Bevacizumab (antivascular
endothelial growth factor [anti-
VEGF]) and
cetuximab (antiepidermal
growth factor receptor [anti-EGFR]) are approved
antibodies for treatment of
cancer. However, in advanced
colorectal cancer, the combination fails to improve survival. As the reason for the lack of activity is unknown, our study aims to determine the effect of
bevacizumab on targeting of anti-EGFR and
insulin-like growth factor 1 receptor (IGF-1R)
antibodies in
tumors with single-photon emission computed tomography (SPECT)/CT imaging. Mice with subcutaneous EGFR and IGF-1R-expressing SUM149 xenografts received a single dose of
bevacizumab (10 mg/kg) or saline. After 4 days, mice were injected with radiolabeled
cetuximab or
R1507, an anti-IGF-1R antibody. A control group received a radiolabeled irrelevant
IgG (
hLL2). Three days later, SPECT/CT images were acquired and mice were dissected to determine the concentration of
antibodies in the tissues.
Tumors were analyzed immunohistochemically to determine vascular density (CD34),
VEGF, EGFR and IGF-1R expression. SPECT/CT imaging revealed that
bevacizumab treatment significantly reduced
tumor targeting of radiolabeled
cetuximab by 40% from 33.1 ± 1.1 %ID/g to 19.8 ± 5.7 %ID/g (p = 0.009) for untreated and
bevacizumab-treated
tumors, respectively. A similar effect was found for (111) In-
R1507:
tumor targeting of
R1507 decreased by 35%. No significant differences in
tumor uptake were observed in mice that received an irrelevant
IgG. Uptake in normal organs was not altered by
bevacizumab. Immunohistochemical analysis showed that vascular density decreased with 43%, whereas EGFR and IGF-1R expression was unaltered. In conclusion,
bevacizumab treatment significantly reduces
tumor targeting of anti-EGFR and anti-IGF-1R
antibodies. This emphasizes the importance of timing and sequencing of
bevacizumab in combination with other
antibodies.