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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-09-05

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

ABSTRACT

PurposeAlmost 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.MethodsCetuximab, 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.ConclusionDFO*-mAb conjugates provide lower bone uptake than their DFO analogues; thus, DFO* is a superior candidate for preclinical and clinical 89Zr-immuno-PET. More... »

PAGES

694-707

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00259-020-05002-7

DOI

http://dx.doi.org/10.1007/s00259-020-05002-7

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1130621160

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/32889615


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18 schema:description PurposeAlmost 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.MethodsCetuximab, 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.ConclusionDFO*-mAb conjugates provide lower bone uptake than their DFO analogues; thus, DFO* is a superior candidate for preclinical and clinical 89Zr-immuno-PET.
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25 schema:keywords A431
26 A431 tumor-bearing mice
27 B12
28 BT-474 breast cancer cells
29 DFO chelator
30 DFO conjugates
31 DFO-NCS
32 N87
33 NC
34 NCS
35 PET
36 accurate detection
37 analogues
38 antibodies
39 benefits
40 bone
41 bone metastases
42 bone metastasis model
43 bone metastasis mouse model
44 bone uptake
45 breast cancer cells
46 cancer cells
47 candidates
48 cells
49 cetuximab
50 chelator desferrioxamine
51 chelators
52 comparison
53 complexation
54 complexes
55 conditions
56 conjugates
57 counterparts
58 desferrioxamine
59 detection
60 esters
61 excellent stability
62 experiments
63 formulation solution
64 good candidate
65 head
66 head comparison
67 instability
68 low bone uptake
69 metal complexes
70 metastasis
71 metastasis model
72 metastasis mouse model
73 mice
74 model
75 mouse model
76 novel analogues
77 pilot experiment
78 practical benefits
79 radiolabelling
80 reagents
81 selection
82 serum
83 signals
84 solution
85 stability
86 stable complexation
87 superior candidate
88 superior detection
89 system
90 trastuzumab
91 tumor uptake
92 tumor-bearing mice
93 tumor-specific signals
94 unwanted uptake
95 uptake
96 vitro
97 vivo
98 xenograft model
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