Specific imaging of VEGF‐A expression with radiolabeled anti‐VEGF monoclonal antibody

Abstract

Vascular endothelial growth factor‐A (VEGF‐A) is one of the most important angiogenic factors. Here, we studied in a nude mouse model whether the expression of VEGF‐A in a tumor could be imaged with a radiolabeled anti‐VEGF antibody. The humanized anti‐VEGF‐A antibody A.4.6.1. (bevacizumab), which is reactive with all VEGF‐A isoforms, was radiolabeled with In‐111 or with I‐125. The accumulation of the radiolabeled antibodies in VEGF‐A expressing tumors (LS174T) in nude mice was examined in biodistribution studies and by gamma camera imaging. The uptake of the In‐111‐bevacizumab in the tumor at 3 days p.i. was significantly higher than that of I‐125‐bevacizumab (19.4 ± 7.0 %ID/g vs. 9.6 ± 3.3 %ID/g, p = 0.04). Coinjection of an excess unlabeled antibody resulted in a significant decrease in radioactivity concentration in the tumor (<2.9 ± 1.9 %ID/g, p < 0.005), indicating VEGF‐mediated antibody uptake. Highest uptake in the tumor was observed at relatively low antibody protein doses (<3 μg) (20–25 %ID/g). VEGF‐A‐expressing tumors could be clearly visualized on planar scintigraphic images from 24‐hr post injection onwards. In conclusion, VEGF‐A expression in tumors can be visualized specifically with radiolabeled anti‐VEGF‐A‐mAb. © 2008 Wiley‐Liss, Inc.

111In-Bevacizumab Imaging of Renal Cell Cancer and Evaluation of Neoadjuvant Treatment with the Vascular Endothelial Growth Factor Receptor Inhibitor Sorafenib

“…Vessel characteristics can influence 111 In-bevacizumab uptake in 2 ways: nonspecific accumulation of antibodies due to enhanced vascular permeability or insufficient delivery of antibodies due to poor vascularization. Studies in nude mice with human tumors did not demonstrate any accumulation when an antigenblocking dose of antibody was coadministered, suggesting that accumulation of bevacizumab in the tumor was antigen-specific (12,13). Obviously, it is difficult to extrapolate results obtained in xenografted mice to patients with RCC.…”

“…Kits containing 1 mg of bevacizumab-DTPA conjugate in 1.0 mL of 0.15 M citrate buffer, pH 5.5, ready for radiolabeling were stored at 220°C until use. The dose of 1 mg was selected for imaging because optimal accumulation in VEGF-A-expressing tumors is obtained at relatively low antibody protein doses (13). On referral of a patient, a kit was labeled with 100 MBq of 111 In (Covidien).…”

“…Accumulation of antibodies such as bevacizumab in tumors is the result of multiple factors, such as antigen density, circulating antigen concentration, and tumor physiologic parameters such as microvessel density, vessel permeability, blood flow, and interstitial fluid pressure. In 2 animal studies and 1 clinical study, tumorspecific accumulation of radiolabeled bevacizumab has been described (12)(13)(14). Remarkably, no correlation between VEGF-A levels in plasma or tumor tissue extracts and bevacizumab uptake was observed in a study in patients with metastatic colorectal cancer (14).…”

Bevacizumab

“…The distribution of bevacizumab was limited to the tumor vasculature with minimal extravascular distribution [26]. In addition, scintigraphic visualization of VEGF expression in mouse models showed the accumulation of radiolabeled bevacizumab to be higher in tumor tissues than in normal tissues, and that the uptake in normal tissues decreased over time [27].…”

Early Assessment of Tumor Response to Gefitinib Treatment by Noninvasive Optical Imaging of Tumor Vascular Endothelial Growth Factor Expression in Animal Models

“…For this purpose, the BevF(ab9) 2 probe targeting VEGF was designed using the F(ab9) 2 fragment of the anti-VEGF antibody bevacizumab. Bevacizumab has been labeled with various radioisotopes for PET and SPECT imaging of VEGF expression (16)(17)(18)(19)(20). One limitation of using intact antibodies for molecular imaging is the long half-life and propensity to accumulate in the liver due to a high molecular weight (21,22).…”