Tumor accumulation of radiolabeled bevacizumab due to targeting of cell- and matrix-associated VEGF-A isoforms.
OBJECTIVE
Vascular endothelial growth factor-A (VEGF-A) is one of the most important factors inducing angiogenesis in tumors. Nine splice-variant isoforms of VEGF-A have been identified, each having different properties. Recently, we showed that radiolabeled anti-VEGF monoclonal antibody, bevacizumab, accumulates specifically in VEGF-A expressing tumors. In this study, we investigated in a nude mouse model which VEGF-isoforms are responsible for tumor accretion.


METHODS
The humanized anti-VEGF-A antibody, A.4.6.1. (bevacizumab), was radiolabeled with In-111. The originally VEGF-negative Mel57 tumor was transfected with different VEGF isoforms (VEGF-121, VEGF-165, and VEGF-189). The obtained melanoma xenografts specifically expressing different VEGF-isoforms were used in mice. The bevacizumab uptake was examined in biodistribution studies and by gamma-camera imaging.


RESULTS
The tumor cell line expressing VEGF-121 did not show specific uptake, most likely as a result of the fact that this isoform is freely diffusible. Tumors expressing VEGF-165 and -189 were clearly visualized by using gamma-camera imaging.


CONCLUSIONS
The accumulation of radiolabeled bevacizumab in the tumor is due to interaction with VEGF-A isoforms that are associated with the tumor cell surface and/or the extracellular matrix. Scintigraphic imaging of the expression of these VEGF isoforms may thus be useful to predict response to angiogenic therapy.
Stollman
Thamar H
TH
Department of Surgery, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. T.Stollman@chir.umcn.nl
Scheer
Marian G W
MG
Franssen
Gerben M
GM
Verrijp
Kiek N
KN
Oyen
Wim J G
WJ
Ruers
Theo J M
TJ
Leenders
William P J
WP
Boerman
Otto C
OC
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics*; D007205:Indium Radioisotopes; D008545:Melanoma / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism; D020033:Protein Isoforms; D011877:Radionuclide Imaging; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000068258:Bevacizumab