In Vivo VEGF Imaging with Radiolabeled Bevacizumab in a Human Ovarian Tumor Xenograft

¹ Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
² Department of Nuclear Medicine and Molecular Imaging, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
³ Department of Pathology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
⁴ Department of Nuclear Medicine and PET Research, VU Medical Center, Amsterdam, The Netherlands
⁵ Department of Nuclear Medicine and Molecular Imaging, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands; Department of Hospital and Clinical Pharmacy, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands

^* To whom correspondence should be addressed. E-mail: e.g.e.de.vries{at}int.umcg.nl.

	Abstract

Vascular endothelial growth factor (VEGF), released by tumor cells, is an important growth factor in tumor angiogenesis. The humanized monoclonal antibody bevacizumab blocks VEGF-induced tumor angiogenesis by binding, thereby neutralizing VEGF. Our aim was to develop radiolabeled bevacizumab for noninvasive in vivo VEGF visualization and quantification with the single -emitting isotope ¹¹¹In and the PET isotope ⁸⁹Zr. Methods: Labeling, stability, and binding studies were performed. Nude mice with a human SKOV-3 ovarian tumor xenograft were injected with ⁸⁹Zr-bevacizumab, ¹¹¹In-bevacizumab, or human ⁸⁹Zr-IgG. Human ⁸⁹Zr-IgG served as an aspecific control antibody. Small-animal PET and microCT studies were obtained at 24, 72, and 168 h after injection of ⁸⁹Zr-bevacizumab and ⁸⁹Zr-IgG (3.5 ± 0.5 MBq, 100 ± 6 µg, 0.2 mL [mean ± SD]). Small-animal PET and microCT images were fused to calculate tumor uptake and compared with ex vivo biodistribution at 168 h after injection. ⁸⁹Zr- and ¹¹¹In-bevacizumab ex vivo biodistribution was compared at 24, 72, and 168 h after injection (2.0 ± 0.5 MBq each, 100 ± 4 µg in total, 0.2 mL). Results: Labeling efficiencies, radiochemical purity, stability, and binding properties were optimal for the radioimmunoconjugates. Small-animal PET showed uptake in well-perfused organs at 24 h and clear tumor localization from 72 h onward. Tumor uptake determined by quantification of small-animal PET images was higher for ⁸⁹Zr-bevacizumab--namely, 7.38 ± 2.06 %ID/g compared with 3.39 ± 1.16 %ID/g (percentage injected dose per gram) for human ⁸⁹Zr-IgG (P = 0.011) at 168 h and equivalent to ex vivo biodistribution studies. Tracer uptake in other organs was seen primarily in liver and spleen. ⁸⁹Zr- and ¹¹¹In-bevacizumab biodistribution was comparable. Conclusion: Radiolabeled bevacizumab showed higher uptake compared with radiolabeled human IgG in a human SKOV-3 ovarian tumor xenograft. Noninvasive quantitative small-animal PET was similar to invasive ex vivo biodistribution. Radiolabeled bevacizumab is a new tracer for noninvasive in vivo imaging of VEGF in the tumor microenvironment.

Key Words: VEGF, bevacizumab, small-animal PET, xenograft, in vivo

This article has been cited by other articles:

				M. G.W. Scheer, T. H. Stollman, W. V. Vogel, O. C. Boerman, W. J.G. Oyen, and T. J.M. Ruers Increased Metabolic Activity of Indolent Liver Metastases After Resection of a Primary Colorectal Tumor J. Nucl. Med., June 1, 2008; 49(6): 887 - 891. [Abstract] [Full Text] [PDF]

				W. Cai and X. Chen Multimodality Molecular Imaging of Tumor Angiogenesis J. Nucl. Med., June 1, 2008; 49(Suppl_2): 113S - 128S. [Abstract] [Full Text] [PDF]

				G. A.M.S. van Dongen, G. W.M. Visser, M. N. Lub-de Hooge, E. G. de Vries, and L. R. Perk Immuno-PET: A Navigator in Monoclonal Antibody Development and Applications Oncologist, December 1, 2007; 12(12): 1379 - 1389. [Abstract] [Full Text] [PDF]