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Reduction of the Renal Radioactivity of (111)In-DOTA-Labeled Antibody Fragments with a Linkage Cleaved by the Renal Brush Border Membrane Enzymes

[Image: see text] The interposition of a cleavable linkage by enzymes on the renal brush border membrane constitutes a promising approach for reducing the renal radioactivity levels of radiolabeled low-molecular-weight antibody fragments and constructs (LMW Abs). Herein, we applied the molecular des...

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Autores principales: Suzuki, Hiroyuki, Araki, Mari, Tatsugi, Kouki, Ichinohe, Kento, Uehara, Tomoya, Arano, Yasushi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10350918/
https://www.ncbi.nlm.nih.gov/pubmed/37322876
http://dx.doi.org/10.1021/acs.jmedchem.3c00258
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author Suzuki, Hiroyuki
Araki, Mari
Tatsugi, Kouki
Ichinohe, Kento
Uehara, Tomoya
Arano, Yasushi
author_facet Suzuki, Hiroyuki
Araki, Mari
Tatsugi, Kouki
Ichinohe, Kento
Uehara, Tomoya
Arano, Yasushi
author_sort Suzuki, Hiroyuki
collection PubMed
description [Image: see text] The interposition of a cleavable linkage by enzymes on the renal brush border membrane constitutes a promising approach for reducing the renal radioactivity levels of radiolabeled low-molecular-weight antibody fragments and constructs (LMW Abs). Herein, we applied the molecular design to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-based reagents for radiotheranostic applications with trivalent radiometals. DOTA or a derivative thereof was conjugated to a Fab through an FGK linkage ([(111)In]In-DO3AiBu-Bn-FGK-Fab or [(111)In]In-DOTA-Bn-FGK-Fab). When injected into mice, both generated radiometabolites, [(111)In]In-DO3AiBu-Bn-F and [(111)In]In-DOTA-Bn-F, by the angiotensin-converting enzyme at similar rates. Both exhibited significantly lower renal radioactivity levels than a (111)In-labeled Fab prepared by the conventional procedure ([(111)In]In-DOTA-Bn-SCN-Fab). The different elimination rates of each radiometabolite from the kidney significantly affected the renal radioactivity levels. [(111)In]In-DO3AiBu-Bn-FGK-Fab preferentially reduced the renal localization without impairing tumor accumulation. These findings would pave the way for developing a DOTA-based radiotheranostic platform for LMW Abs bearing cleavable linkers for renal brush border enzymes.
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spelling pubmed-103509182023-07-18 Reduction of the Renal Radioactivity of (111)In-DOTA-Labeled Antibody Fragments with a Linkage Cleaved by the Renal Brush Border Membrane Enzymes Suzuki, Hiroyuki Araki, Mari Tatsugi, Kouki Ichinohe, Kento Uehara, Tomoya Arano, Yasushi J Med Chem [Image: see text] The interposition of a cleavable linkage by enzymes on the renal brush border membrane constitutes a promising approach for reducing the renal radioactivity levels of radiolabeled low-molecular-weight antibody fragments and constructs (LMW Abs). Herein, we applied the molecular design to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-based reagents for radiotheranostic applications with trivalent radiometals. DOTA or a derivative thereof was conjugated to a Fab through an FGK linkage ([(111)In]In-DO3AiBu-Bn-FGK-Fab or [(111)In]In-DOTA-Bn-FGK-Fab). When injected into mice, both generated radiometabolites, [(111)In]In-DO3AiBu-Bn-F and [(111)In]In-DOTA-Bn-F, by the angiotensin-converting enzyme at similar rates. Both exhibited significantly lower renal radioactivity levels than a (111)In-labeled Fab prepared by the conventional procedure ([(111)In]In-DOTA-Bn-SCN-Fab). The different elimination rates of each radiometabolite from the kidney significantly affected the renal radioactivity levels. [(111)In]In-DO3AiBu-Bn-FGK-Fab preferentially reduced the renal localization without impairing tumor accumulation. These findings would pave the way for developing a DOTA-based radiotheranostic platform for LMW Abs bearing cleavable linkers for renal brush border enzymes. American Chemical Society 2023-06-16 /pmc/articles/PMC10350918/ /pubmed/37322876 http://dx.doi.org/10.1021/acs.jmedchem.3c00258 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Suzuki, Hiroyuki
Araki, Mari
Tatsugi, Kouki
Ichinohe, Kento
Uehara, Tomoya
Arano, Yasushi
Reduction of the Renal Radioactivity of (111)In-DOTA-Labeled Antibody Fragments with a Linkage Cleaved by the Renal Brush Border Membrane Enzymes
title Reduction of the Renal Radioactivity of (111)In-DOTA-Labeled Antibody Fragments with a Linkage Cleaved by the Renal Brush Border Membrane Enzymes
title_full Reduction of the Renal Radioactivity of (111)In-DOTA-Labeled Antibody Fragments with a Linkage Cleaved by the Renal Brush Border Membrane Enzymes
title_fullStr Reduction of the Renal Radioactivity of (111)In-DOTA-Labeled Antibody Fragments with a Linkage Cleaved by the Renal Brush Border Membrane Enzymes
title_full_unstemmed Reduction of the Renal Radioactivity of (111)In-DOTA-Labeled Antibody Fragments with a Linkage Cleaved by the Renal Brush Border Membrane Enzymes
title_short Reduction of the Renal Radioactivity of (111)In-DOTA-Labeled Antibody Fragments with a Linkage Cleaved by the Renal Brush Border Membrane Enzymes
title_sort reduction of the renal radioactivity of (111)in-dota-labeled antibody fragments with a linkage cleaved by the renal brush border membrane enzymes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10350918/
https://www.ncbi.nlm.nih.gov/pubmed/37322876
http://dx.doi.org/10.1021/acs.jmedchem.3c00258
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