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⁸⁹Zr Immuno-PET: Comprehensive Procedures for the Production of ⁸⁹Zr-Labeled Monoclonal Antibodies

¹ Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands
² Radionuclide Center, VU University, Amsterdam, The Netherlands
³ Department of Nuclear Medicine/PET Center, VU University Medical Center, Amsterdam, The Netherlands

The use of immuno-PET, the combination of PET with monoclonal antibodies (mAbs), is an attractive option to improve tumor detection and mAb quantification. The long-lived positron emitter ⁸⁹Zr has ideal physical characteristics for immuno-PET, such as a half-life of 3.27 d, which is compatible with the time needed for intact mAbs to achieve optimal tumor-to-nontumor ratios. Thus far, a major limitation in the use of ⁸⁹Zr has been the lack of suitable methods for its stable coupling to mAbs. In this article, practical protocols for reproducible isolation of highly pure ⁸⁹Zr and the production of optimal-quality mAb-⁸⁹Zr conjugates are provided. Methods: ⁸⁹Zr was produced by a (p,n) reaction on natural yttrium (⁸⁹Y), isolated with a hydroxamate column, and used for labeling of premodified mAbs. mAbs were premodified with a novel bifunctional derivative of the chelate desferrioxamine B (Df) via a new linker chemistry. To this end, Df was initially succinylated (N-sucDf), temporarily filled with Fe(III), esterified by use of tetrafluorophenol, and then directly coupled to mAbs. Chimeric mAb (cmAb) U36, directed against head and neck cancer, was used for in vitro and in vivo evaluation. The in vitro stability of cmAb U36-N-sucDf-⁸⁹Zr was assessed in human serum, and its in vivo behavior was evaluated by biodistribution and PET imaging studies in tumor-bearing nude mice. A cmAb U36-Df-⁸⁹Zr conjugate containing a previously described succinimide ring–thioether unit in the linker was used as a reference. Results: ⁸⁹Zr was produced in large batches (6.5–13.5 GBq) and isolated with improved radionuclidic purity (>99.99%) and high yield (>94%). The Df-premodified mAbs gave ⁸⁹Zr-labeling efficiencies of 80% within 30 min, resulting in conjugates with preserved integrity and immunoreactivity. With respect to stability, the novel cmAb U36-N-sucDf-⁸⁹Zr conjugate appeared to be superior to the reference conjugate. In vivo, the novel conjugate demonstrated selective tumor targeting, and on PET images obtained at 24, 48, and 72 h after injection of this conjugate, small tumors in the range of 19–154 mg were readily visualized. Conclusion: Methods were developed for improved purification of the long-lived positron emitter ⁸⁹Zr. Moreover, a novel bifunctional Df chelate was synthesized for the reproducible coupling of ⁸⁹Zr to mAbs. The suitability of such conjugates to detect millimeter-sized tumors in xenograft-bearing nude mice was demonstrated.

Key Words: ⁸⁹Zr • PET • radioimmunoconjugates • tumor detection • xenograft-bearing nude mice

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