Site-Specific, Platform-Based Conjugation Strategy for the Synthesis of Dual-Labeled Immunoconjugates for Bimodal PET/NIRF Imaging of HER2-Positive Tumors.
Fiche publication
Date publication
mars 2022
Journal
Bioconjugate chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Pr DENAT Franck, Dr GONCALVES Victor
Tous les auteurs :
Adumeau P, Raavé R, Boswinkel M, Heskamp S, Wessels HJCT, van Gool AJ, Moreau M, Bernhard C, Da Costa L, Goncalves V, Denat F
Lien Pubmed
Résumé
Because positron emission tomography (PET) and optical imaging are very complementary, the combination of these two imaging modalities is very enticing in the oncology field. Such bimodal imaging generally relies on imaging agents bearing two different imaging reporters. In the bioconjugation field, this is mainly performed by successive random conjugations of the two reporters on the protein vector, but these random conjugations can alter the vector properties. In this study, we aimed at abrogating the heterogeneity of the bimodal imaging immunoconjugate and mitigating the impact of multiple random conjugations. A trivalent platform bearing a DFO chelator for Zr labeling, a NIR fluorophore, IRDye800CW, and a bioconjugation handle was synthesized. This bimodal probe was site-specifically grafted to trastuzumab via glycan engineering. This new bimodal immunoconjugate was then investigated in terms of radiochemistry, and , and compared to the clinically relevant random equivalent. and , our strategy provides several improvements over the current clinical standard. The combination of site-specific conjugation with the monomolecular platform reduced the heterogeneity of the final immunoconjugate, improved the resistance of the fluorophore toward radiobleaching, and reduced the nonspecific uptake in the spleen and liver compared to the standard random immunoconjugate. To conclude, the strategy developed is very promising for the synthesis of better defined dual-labeled immunoconjugates, although there is still room for improvement. Importantly, this conjugation strategy is highly modular and could be used for the synthesis of a wide range of dual-labeled immunoconjugates.
Référence
Bioconjug Chem. 2022 Mar 1;: