| Autor: |
Meyer JP; Department of Radiology and ∥Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.; Department of Pharmacology and §Department of Radiology, Weill Cornell Medical College , 1300 York Avenue, New York, New York 10065, United States., Tully KM; Department of Radiology and ∥Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.; Department of Pharmacology and §Department of Radiology, Weill Cornell Medical College , 1300 York Avenue, New York, New York 10065, United States., Jackson J; Department of Radiology and ∥Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.; Department of Pharmacology and §Department of Radiology, Weill Cornell Medical College , 1300 York Avenue, New York, New York 10065, United States., Dilling TR; Department of Radiology and ∥Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.; Department of Pharmacology and §Department of Radiology, Weill Cornell Medical College , 1300 York Avenue, New York, New York 10065, United States., Reiner T; Department of Radiology and ∥Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.; Department of Pharmacology and §Department of Radiology, Weill Cornell Medical College , 1300 York Avenue, New York, New York 10065, United States., Lewis JS; Department of Radiology and ∥Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.; Department of Pharmacology and §Department of Radiology, Weill Cornell Medical College , 1300 York Avenue, New York, New York 10065, United States. |
| Abstrakt: |
Pretargeting strategies have gained popularity for the in vivo imaging and therapy of cancer by combining antibodies with small molecule radioligands. In vivo recombination of both moieties can be achieved using the bioorthogonal inverse electron demand Diels-Alder (IEDDA) chemistry between tetrazine (Tz) and trans-cyclooctene (TCO). An issue that arises with pretargeting strategies is that while part of the antibody dose accumulates at antigen-expressing tumor tissue, there is a significant portion of the injected antibody that remains in circulation, causing a reduction in target-to-background ratios. Herein, we report the development of a novel TCO scavenger, the masking agent DP-Tz. DP-Tz is based on Tz-modified dextran polymers (DP, MW = 0.5-2 MDa). Large dextran polymers were reported to exhibit low penetration of tumor vasculature and appeared nontoxic, nonimmunogenic, and easily modifiable. Our newly developed masking agent deactivates the remaining TCO-moieties on the circulating mAbs yet does not impact the tumor uptake of the Tz-radioligand. In pretargeting studies utilizing a 68 Ga-labeled tetrazine radioligand ([ 68 Ga]Ga-NOTA-PEG 11 -tetrazine), DP-Tz constructs (Tz/DP ratios of 62-254) significantly increased TTB ratios from 0.8 ± 0.3 (control cohorts) to up to 5.8 ± 2.3 at 2 h postinjection. Tumor tissue delineation in PET imaging experiments employing DP-Tz is significantly increased compared to control. Uptake values of other significant organs, such as heart, lungs, pancreas, and stomach, were decreased on average by 2-fold when using DP-Tz. Overall, pretargeting experiments utilizing DP-Tz showed significantly improved tumor delineation, enhanced PET image quality, and reduced uptake in vital organs. We believe that this new masking agent is a powerful new addition to the IEDDA-based pretargeting tool box and, due to its properties, an excellent candidate for clinical translation. |
