Bevacizumab reduces tumor targeting of antiepidermal growth factor and anti‐insulin‐like growth factor 1 receptor antibodies

• Published in: International journal of cancer Vol. 133; no. 2; pp. 307 - 314
• Main Authors: Heskamp, Sandra, Boerman, Otto C., Molkenboer‐Kuenen, Janneke D.M., Oyen, Wim J.G., Graaf, Winette T.A., Laarhoven, Hanneke W.M.
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley-Blackwell 15.07.2013; Wiley Subscription Services, Inc
• Subjects: Animal tumors. Experimental tumors; Animals; Antibodies, Monoclonal, Humanized - pharmacology; Antigens, CD34 - metabolism; Antineoplastic agents; Bevacizumab; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer; Cell Line, Tumor; Cetuximab; Chemotherapy; Colorectal cancer; EGFR; Experimental tumors, general aspects; Female; Humans; IGF‐1R; Immunoglobulins; Immunohistochemistry; Immunotherapy; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Multimodal Imaging; Neoplasm Transplantation; Pharmacology. Drug treatments; Positron-Emission Tomography; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - immunology; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - immunology; Sialic Acid Binding Ig-like Lectin 2 - metabolism; SPECT; Tomography, X-Ray Computed; Tumors; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Radionuclide study; Antineoplastic agent; Targeted therapy; Monoclonal antibody; Epidermal growth factor receptor; type I insulin-like growth factor receptor; EGFR; SPECT; Bevacizumab; Cancerology; Immunotherapy; Established cell line; Antiangiogenic agent; Cetuximab; IGF-1R; Biological receptor; Human; Rodentia; Single photon emission tomography; Malignant tumor; Insulin like growth factor 1; Immunomodulator; Vertebrata; Mammalia; Vascular endothelium growth factor; Treatment; Tumor growth; Mouse; Animal; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28046

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 111In‐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. What's new? In advanced colorectal cancer, combining two antibody‐based treatments –bevacizumab (angiogenesis inhibitor) and cetuximab (epidermal growth factor receptor inhibitor)‐ fails to improve survival. The reason for this lack of synergy is unknown. Heskamp and colleagues tested the hypothesis that bevacizumab treatment reduces the delivery of other antibodies to the tumor. SPECT/CT showed that bevacizumab treatment significantly reduced tumor targeting of radiolabeled anti‐EGFR and anti‐IGF‐1R antibodies. This emphasizes the importance of timing and sequencing of bevacizumab in combination with other antibodies.