Establishment of the in vivo efficacy of pretargeted radioimmunotherapy utilizing inverse electron demand Diels-Alder click chemistry Journal Article


Authors: Houghton, J. L.; Membreno, R.; Abdel-Atti, D.; Cunanan, K. M.; Carlin, S.; Scholz, W. W.; Zanzonico, P. B.; Lewis, J. S.; Zeglis, B. M.
Article Title: Establishment of the in vivo efficacy of pretargeted radioimmunotherapy utilizing inverse electron demand Diels-Alder click chemistry
Abstract: The pretargeting system based on the inverse electron demand Diels-Alder reaction (IEDDA) between trans-cyclooctene (TCO) and tetrazine (Tz) combines the favorable pharmacokinetic properties of radiolabeled small molecules with the affinity and specificity of antibodies. This strategy has proven to be an efficient method for the molecularly targeted delivery of pharmaceuticals, including isotopes for radiological imaging. Despite encouraging results from in vivo PET imaging studies, this promising system has yet to be thoroughly evaluated for pretargeted radioimmunotherapy (PRIT). Toward that end, we synthesized two novel 177Lu-labeled tetrazinebearing radioligands. Next, we compared the usefulness of our ligands for PRIT when paired with TCO-modified 5B1-a human, anti-CA19.9 mAb-in preclinical murine models of pancreatic cancer. The exemplary ligand, 177Lu-DOTA-PEG7 -Tz, showed rapid (4.6 0.8% ID/g at 4 hours) and persistent (16.8 3.9% ID/g at 120 hours) uptake in tumors while concurrently clearing from blood and nontarget tissues. Single-dose therapy studies using 5B1-TCO and varying amounts of 177Lu-DOTA-PEG7-Tz (400, 800, and 1,200 mCi) showed that our system elicits a dose-dependent therapeutic response in mice bearing human xenografts. Furthermore, dosimetry calculations suggest that our approach is amenable to clinical applications with its excellent dosimetric profile in organs of clearance (i.e., liver and kidneys) as well as in dose-limiting tissues, such as red marrow. This study established that a pretargeted methodology utilizing the IEDDA reaction can rapidly and specifically deliver a radiotherapeutic payload to tumor tissue, thus illustrating its excellent potential for clinical translation. © 2016 American Association for Cancer Research.
Journal Title: Molecular Cancer Therapeutics
Volume: 16
Issue: 1
ISSN: 1535-7163
Publisher: American Association for Cancer Research  
Date Published: 2017-01-01
Start Page: 124
End Page: 133
Language: English
DOI: 10.1158/1535-7163.mct-16-0503
PROVIDER: scopus
PMCID: PMC5221649
PUBMED: 28062708
DOI/URL:
Notes: Article -- Export Date: 2 February 2017 -- Source: Scopus
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MSK Authors
  1. Pat B Zanzonico
    299 Zanzonico
  2. Brian Zeglis
    87 Zeglis
  3. Jason S Lewis
    360 Lewis
  4. Sean Denis Carlin
    83 Carlin
  5. Kristen   Cunanan
    16 Cunanan