Pretargeted PET imaging using a site-specifically labeled immunoconjugate Journal Article
| Authors: | Cook, B. E.; Adumeau, P.; Membreno, R.; Carnazza, K. E.; Brand, C.; Reiner, T.; Agnew, B. J.; Lewis, J. S.; Zeglis, B. M. |
| Article Title: | Pretargeted PET imaging using a site-specifically labeled immunoconjugate |
| Abstract: | In recent years, both site-specific bioconjugation techniques and bioorthogonal pretargeting strategies have emerged as exciting technologies with the potential to improve the safety and efficacy of antibody-based nuclear imaging. In the work at hand, we have combined these two approaches to create a pretargeted PET imaging strategy based on the rapid and bioorthogonal inverse electron demand Diels-Alder reaction between a 64Cu-labeled tetrazine radioligand (64Cu-Tz-SarAr) and a site-specifically modified huA33-trans-cyclooctene immunoconjugate (sshuA33-PEG12-TCO). A bioconjugation strategy that harnesses enzymatic transformations and strain-promoted azide-alkyne click chemistry was used to site-specifically append PEGylated TCO moieties to the heavy chain glycans of the colorectal cancer-targeting huA33 antibody. Preclinical in vivo validation studies were performed in athymic nude mice bearing A33 antigen-expressing SW1222 human colorectal carcinoma xenografts. To this end, mice were administered sshuA33-PEG12-TCO via tail vein injection and - following accumulation intervals of 24 or 48 h - 64Cu-Tz-SarAr. PET imaging and biodistribution studies reveal that this strategy clearly delineates tumor tissue as early as 1 h post-injection (6.7 ± 1.7%ID/g at 1 h p.i.), producing images with excellent contrast and high tumor-to-background activity concentration ratios (tumor:muscle = 21.5 ± 5.6 at 24 h p.i.). Furthermore, dosimetric calculations illustrate that this pretargeting approach produces only a fraction of the overall effective dose (0.0214 mSv/MBq; 0.079 rem/mCi) of directly labeled radioimmunoconjugates. Ultimately, this method effectively facilitates the high contrast pretargeted PET imaging of colorectal carcinoma using a site-specifically modified immunoconjugate. © 2016 American Chemical Society. |
| Journal Title: | Bioconjugate Chemistry |
| Volume: | 27 |
| Issue: | 8 |
| ISSN: | 1043-1802 |
| Publisher: | American Chemical Society |
| Date Published: | 2016-08-17 |
| Start Page: | 1789 |
| End Page: | 1795 |
| Language: | English |
| DOI: | 10.1021/acs.bioconjchem.6b00235 |
| PROVIDER: | scopus |
| PUBMED: | 27356886 |
| PMCID: | PMC5102008 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 October 2016 -- Source: Scopus |
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