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Modular Strategy for the Construction of Radiometalated Antibodies for Positron Emission Tomography Based on Inverse Electron Demand Diels–Alder Click Chemistry
[Image: see text] A modular system for the construction of radiometalated antibodies was developed based on the bioorthogonal cycloaddition reaction between 3-(4-benzylamino)-1,2,4,5-tetrazine and the strained dienophile norbornene. The well-characterized, HER2-specific antibody trastuzumab and the...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2011
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197258/ https://www.ncbi.nlm.nih.gov/pubmed/21877749 http://dx.doi.org/10.1021/bc200288d |
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author | Zeglis, Brian M. Mohindra, Priya Weissmann, Gabriel I. Divilov, Vadim Hilderbrand, Scott A. Weissleder, Ralph Lewis, Jason S. |
author_facet | Zeglis, Brian M. Mohindra, Priya Weissmann, Gabriel I. Divilov, Vadim Hilderbrand, Scott A. Weissleder, Ralph Lewis, Jason S. |
author_sort | Zeglis, Brian M. |
collection | PubMed |
description | [Image: see text] A modular system for the construction of radiometalated antibodies was developed based on the bioorthogonal cycloaddition reaction between 3-(4-benzylamino)-1,2,4,5-tetrazine and the strained dienophile norbornene. The well-characterized, HER2-specific antibody trastuzumab and the positron emitting radioisotopes (64)Cu and (89)Zr were employed as a model system. The antibody was first covalently coupled to norbornene, and this stock of norbornene-modified antibody was then reacted with tetrazines bearing the chelators 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA) or desferrioxamine (DFO) and subsequently radiometalated with (64)Cu and (89)Zr, respectively. The modification strategy is simple and robust, and the resultant radiometalated constructs were obtained in high specific activity (2.7–5.3 mCi/mg). For a given initial stoichiometric ratio of norbornene to antibody, the (64)Cu-DOTA- and (89)Zr-DFO-based probes were shown to be nearly identical in terms of stability, the number of chelates per antibody, and immunoreactivity (>93% in all cases). In vivo PET imaging and acute biodistribution experiments revealed significant, specific uptake of the (64)Cu- and (89)Zr-trastuzumab bioconjugates in HER2-positive BT-474 xenografts, with little background uptake in HER2-negative MDA-MB-468 xenografts or other tissues. This modular system—one in which the divergent point is a single covalently modified antibody stock that can be reacted selectively with various chelators—will allow for both greater versatility and more facile cross-comparisons in the development of antibody-based radiopharmaceuticals. |
format | Online Article Text |
id | pubmed-3197258 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-31972582011-10-19 Modular Strategy for the Construction of Radiometalated Antibodies for Positron Emission Tomography Based on Inverse Electron Demand Diels–Alder Click Chemistry Zeglis, Brian M. Mohindra, Priya Weissmann, Gabriel I. Divilov, Vadim Hilderbrand, Scott A. Weissleder, Ralph Lewis, Jason S. Bioconjug Chem [Image: see text] A modular system for the construction of radiometalated antibodies was developed based on the bioorthogonal cycloaddition reaction between 3-(4-benzylamino)-1,2,4,5-tetrazine and the strained dienophile norbornene. The well-characterized, HER2-specific antibody trastuzumab and the positron emitting radioisotopes (64)Cu and (89)Zr were employed as a model system. The antibody was first covalently coupled to norbornene, and this stock of norbornene-modified antibody was then reacted with tetrazines bearing the chelators 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA) or desferrioxamine (DFO) and subsequently radiometalated with (64)Cu and (89)Zr, respectively. The modification strategy is simple and robust, and the resultant radiometalated constructs were obtained in high specific activity (2.7–5.3 mCi/mg). For a given initial stoichiometric ratio of norbornene to antibody, the (64)Cu-DOTA- and (89)Zr-DFO-based probes were shown to be nearly identical in terms of stability, the number of chelates per antibody, and immunoreactivity (>93% in all cases). In vivo PET imaging and acute biodistribution experiments revealed significant, specific uptake of the (64)Cu- and (89)Zr-trastuzumab bioconjugates in HER2-positive BT-474 xenografts, with little background uptake in HER2-negative MDA-MB-468 xenografts or other tissues. This modular system—one in which the divergent point is a single covalently modified antibody stock that can be reacted selectively with various chelators—will allow for both greater versatility and more facile cross-comparisons in the development of antibody-based radiopharmaceuticals. American Chemical Society 2011-08-31 2011-10-19 /pmc/articles/PMC3197258/ /pubmed/21877749 http://dx.doi.org/10.1021/bc200288d Text en Copyright © 2011 American Chemical Society http://pubs.acs.org This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org. |
spellingShingle | Zeglis, Brian M. Mohindra, Priya Weissmann, Gabriel I. Divilov, Vadim Hilderbrand, Scott A. Weissleder, Ralph Lewis, Jason S. Modular Strategy for the Construction of Radiometalated Antibodies for Positron Emission Tomography Based on Inverse Electron Demand Diels–Alder Click Chemistry |
title | Modular Strategy for the Construction of Radiometalated Antibodies for Positron Emission Tomography Based on Inverse Electron Demand Diels–Alder Click Chemistry |
title_full | Modular Strategy for the Construction of Radiometalated Antibodies for Positron Emission Tomography Based on Inverse Electron Demand Diels–Alder Click Chemistry |
title_fullStr | Modular Strategy for the Construction of Radiometalated Antibodies for Positron Emission Tomography Based on Inverse Electron Demand Diels–Alder Click Chemistry |
title_full_unstemmed | Modular Strategy for the Construction of Radiometalated Antibodies for Positron Emission Tomography Based on Inverse Electron Demand Diels–Alder Click Chemistry |
title_short | Modular Strategy for the Construction of Radiometalated Antibodies for Positron Emission Tomography Based on Inverse Electron Demand Diels–Alder Click Chemistry |
title_sort | modular strategy for the construction of radiometalated antibodies for positron emission tomography based on inverse electron demand diels–alder click chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197258/ https://www.ncbi.nlm.nih.gov/pubmed/21877749 http://dx.doi.org/10.1021/bc200288d |
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