Dendrimer scaffold for the amplification of in vivo pretargeting ligations Journal Article
| Authors: | Cook, B. E.; Membreno, R.; Zeglis, B. M. |
| Article Title: | Dendrimer scaffold for the amplification of in vivo pretargeting ligations |
| Abstract: | The development of immunoconjugates requires a careful balance between preserving the functionality of the antibody and modifying the immunoglobulin with the desired cargo. Herein, we describe the synthesis, development, and in vivo evaluation of a novel bifunctional dendrimeric scaffold and its application in pretargeted PET imaging. The site-specific modification of the huA33 antibody with this dendrimeric scaffold yields an immunoconjugate-(ss)huA33-DEN-TCO-decorated with similar to 8 trans-cyclooctene (TCO) moieties, a marked increase compared to the similar to 2 TCO/mAb of a nondendrimeric control immunoconjugate ((ss)huA33-PEG(12)-TCO). Pretargeted PET imaging and biodistribution experiments were used to compare the in vivo performance of these two immunoconjugates in athymic nude mice bearing subcutaneous SW1222 human colorectal cancer xenografts. To this end, the mice were administered 100 mu g of each immunoconjugate followed 120 h later by the injection of a tetrazine-bearing radioligand, [Cu-64]Cu-SarAr-Tz. Pretargeting with (ss)huA33-DEN-TCO produced excellent tumoral uptake at 24 h (8.9 +/- 1.9 %ID/g), more than double that created by (ss)huA33-PEG(12)-TCO (4.1 +/- 1.3 %ID/g). Critically-and somewhat surprisingly-the attachment of the G(0.5) dendrimeric structures did not hamper the in vivo behavior of the immunoconjugate, suggesting that this versatile bifunctional scaffold may have applications beyond pretargeting. |
| Keywords: | immunoreactivity; radioimmunotherapy; optimization; conjugation; monoclonal-antibody; strategy; in-111; alder click chemistry; metal-chelating polymers; c-11-labeled tetrazine |
| Journal Title: | Bioconjugate Chemistry |
| Volume: | 29 |
| Issue: | 8 |
| ISSN: | 1043-1802 |
| Publisher: | American Chemical Society |
| Date Published: | 2018-08-15 |
| Start Page: | 2734 |
| End Page: | 2740 |
| Language: | English |
| ACCESSION: | WOS:000442185500025 |
| DOI: | 10.1021/acs.bioconjchem.8b00385 |
| PROVIDER: | wos |
| PUBMED: | 29969558 |
| PMCID: | PMC6432625 |
| Notes: | Article -- Source: Wos |
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