In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft

Wouter B. Nagengast, Elisabeth G. De Vries, Geke A. Hospers, Nanno H. Mulder, Johan R. De Jong, Harry Hollema, Adrienne H. Brouwers, Guus A. Van Dongen, Lars R. Perk, Marjolijn N. Lub-de Hooge

Research output: Contribution to journalArticleAcademicpeer-review

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 γ-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 39Zr-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.

Original languageEnglish
Pages (from-to)1313-1319
Number of pages7
JournalJournal of Nuclear Medicine
Volume48
Issue number8
DOIs
Publication statusPublished - 1 Aug 2007

Cite this

Nagengast, W. B., De Vries, E. G., Hospers, G. A., Mulder, N. H., De Jong, J. R., Hollema, H., ... Lub-de Hooge, M. N. (2007). In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft. Journal of Nuclear Medicine, 48(8), 1313-1319. https://doi.org/10.2967/jnumed.107.041301
Nagengast, Wouter B. ; De Vries, Elisabeth G. ; Hospers, Geke A. ; Mulder, Nanno H. ; De Jong, Johan R. ; Hollema, Harry ; Brouwers, Adrienne H. ; Van Dongen, Guus A. ; Perk, Lars R. ; Lub-de Hooge, Marjolijn N. / In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft. In: Journal of Nuclear Medicine. 2007 ; Vol. 48, No. 8. pp. 1313-1319.
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title = "In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft",
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 γ-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 39Zr-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.",
keywords = "Bevacizumab, In vivo, Small-animal PET, VEGF, Xenograft",
author = "Nagengast, {Wouter B.} and {De Vries}, {Elisabeth G.} and Hospers, {Geke A.} and Mulder, {Nanno H.} and {De Jong}, {Johan R.} and Harry Hollema and Brouwers, {Adrienne H.} and {Van Dongen}, {Guus A.} and Perk, {Lars R.} and {Lub-de Hooge}, {Marjolijn N.}",
year = "2007",
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language = "English",
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pages = "1313--1319",
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Nagengast, WB, De Vries, EG, Hospers, GA, Mulder, NH, De Jong, JR, Hollema, H, Brouwers, AH, Van Dongen, GA, Perk, LR & Lub-de Hooge, MN 2007, 'In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft' Journal of Nuclear Medicine, vol. 48, no. 8, pp. 1313-1319. https://doi.org/10.2967/jnumed.107.041301

In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft. / Nagengast, Wouter B.; De Vries, Elisabeth G.; Hospers, Geke A.; Mulder, Nanno H.; De Jong, Johan R.; Hollema, Harry; Brouwers, Adrienne H.; Van Dongen, Guus A.; Perk, Lars R.; Lub-de Hooge, Marjolijn N.

In: Journal of Nuclear Medicine, Vol. 48, No. 8, 01.08.2007, p. 1313-1319.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft

AU - Nagengast, Wouter B.

AU - De Vries, Elisabeth G.

AU - Hospers, Geke A.

AU - Mulder, Nanno H.

AU - De Jong, Johan R.

AU - Hollema, Harry

AU - Brouwers, Adrienne H.

AU - Van Dongen, Guus A.

AU - Perk, Lars R.

AU - Lub-de Hooge, Marjolijn N.

PY - 2007/8/1

Y1 - 2007/8/1

N2 - 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 γ-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 39Zr-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.

AB - 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 γ-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 39Zr-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.

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KW - In vivo

KW - Small-animal PET

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KW - Xenograft

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Nagengast WB, De Vries EG, Hospers GA, Mulder NH, De Jong JR, Hollema H et al. In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft. Journal of Nuclear Medicine. 2007 Aug 1;48(8):1313-1319. https://doi.org/10.2967/jnumed.107.041301