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European Journal of Nuclear Medicine and Molecular Imaging
Published in: European Journal of Nuclear Medicine and Molecular Imaging 3/2021

Open Access 01-03-2021 | Bone Metastasis | Original Article

Head-to-head comparison of DFO* and DFO chelators: selection of the best candidate for clinical 89Zr-immuno-PET

Authors: Marion Chomet, Maxime Schreurs, Maria J. Bolijn, Mariska Verlaan, Wissam Beaino, Kari Brown, Alex J. Poot, Albert D. Windhorst, Herman Gill, Jan Marik, Simon Williams, Joseph Cowell, Gilles Gasser, Thomas L. Mindt, Guus A. M. S van Dongen, Danielle J. Vugts

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 3/2021

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Abstract

Purpose

Almost all radiolabellings of antibodies with 89Zr currently employ the hexadentate chelator desferrioxamine (DFO). However, DFO can lead to unwanted uptake of 89Zr in bones due to instability of the resulting metal complex. DFO*-NCS and the squaramide ester of DFO, DFOSq, are novel analogues that gave more stable 89Zr complexes than DFO in pilot experiments. Here, we directly compare these linker-chelator systems to identify optimal immuno-PET reagents.

Methods

Cetuximab, trastuzumab and B12 (non-binding control antibody) were labelled with 89Zr via DFO*-NCS, DFOSq, DFO-NCS or DFO*Sq. Stability in vitro was compared at 37 °C in serum (7 days), in formulation solution (24 h ± chelator challenges) and in vivo with N87 and A431 tumour-bearing mice. Finally, to demonstrate the practical benefit of more stable complexation for the accurate detection of bone metastases, [89Zr]Zr-DFO*-NCS and [89Zr]Zr-DFO-NCS-labelled trastuzumab and B12 were evaluated in a bone metastasis mouse model where BT-474 breast cancer cells were injected intratibially.

Results

[89Zr]Zr-DFO*-NCS-trastuzumab and [89Zr]Zr-DFO*Sq-trastuzumab showed excellent stability in vitro, superior to their [89Zr]Zr-DFO counterparts under all conditions. While tumour uptake was similar for all conjugates, bone uptake was lower for DFO* conjugates. Lower bone uptake for DFO* conjugates was confirmed using a second xenograft model: A431 combined with cetuximab. Finally, in the intratibial BT-474 bone metastasis model, the DFO* conjugates provided superior detection of tumour-specific signal over the DFO conjugates.

Conclusion

DFO*-mAb conjugates provide lower bone uptake than their DFO analogues; thus, DFO* is a superior candidate for preclinical and clinical 89Zr-immuno-PET.
Appendix
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Metadata
Title
Head-to-head comparison of DFO* and DFO chelators: selection of the best candidate for clinical 89Zr-immuno-PET
Authors
Marion Chomet
Maxime Schreurs
Maria J. Bolijn
Mariska Verlaan
Wissam Beaino
Kari Brown
Alex J. Poot
Albert D. Windhorst
Herman Gill
Jan Marik
Simon Williams
Joseph Cowell
Gilles Gasser
Thomas L. Mindt
Guus A. M. S van Dongen
Danielle J. Vugts
Publication date
01-03-2021
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 3/2021
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-020-05002-7

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