Abstract
PurposeAll clinical 89Zr-immuno-PET studies are currently performed with the chelator desferrioxamine (DFO). This chelator provides hexadentate coordination to zirconium, leaving two coordination sites available for coordination with, e.g., water molecules, which are relatively labile ligands. The unsaturated coordination of DFO to zirconium has been suggested to result in impaired stability of the complex in vivo and consequently in unwanted bone uptake of 89Zr. Aiming at clinical improvements, we report here on a bifunctional isothiocyanate variant of the octadentate chelator DFO* and the in vitro and in vivo comparison of its 89Zr-DFO*-mAb complex with 89Zr-DFO-mAb.MethodsThe bifunctional chelator DFO*-pPhe-NCS was prepared from previously reported DFO* and p-phenylenediisothiocyanate. Subsequently, trastuzumab was conjugated with either DFO*-pPhe-NCS or commercial DFO-pPhe-NCS and radiolabeled with Zr-89 according to published procedures. In vitro stability experiments were carried out in saline, a histidine/sucrose buffer, and blood serum. The in vivo performance of the chelators was compared in N87 tumor-bearing mice by biodistribution studies and PET imaging.ResultsIn 0.9 % NaCl 89Zr-DFO*-trastuzumab was more stable than 89Zr-DFO-trastuzumab; after 72 h incubation at 2-8 °C 95 % and 58 % intact tracer were left, respectively, while in a histidine-sucrose buffer no difference was observed, both products were ≥ 92 % intact. In vivo uptake at 144 h post injection (p.i.) in tumors, blood, and most normal organs was similar for both conjugates, except for skin, liver, spleen, ileum, and bone. Tumor uptake was 32.59 ± 11.95 and 29.06 ± 8.66 % ID/g for 89Zr-DFO*-trastuzumab and 89Zr-DFO-trastuzumab, respectively. The bone uptake was significantly lower for 89Zr-DFO*-trastuzumab compared to 89Zr-DFO-trastuzumab. At 144 h p.i. for 89Zr-DFO*-trastuzumab and 89Zr-DFO-trastuzumab, the uptake in sternum was 0.92 ± 0.16 and 3.33 ± 0.32 % ID/g, in femur 0.78 ± 0.11 and 3.85, ± 0.80 and in knee 1.38 ± 0.23 and 8.20 ± 2.94 % ID/g, respectively. The uptake in bone decreased from 24 h to 144 h p.i. about two fold for the DFO* conjugate, while it increased about two fold for the DFO conjugate.ConclusionsZr-DFO*-trastuzumab showed superior in vitro stability and in vivo performance when compared to 89Zr-DFO-trastuzumab. This makes the new octadentate DFO* chelator a candidate successor of DFO for future clinical 89Zr-immuno-PET.
Highlights
PET imaging with 89Zr-labeled monoclonal antibodies or other targeted vehicles, collectively called 89Zr-immuno-PET, can be used for better understanding of disease targets and the in vivo behavior of targeted drugs [1]. 89Zr is ideally suited for this purpose because its physical half-life of 78.4 h matches the residence time of intact mAbs in the body
We describe the synthesis of the bifunctional DFO*-pPhe-NCS, its coupling to mAbs, and the subsequent labeling with 89Zr
89Zr-DFO*-trastuzumab and 89Zr-DFO-trastuzumab were prepared to postlabeling procedures described by Vosjan et al [6]
Summary
PET imaging with 89Zr-labeled monoclonal antibodies (mAbs) or other targeted vehicles (e.g., peptides, nanoparticles, and cells), collectively called 89Zr-immuno-PET, can be used for better understanding of disease targets and the in vivo behavior of targeted drugs [1]. 89Zr is ideally suited for this purpose because its physical half-life of 78.4 h matches the residence time of intact mAbs in the body (typically several days). PET imaging with 89Zr-labeled monoclonal antibodies (mAbs) or other targeted vehicles (e.g., peptides, nanoparticles, and cells), collectively called 89Zr-immuno-PET, can be used for better understanding of disease targets and the in vivo behavior of targeted drugs [1]. The recent introduction of the generation of mAbs, characterised by increased potency (e.g., antibody-drug conjugates and immune checkpoint inhibiting mAbs), multiple binding domains, and/ or high costs, makes finding answers about their in vivo behavior in individual subjects even more urgent [5].
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