Toward the optimization of click-mediated pretargeted radioimmunotherapy Journal Article
| Authors: | Membreno, R.; Keinänen, O. M.; Cook, B. E.; Tully, K. M.; Fung, K. C.; Lewis, J. S.; Zeglis, B. M. |
| Article Title: | Toward the optimization of click-mediated pretargeted radioimmunotherapy |
| Abstract: | Pretargeted radioimmunotherapy (PRIT) based on the inverse electron demand Diels-Alder reaction has shown promise in murine models of disease, yet the radiation dosimetry of this approach must be optimized to make it a viable clinical option. To this end, we have leveraged two recent developments in pretargeted imaging - dendritic scaffolds and masking agents - to improve the dosimetric profile of a proof-of-concept PRIT system that is based on the huA33 antibody, a 177 Lu-labeled tetrazine radioligand ([ 177 Lu]Lu-DOTA-PEG 7 -Tz), and a mouse model of A33 antigen-expressing colorectal carcinoma. Pretargeting using an huA33 immunoconjugate bearing a trans-cyclooctene-decorated dendritic scaffold ( ss huA33-DEN-TCO) produced significantly higher tumoral activity concentrations at 120 h post-injection (23.0 ± 2.2 %ID/g) than those achieved with an analogous, dendrimer-lacking immunoconjugate (12.7 ± 2.6 %ID/g). However, pretargeting using ss huA33-DEN-TCO also resulted in increased activity concentrations in the blood at the same time point (1.9 ± 0.4 %ID/g) compared to the dendrimer-lacking construct (0.7 ± 0.2 %ID/g), thereby curtailing improvements to the tumor-to-blood therapeutic ratio of the system. In order to circumvent this issue, a tetrazine-labeled, dextran-based masking agent (Tz-DP) was injected prior to the radioligand to prevent the ligation between [ 177 Lu]Lu-DOTA-PEG 7 -Tz and circulating immunoconjugate. This approach dramatically decreased the absorbed dose to the blood but also attenuated the absorbed dose to the tumor and increased the absorbed dose to the lungs. Ultimately, these data suggest that dendritic scaffolds and masking agents could be used to improve the dosimetry of PRIT, but the combination of these technologies will require extensive optimization. © Copyright 2019 American Chemical Society. |
| Keywords: | colorectal cancer; radioimmunotherapy; click chemistry; dendrimer; pretargeted radioimmunotherapy; pretargeting; tetrazine; lu-177; trans-cyclooctene; inverse electron demand diels-alder reaction; masking agent |
| Journal Title: | Molecular Pharmaceutics |
| Volume: | 16 |
| Issue: | 5 |
| ISSN: | 1543-8384 |
| Publisher: | American Chemical Society |
| Date Published: | 2019-05-06 |
| Start Page: | 2259 |
| End Page: | 2263 |
| Language: | English |
| DOI: | 10.1021/acs.molpharmaceut.9b00062 |
| PUBMED: | 30912951 |
| PROVIDER: | scopus |
| PMCID: | PMC7047588 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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