TY - JOUR
T1 - Head-to-head comparison of DFO* and DFO chelators
T2 - selection of the best candidate for clinical 89Zr-immuno-PET
AU - Chomet, Marion
AU - Schreurs, Maxime
AU - Bolijn, Maria J.
AU - Verlaan, Mariska
AU - Beaino, Wissam
AU - Brown, Kari
AU - Poot, Alex J.
AU - Windhorst, Albert D.
AU - Gill, Herman
AU - Marik, Jan
AU - Williams, Simon
AU - Cowell, Joseph
AU - Gasser, Gilles
AU - Mindt, Thomas L.
AU - van Dongen, Guus A. M. S.
AU - Vugts, Danielle J.
N1 - Funding Information: Open access funding provided by Amsterdam UMC (Vrije Universiteit Amsterdam). This research has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska–Curie grant agreement no. 675417. This work was funded by the Swiss National Science Foundation (grant Nr. SNSF 205321_157216 to G.G. and T.L.M.). Acknowledgements Publisher Copyright: © 2020, The Author(s).
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - Bone metastasis model
KW - DFO
KW - DFO
KW - DFOSq
KW - DFOSq
KW - Zr-immuno-PET
UR - http://www.scopus.com/inward/record.url?scp=85090305630&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00259-020-05002-7
DO - https://doi.org/10.1007/s00259-020-05002-7
M3 - Article
C2 - 32889615
SN - 1619-7070
VL - 48
SP - 694
EP - 707
JO - European journal of nuclear medicine and molecular imaging
JF - European journal of nuclear medicine and molecular imaging
IS - 3
ER -