drug conjugates (ADCs) have emerged as a core class of therapeutics, used primarily in oncology. This expansion is the result of an increased understanding of the factors influencing the efficacy and toxicity of immunoconjugates, improved antibody engineering, advances in coupling technologies to cytotoxic agents, as well as improved target and cytotoxic agent selection. However, the development and optimization of ADCs requires accurate determination of the plasma and tissue profiles of the protein and its drug conjugate because, due to their duality, determining the in vivo fate of the two components of the conjugate can be difficult and requires the use of multiple and complementary bioanalytical approaches.
In this context, the authors have developed an innovative and original bioanalytical approach based on a double 14C-3H isotopic labeling of an antibody-drug conjugate. The team produced several anti-MMP-14 (Matrix Metalloproteinase-14) antibody fragments (Fabs), which were then conjugated to monomethyl auristatin E (MMAE) using a cleavable or non-cleavable linker, in which the protein part (Fab) is labeled with carbon 14 and the drug part (MMAE) with tritium. By combining liquid scintillation counting and ex vivo dual-isotope digital radio-imaging, it was possible not only to follow both components simultaneously during their circulating phase in plasma, but also to accurately quantify their accumulated amount in different organs and tumors of mice (standard and preclinical breast cancer model). In particular, the concentration of both components could be accurately determined at the tumor site and the effective release of 3H-MMAE into the tumor was confirmed by high-performance liquid chromatography (HPLC). This innovative strategy can be used to compare the stability and in vivo performance of protein-drug conjugates in preclinical models, thus facilitating the identification of high potential conjugates for future clinical evaluations. Contact : Laurent Devel firstname.lastname@example.org
H Cahuzac, A Sallustrau, C Malgorn, F Beau, P Barbe, V Babin, S Dubois, A Palazzolo, R Thai, I Correia, K Baek Lee, S Garcia-Argote, O Lequin, M Keck, H Nozach, S Feuillastre, X Ge, G Pieters, D Audisio, L Devel. Monitoring In Vivo Performances of Protein−Drug Conjugates Using Site-Selective Dual Radiolabeling and Ex Vivo Digital Imaging. J. Med. Chem 2022 65 (9), 6953-6968 https://dx.doi.org/10.1021/acs.jmedchem.2c00401
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