Moving Beyond Isothiocyanates: A Look at the Stability of Conjugation Links Toward Radiolysis in 89 Zr-Labeled Immunoconjugates - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Bioconjugate Chemistry Année : 2024

Moving Beyond Isothiocyanates: A Look at the Stability of Conjugation Links Toward Radiolysis in 89 Zr-Labeled Immunoconjugates

Résumé

Zirconium-89 is the most widely used radioisotope for immunoPET because its physical half-life (78.2 h) suits the one of antibodies. Desferrioxamine B (DFO) is the standard chelator for the complexation of zirconium(IV), and its bifunctional version, containing a phenylisothiocyanate function, is the most commonly used for the conjugation of DFO to proteins. However, preliminary results have shown that the thiourea link obtained from the conjugation of isothiocyanate and lysines is sensitive to the ionizing radiation generated by the radioisotope, leading to the rupture of the link and the release of the chelator/radiometal complex. This radiolysis phenomenon could produce nonspecific signal and prevent the detection of bone metastasis, as free zirconium accumulates into the bones. The aim of this work was to study the stability of a selection of conjugation linkers in 89Zr-labeled immunoconjugates. We have synthesized several DFO-based bifunctional chelators appended with an isothiocyanate moiety, a bicyclononyne, or a squaramate ester. Two antibodies (trastuzumab and rituximab) were conjugated and radiolabeled with zirconium-89. The effect of increasing activities of zirconium-89 on the integrity of the bioconjugate bearing thiourea links was evaluated as well as the impact of the presence of a radioprotectant. The stability of the radiolabeled antibodies was studied over 7 days in PBS and human plasma. Radioconjugates’ integrity was evaluated using iTLC and size-exclusion chromatography. This study shows that the nature of the linker between the chelator and biomolecule can have a strong impact on the stability of the 89Zr-labeled conjugates, as well as on the aggregation of the conjugates.
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hal-04562036 , version 1 (30-04-2024)

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Romane Vizier, Pierre Adumeau, Mathieu Moreau, Victor Goncalves, Franck Denat. Moving Beyond Isothiocyanates: A Look at the Stability of Conjugation Links Toward Radiolysis in 89 Zr-Labeled Immunoconjugates. Bioconjugate Chemistry, In press, ⟨10.1021/acs.bioconjchem.4c00105⟩. ⟨hal-04562036⟩
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