89Zr as a PET surrogate radioisotope for scouting biodistribution of the therapeutic radiometals 90Y and 177Lu in tumor-bearing nude mice after coupling to the internalizing antibody cetuximab

Lars R. Perk, Gerard W.M. Visser, Maria J.W.D. Vosjan, Marijke Stigter-Van Walsum, Bernard M. Tijink, C. René Leemans, Guus A.M.S. Van Dongen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Immuno-PET as a scouting procedure before radioimmunotherapy (RIT) aims at confirming tumor targeting and accurately estimating radiation dose delivery to both tumor and normal tissues and might therefore be of value for selection of patient candidates for RIT. A prerequisite for this approach is that PET radioimmunoconjugates and RIT radioimmunoconjugates must show a similar biodistribution. In the present study, we evaluated the potential of the long-lived positron emitter 89Zr to predict biodistribution of the residualizing therapeutic radiometals 88Y (as a substitute for 90Y) and 177Lu when labeled to the monoclonal antibody (mAb) cetuximab via different types of chelates. Cetuximab was selected as a model mAb because it abundantly internalizes after binding to the epidermal growth factor receptor. Methods: Cetuximab was labeled with 89Zr using succinylated desferrioxamine B (N-sucDf). The chelates p-benzyl isothiocyanate-1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (p-SCN-Bz-DOTA) and p-isothiocyanatobenzyl diethylenetriaminepentaacetic acid (p-SCN-Bz-DTPA) were both used for radiolabeling with 88Y and 177Lu. For measurement of the in vitro stability of each of the 5 radioimmuno-conjugates, samples were incubated in freshly prepared human serum at 37°C up to 16 d. Biodistribution was assessed at 24, 48, 72, and 144 h after intraperitoneal coinjection of the PET and RIT conjugates in nude mice bearing the squamous cell carcinoma xenograft line A431. Results: Cetuximab premodification with N-sucDf, p-SCN-Bz-DOTA, or p-SCN-Bz-DTPA resulted in chelate-to-mAb molar ratios of about 1. After radiolabeling and purification, the radiochemical purity and immunoreactive fraction of the conjugates always exceeded 97% and 93%, respectively. All conjugates were stable in serum, showing a radioactivity release of less than 5% until day 7. From day 7 until day 16, an enhanced release was observed for the 89Zr-N-sucDf, 88Y-p-SCN-Bz-DTPA, and 177Lu-p-SCN-Bz-DTPA conjugates. The coinjected PET and RIT conjugates showed similar biodistributions, except for the thighbone and sternum. For example, the 89Zr-N-sucDf conjugate showed a 2.0-2.5 times higher radioactivity accretion in the thighbone than did the RIT conjugates at 72 h after injection. Conclusion: In view of the advantages of PET over SPECT, 89Zr-immuno-PET is a promising modality for in vivo scouting of 90Y- and 177Lu-labeled mAbs, although care should be taken when estimating bone marrow doses.

Original languageEnglish
Pages (from-to)1898-1906
Number of pages9
JournalJournal of Nuclear Medicine
Volume46
Issue number11
Publication statusPublished - 1 Nov 2005

Cite this