Page 25 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Dosimetry of immuno-PET with 89Zr-cmAb U36
INTRODUCTION
Monoclonal antibodies (mAbs) have been approved for use as diagnostics and therapeutics in a broad range of medical indications, but especially in oncology 2 (1). Immuno-PET, the tracking and quantification of mAbs with PET in vivo, is an
exciting novel option to improve diagnostic imaging and to guide mAb-based
therapy (2-6).
To enable PET imaging of mAbs , an appropriate positron emitter, with a half-life (t1/2) that is compatible with the time needed to achieve optimal tumor-to- nontumor ratios (typically 2-4 days for intact mAbs), has to be securely coupled to the targeting molecule. 124I (t1/2 100.3 h) and 89Zr (t1/2 78.4 h) are particularly suitable in combination with intact mAbs, because their long half-lives allow imaging at late time points for obtaining maximum information. While the non-residualizing positron emitter 124I is particular suitable for immuno-PET when used in combination with non-internalizing intact mAbs, the residualizing positron emitter 89Zr may be optimal in combination with internalizing intact mAbs, since 89Zr stays in the targeted cell (“residualization”) after intracellular catabolism of the radioimmunoconjugate (7). 89Zr can also be used as a PET surrogate label for prediction of the biodistribution and dosimetry of 177Lu-mAb and 90Y-mAb conjugates as used in radioimmunotherapy trials, although deviations have to be anticipated due to subtle differences in the metal-chelate complexes used (8,9).
While first clinical immuno-PET studies with 124I-labeled mAbs have been performed about 15 years ago, technology for 89Zr-immuno-PET became available just recently (10). For this purpose, we developed the large scale production of pure 89Zr and a strategy for labeling mAbs with 89Zr via a multi-step synthesis using a succinylated-derivative of desferrioxamine B (Df) as bifunctional chelate (10). Labeling technology is universal and, therefore, can be used for each individual mAb or other type of protein. In the mean time, several preclinical immuno-PET studies have been performed with 89Zr-labeled mAbs as prelude to clinical trials, for example with chimeric (mouse/human) mAb (cmAb) U36 (anti- CD44v6) (10), DN30 (anti-cMet) (11), G250 (anti-carbonic anhydrase IX)(12), ibritumomab tiuxetan and rituximab (anti-CD20)(9), bevacizumab (anti-VEGF) (13), cetuximab (anti-epidermal growth factor receptor)(8,14), and trastuzumab (anti-human epidermal growth factor receptor-2)(15).
In a first-in-man 89Zr-immuno-PET clinical trial, we recently determined the diagnostic value of immuno-PET with anti-CD44v6 89Zr-cmAb U36 in patients
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