title: Bevacizumab reduces tumor targeting of antiepidermal growth factor and anti-insulin-like growth factor 1 receptor antibodies.
abstract: 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.
authors: Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. s.heskamp@nucmed.umcn.nl
authors: Sandra
authors: S
authors: Heskamp
authors: Otto C
authors: OC
authors: Boerman
authors: Janneke D M
authors: JD
authors: Molkenboer-Kuenen
authors: Wim J G
authors: WJ
authors: Oyen
authors: Winette T A
authors: WT
authors: van der Graaf
authors: Hanneke W M
authors: HW
authors: van Laarhoven
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D018952:Antigens, CD34 / Q000378:metabolism; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D064847:Multimodal Imaging; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000276:immunology*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018952:Antigens, CD34; D051918:Sialic Acid Binding Ig-like Lectin 2; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D000068818:Cetuximab