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Renal Handling of 99mTc-Labeled Antibody Fab Fragments with a Linkage Cleavable by Enzymes on Brush Border Membrane
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-10-21 , DOI: 10.1021/acs.bioconjchem.0c00541 Tomoya Uehara 1 , Naoki Kanazawa 1 , Chie Suzuki 2 , Yuki Mizuno 1 , Hiroyuki Suzuki 1 , Hirofumi Hanaoka 3 , Yasushi Arano 1
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-10-21 , DOI: 10.1021/acs.bioconjchem.0c00541 Tomoya Uehara 1 , Naoki Kanazawa 1 , Chie Suzuki 2 , Yuki Mizuno 1 , Hiroyuki Suzuki 1 , Hirofumi Hanaoka 3 , Yasushi Arano 1
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The high and persistent renal radioactivity levels after injection of radiolabeled low-molecular-weight polypeptides constitute a significant problem for their diagnostic and therapeutic applications, especially when they are labeled with metallic radionuclides. To improve the renal radioactivity levels of technetium-99m (99mTc)-labeled Fab fragments, a mercaptoacetyltriglycine (MAG3)-based new bifunctional chelating agent with a cleavable glycyl-phenylalanyl-lysine (GFK) linkage, MAG3-GFK-suc-TFP, was designed, synthesized, and evaluated. 99mTc-labeled Fab was obtained by reacting MAG3-GFK-Fab conjugate with 99mTc-glucarate. The GFK linkage remained stable in plasma but was cleaved by enzymes on the renal brush border membrane. The comparative biodistribution studies with indium-111 (111In)-labeled Fab using SCN-CHX-A″-DTPA showed that while both radiolabeled Fabs exhibited similar elimination rates from the blood, [99mTc]Tc-MAG3-GFK-Fab registered much lower renal radioactivity levels from 30 min post-injection onward due to the release and subsequent urinary excretion of [99mTc]Tc-MAG3-Gly. However, [99mTc]Tc-MAG3-GFK-Fab showed an increase in the intestinal radioactivity levels with the time that was not observed with 111In-labeled Fab. The analysis of the intestinal contents suggested the redistribution of [99mTc]Tc-MAG3-Gly to the intestine. The retrospective comparison of [99mTc]Tc-MAG3-GFK-Fab with the radiolabeled Fabs so far prepared under the identical concept suggested that some portion of [99mTc]Tc-MAG3-Gly was generated after the coated vesicle formation and they were excreted into the blood, and subsequently redistributed in the intestine via hepatobiliary excretion. In conclusion, MAG3-GFK-suc-TFP provided 99mTc-labeled Fabs that exhibit low renal radioactivity shortly after injection by the post-labeling procedure. The present study indicated that, contrary to our earlier proposal, the generation of the radiometabolites would proceed not only during the internalization process of the parental antibody fragments but also after coated vesicle formation. This study also showed that the intracellular behaviors of radiometabolites played crucial roles in the elimination rates and the routes of the radioactivity from the kidney.
中文翻译：
肾处理99m Tc标签的抗体Fab片段的连接被酶在刷缘膜上裂解的连接。
注射放射性标记的低分子量多肽后，肾脏的高且持续的放射性水平构成了其诊断和治疗应用的重大问题，尤其是当它们被金属放射性核素标记时。为了提高tech 99m（99m Tc）标记的Fab片段的肾脏放射性水平，基于巯基乙酰基三甘氨酸（MAG 3）的新型双功能螯合剂具有可裂解的甘氨酰-苯丙氨酰-赖氨酸（GFK）键，MAG 3 -GFK-suc -TFP被设计，合成和评估。通过使MAG 3 -GFK-Fab共轭物与99m反应获得99m Tc标记的Fab葡萄糖酸甘油酯。GFK连接在血浆中保持稳定，但被肾刷缘膜上的酶裂解。使用SCN-CHX-A''-DTPA进行铟111（111 In）标记的Fab的比较生物分布研究表明，尽管两种放射性标记的Fab均显示出从血液中的相似消除率，但[ 99m Tc] Tc-MAG 3 -GFK-Fab从注射后30分钟开始，由于[ 99m Tc] Tc-MAG 3 -Gly的释放和随后的尿排泄，肾脏放射性水平大大降低。然而，[ 99m Tc] Tc-MAG 3 -GFK-Fab显示出随着时间的推移，肠道放射性水平增加，而111标记的Fab。肠内容物的分析表明[ 99m Tc] Tc-MAG 3 -Gly在肠中的重新分布。[ 99m Tc] Tc-MAG 3 -GFK-Fab与迄今为止在相同概念下制备的放射性标记Fab的回顾性比较表明，[ 99m Tc] Tc-MAG 3 -Gly的某些部分是在包被的囊泡形成后产生的。它们被排泄到血液中，然后通过肝胆排泄物在肠内重新分布。总之，MAG 3 -GFK-suc-TFP提供了99mTc标记的Fab在注射后不久即表现出较低的肾放射性。本研究表明，与我们先前的提议相反，放射性代谢产物的产生不仅将在亲本抗体片段的内在化过程中进行，而且还将在包被的囊泡形成后进行。这项研究还表明，放射性代谢产物的细胞内行为在肾脏的清除率和放射途径中起着至关重要的作用。
更新日期：2020-11-18
中文翻译：
肾处理99m Tc标签的抗体Fab片段的连接被酶在刷缘膜上裂解的连接。
注射放射性标记的低分子量多肽后，肾脏的高且持续的放射性水平构成了其诊断和治疗应用的重大问题，尤其是当它们被金属放射性核素标记时。为了提高tech 99m（99m Tc）标记的Fab片段的肾脏放射性水平，基于巯基乙酰基三甘氨酸（MAG 3）的新型双功能螯合剂具有可裂解的甘氨酰-苯丙氨酰-赖氨酸（GFK）键，MAG 3 -GFK-suc -TFP被设计，合成和评估。通过使MAG 3 -GFK-Fab共轭物与99m反应获得99m Tc标记的Fab葡萄糖酸甘油酯。GFK连接在血浆中保持稳定，但被肾刷缘膜上的酶裂解。使用SCN-CHX-A''-DTPA进行铟111（111 In）标记的Fab的比较生物分布研究表明，尽管两种放射性标记的Fab均显示出从血液中的相似消除率，但[ 99m Tc] Tc-MAG 3 -GFK-Fab从注射后30分钟开始，由于[ 99m Tc] Tc-MAG 3 -Gly的释放和随后的尿排泄，肾脏放射性水平大大降低。然而，[ 99m Tc] Tc-MAG 3 -GFK-Fab显示出随着时间的推移，肠道放射性水平增加，而111标记的Fab。肠内容物的分析表明[ 99m Tc] Tc-MAG 3 -Gly在肠中的重新分布。[ 99m Tc] Tc-MAG 3 -GFK-Fab与迄今为止在相同概念下制备的放射性标记Fab的回顾性比较表明，[ 99m Tc] Tc-MAG 3 -Gly的某些部分是在包被的囊泡形成后产生的。它们被排泄到血液中，然后通过肝胆排泄物在肠内重新分布。总之，MAG 3 -GFK-suc-TFP提供了99mTc标记的Fab在注射后不久即表现出较低的肾放射性。本研究表明，与我们先前的提议相反，放射性代谢产物的产生不仅将在亲本抗体片段的内在化过程中进行，而且还将在包被的囊泡形成后进行。这项研究还表明，放射性代谢产物的细胞内行为在肾脏的清除率和放射途径中起着至关重要的作用。
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