⁸⁹Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art ⁸⁹Zr Radiochemistry

Abstract

Immuno-positron emission tomography (immunoPET) with 89Zr-labeled antibodies has shown great potential in cancer imaging. It can provide important information about the pharmacokinetics and tumor-targeting properties of monoclonal antibodies and may help in anticipating on toxicity. Furthermore, it allows accurate dose planning for individualized radioimmunotherapy and may aid in patient selection and early-response monitoring for targeted therapies. The most commonly used chelator for 89Zr is desferrioxamine (DFO). Preclinical studies have shown that DFO is not an ideal chelator because the 89Zr–DFO complex is partly unstable in vivo, which results in the release of 89Zr from the chelator and the subsequent accumulation of 89Zr in bone. This bone accumulation interferes with accurate interpretation and quantification of bone uptake on PET images. Therefore, there is a need for novel chelators that allow more stable complexation of 89Zr. In this Review, we will describe the most recent developments in 89Zr radiochemistry, including novel chelators and site-specific conjugation methods.

Antibody Fragment and Affibody ImmunoPET Imaging Agents: Radiolabelling Strategies and Applications

“…The longer lived PET radionuclides 89 Zr and 124 I have been used to radiolabel intact antibodies, whilst the faster pharmacokinetics of antibody fragments have enabled the use of the shorter‐lived nuclides 18 F, 64 Cu, 44 Sc and 68 Ga for imaging. The fragment labelling strategy depends on both the particular isotope chosen and the available functionality on the particular fragment for conjugation.…”

“…Zirconium‐89 ( t 1/2 ≈78 h) is a longer lived PET radionuclide that has found applications for the labelling of intact antibodies and for larger antibody fragments such as minibodies and diabodies. The DFO ligand is commonly used to chelate 89 Zr IV , however, studies have demonstrated 89 Zr‐DFO complexes to be unstable in vivo, resulting in 89 Zr release and accumulation of 89 Zr in bone . Despite this, DFO has been mostly used for fragment labelling due to its high chelation yields, mild reaction conditions and reasonable stabilities.…”

“…The longer livedP ET radionuclides 89 Zr and 124 Ih ave been used to radiolabel intact antibodies, [23,24] whilst the faster pharmacokinetics of antibodyf ragments have enabled the use of the shorter-lived nuclides 18 F, 64 Cu, 44 Sc and 68 Ga for imaging. The fragment labelling strategy depends on both the particular isotope chosen and the availablefunctionality on the particular fragment for conjugation.B ecause antibody fragments are large biomolecules and their tertiarys tructures are determined by many complex noncovalent bonds, extreme temperatures, pH and reducing conditions during the radiolabelling process can affect their structurali ntegrity.S electing an appropriate radiolabelling strategy is therefore key to ensuring that the affin- ity and specificity of the antibody fragment is retained.…”

“…The DFO ligand is commonly used to chelate 89 Zr IV , however,s tudies have demonstrated 89 Zr-DFO complexes to be unstablei nv ivo, resulting in 89 Zr releasea nd accumulation of 89 Zr in bone. [23] Despite this, DFO has been mostly used for fragment labelling due to its high chelation yields, mild reac- Figure 5. Cyclic chelators DOTA [14,[72][73][74] and NOTA [75][76][77] that have been conjugated to antibody fragments or affibodies and radiolabelled with gallium-68.…”

Understanding the in vivo fate of radioimmunoconjugates for nuclear imaging

“…Readers interested in these efforts are directed to a comprehensive review by Heskamp et al 131 Though little clinical data is available on the metabolism of 89 Zr-labeled antibodies, it is interesting to note that the bone uptake patterns observed in mice are typically not seen in humans, leading many to believe that DFO is indeed a suitable chelator for 89 Zr in the clinic. 97,[132][133][134][135][136] Studies using 89 Zr-DFO-labeled trastuzumab in HER2-positive esophagogastric adenocarcinoma 136 and 89 Zr-labeled cmAb-U36 antibody in head and neck cancer 131 reported relatively low activity accumulation and retention in the liver and spleen. In contrast, higher activity concentrations were observed in both organs during trials with 89 Zr-huJ591, 97 89 Zrcetuximab, 133 and 89 Zr-rituximab.…”