Modular strategy for the construction of radiometalated antibodies for positron emission tomography based on inverse electron demand diels-alder click chemistry Journal Article
| Authors: | Zeglis, B. M.; Mohindra, P.; Weissmann, G. I.; Divilov, V.; Hilderbrand, S. A.; Weissleder, R.; Lewis, J. S. |
| Article Title: | Modular strategy for the construction of radiometalated antibodies for positron emission tomography based on inverse electron demand diels-alder click chemistry |
| Abstract: | 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 64Cu and 89Zr 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 64Cu and 89Zr, 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 64Cu-DOTA- and 89Zr-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 64Cu- and 89Zr-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. © 2011 American Chemical Society. |
| Keywords: | controlled study; unclassified drug; human cell; drug activity; nonhuman; positron emission tomography; radiopharmaceuticals; neoplasms; mouse; animals; mice; animal experiment; animal model; in vivo study; drug structure; tumor xenograft; cell line, tumor; drug distribution; isotope labeling; mice, nude; positron-emission tomography; antibody specificity; receptor, erbb-2; trastuzumab; diels alder reaction; copper 64; 1,4,7,10 tetraazacyclododecane 1,4,7,10 tetraacetic acid; drug conjugation; zirconium 89; zirconium derivative; deferoxamine; antibody production; electron; click chemistry; cycloaddition; alnus; heterocyclic compounds, 1-ring; chelating agent; antibodies, monoclonal, humanized; norbornene derivative; tetrazine derivative; norbornanes |
| Journal Title: | Bioconjugate Chemistry |
| Volume: | 22 |
| Issue: | 10 |
| ISSN: | 1043-1802 |
| Publisher: | American Chemical Society |
| Date Published: | 2011-10-19 |
| Start Page: | 2048 |
| End Page: | 2059 |
| Language: | English |
| DOI: | 10.1021/bc200288d |
| PROVIDER: | scopus |
| PMCID: | PMC3197258 |
| PUBMED: | 21877749 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 9 December 2011" - "CODEN: BCCHE" - "Source: Scopus" |
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