Review emphasizes the growing importance of 89Zr applications in individualized radioimmunotherapy

Over the past few years, immunoPET applications using 89Zr-labeled antibodies have greatly increased in number and scope. To recap the information available so far, researchers from the Radboud University Medical Center* (The Netherlands) and of the Université Bourgogne Franche-Comté (Dijon, France) have jointly authored a vast review covering the main medical applications of 89Zr-immunoPET as well as manufacturing aspects of 89Zr labeling for this end. The review, published on Bioconjugate Chemistry, is currently available ahead of print [1].

The review emphasizes the various favorable uses of 89Zr-immunoPET, which have spoken for themselves in recent years. Among others, the approach has been successfully used in cancer imaging, where it provides relevant information on the pharmacokinetics and tumor-targeting properties of monoclonal antibodies (mAbs) and can predict treatment toxicity. In addition, 89Zr-immunoPET enables the non-invasive assessment of target antigen expression in tumors and normal tissues; thus, it may be relevant for clinical monitoring, as such expression may change throughout disease progression or treatment. Last but not least, 89Zr-immunoPET has enabled the molecular characterization of tumors and an accurate dose planning for individualized radioimmunotherapy, which may be helpful for patient selection and monitoring of early response for targeted therapies.

Improved 89Zr Chelators
Despite all this potential of 89Zr-immunoPET, the authors argue that the currently available chelators needed for the preparation of 89Zr-radiotracers are suboptimal from a chemical point of view. An ideal 89Zr-labeled antibody for immunoPET should fulfill some criteria, among which: no release of 89Zr. However, the most commonly employed chelator for 89Zr, desferrioxamine (DFO), evinces flaws in this regard: Preclinical studies have shown that the 89Zr-DFO complex is partly unstable in vivo, resulting in 89Zr release from the chelator and subsequent accumulation in bone. Such bone accumulation hinders the accurate interpretation and quantification of bone uptake on PET images. These and other issues have prompted various research groups to identify improved 89Zr chelators in the past three years.

Extended DFO
Although DFO is now recognized to be a suboptimal chelator for 89Zr, the developed alternatives – e.g. extended DFO, such as DFO* or DFO-Sq, hydroxypyridinone, or DOTA – have not been completely satisfying either. Still, all of the invested work has contributed to better understand the important features that a good chelator candidate must exhibit. Based on the recent advances in the field, there seems to be room for improvement in the development of chelators and novel bioconjugation approaches to facilitate the development of ever more efficient 89Zr immunoconjugates.

* BV Cyclotron VU is the manufacturer of 89Zr used by the Department of Radiology and Nuclear Medicine at the Radboud University Medical Center for diagnostic and research purposes.

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[1] Heskamp S, Raavé R, Boerman O, Rijpkema M, Goncalves V, Denat F. 89Zr-immunoPET in Oncology: State of the art 89Zr-radiochemistry. Bioconj Chem. 2017 Aug 24 [Epub ahead of print]. PMID: 28767228.