Pretargeting of internalizing trastuzumab and cetuximab with a (18)F-tetrazine tracer in xenograft models Journal Article

Authors: Keinänen, O.; Fung, K.; Pourat, J.; Jallinoja, V.; Vivier, D.; Pillarsetty, N. K.; Airaksinen, A. J.; Lewis, J. S.; Zeglis, B. M.; Sarparanta, M.
Article Title: Pretargeting of internalizing trastuzumab and cetuximab with a (18)F-tetrazine tracer in xenograft models
Abstract: Background: Pretargeting-based approaches are being investigated for radioimmunoimaging and therapy applications to reduce the effective radiation burden to the patient. To date, only a few studies have used short-lived radioisotopes for pretargeting of antibodies, and such examples with internalizing antibodies are even rarer. Herein, we have investigated pretargeting methodology using inverse electron-demand Diels-Alder (IEDDA) for tracing two clinically relevant, internalizing monoclonal antibodies, cetuximab and trastuzumab. Results: Bioorthogonal reaction between tetrazine and trans-cyclooctene (TCO) was used for tracing cetuximab and trastuzumab in vivo with a fluorine-18 (t½ = 109.8 min) labelled tracer. TCO-cetuximab or TCO-trastuzumab was administered 24, 48, or 72 h prior to the injection of tracer to A431 or BT-474 tumour-bearing mice, respectively. With cetuximab, the highest tumour-to-blood ratios were achieved when the lag time between antibody and tracer injections was 72 h. With trastuzumab, no difference was observed between different lag times. For both antibodies, the tumour could be clearly visualized in the PET images with the highest tumour uptake of 3.7 ± 0.1%ID/g for cetuximab and 1.5 ± 0.1%ID/g for trastuzumab as quantified by ex vivo biodistribution. In vivo IEDDA reaction was observed in the blood for both antibodies, but with trastuzumab, this was to a much lower degree than with cetuximab. Conclusions: We could successfully visualize the tumours by using cetuximab and trastuzumab in pretargeted PET imaging despite the challenging circumstances where the antibody is internalized and there is still some unbound antibody circulating in the blood flow. This clearly demonstrates the potential of a pretargeted approach for targeting internalizing antigens and warrants development of pharmacokinetic optimization of the biorthogonal reactants to this end. © 2017, The Author(s).
Keywords: controlled study; human cell; squamous cell carcinoma; nonhuman; positron emission tomography; mouse; animal model; immunoreactivity; cetuximab; immunoglobulin g; xenograft; breast carcinoma; radioactivity; trastuzumab; fluorine 18; zirconium 89; size exclusion chromatography; pretargeting; tetrazine derivative; fluorine-18; human; female; priority journal; article; tetrazine; trans-cyclooctene; inverse electron-demand diels-alder (iedda) reaction; human igg; matrix-assisted laser desorption-ionization mass spectrometry
Journal Title: EJNMMI Research
Volume: 7
ISSN: 2191-219X
Publisher: Springer  
Date Published: 2017-12-02
Start Page: 95
Language: English
DOI: 10.1186/s13550-017-0344-6
PROVIDER: scopus
PMCID: PMC5712296
PUBMED: 29198065
Notes: Article -- Export Date: 2 January 2018 -- Source: Scopus
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MSK Authors
  1. Brian Zeglis
    62 Zeglis
  2. Jason S Lewis
    242 Lewis
  3. Jacob   Pourat
    6 Pourat
  4. Kimberly Fung
    1 Fung
  5. Delphine Vivier
    2 Vivier