<br>超越异硫氰酸盐：看看 89Zr 标记的免疫偶联物中放射性分解的偶联联系的稳定性,Bioconjugate Chemistry

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超越异硫氰酸盐：看看 89Zr 标记的免疫偶联物中放射性分解的偶联联系的稳定性
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2024-04-24 , DOI: 10.1021/acs.bioconjchem.4c00105
Romane Vizier ₁ , Pierre Adumeau ₁ , Mathieu Moreau ₁ , Victor Goncalves ₁ , Franck Denat ₁

Affiliation

锆 89 是免疫 PET 中使用最广泛的放射性同位素，因为它的物理半衰期（78.2 h）适合抗体的半衰期。去铁胺 B （DFO）是锆（IV）络合的标准螯合剂，其双功能版本含有苯基异硫氰酸酯官能团，是 DFO 与蛋白质偶联最常用的。然而，初步结果表明，从异硫氰酸酯和赖氨酸共轭中获得的硫脲键对放射性同位素产生的电离辐射敏感，导致键断裂和螯合剂/放射性金属络合物的释放。这种放射分解现象会产生非特异性信号并阻止骨转移的检测，因为游离锆会积聚到骨骼中。这项工作的目的是研究 ⁸⁹种 Zr 标记的免疫偶联物中一系列偶联接头的稳定性。我们已经合成了几种基于 DFO 的双功能螯合剂，它们附加有异硫氰酸酯部分、双环壬炔或角酸酯。两种抗体（trastuzumab 和 rituximab）偶联并用锆 89 进行放射性标记。评估了锆 89 活性增加对带有硫脲连接的生物共轭物完整性的影响以及放射防护剂存在的影响。在 PBS 和人血浆中研究了放射性标记抗体的稳定性 7 天。使用 iTLC 和尺寸排阻色谱评估放射性偶联物的完整性。这项研究表明，螯合剂和生物分子之间接头的性质会对 ⁸⁹个 Zr 标记偶联物的稳定性以及偶联物的聚集产生重大影响。

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

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.

更新日期：2024-04-24

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