Pretargeted PET Imaging Using a Site-Specifically Labeled Immunoconjugate

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• 作者：Brendon E. Cook ; Pierre Adumeau ; Rosemery Membreno ; Kathryn E. Carnazza ; Christian Brand ; Thomas Reiner ; Brian J. Agnew ; Jason S. Lewis ; Brian M. Zeglis
• 刊名：Bioconjugate Chemistry
• 出版年：2016
• 出版时间：August 17, 2016
• 年：2016
• 卷：27
• 期：8
• 页码：1789-1795
• 全文大小：361K
• 年卷期：0
• ISSN：1520-4812

文摘

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.