 |
| Chemical name: | 111In-Diethylenetriamine pentaacetic acid-bevacizumab | |
| Abbreviated name: | 111In-DTPA-bevacizumab | |
| Synonym: | ||
| Agent category: | Antibody | |
| Target: | Vascular endothelial growth factor (VEGF) | |
| Target category: | Antigen | |
| Method of detection: | SPECT, gamma planar imaging | |
| Source of signal/contrast: | 111In | |
| Activation: | No | |
| Studies: |
| Click on protein, nucleotide (RefSeq), and gene for more information about VEGF. |
[PubMed]
Vascular endothelial growth factor (VEGF) consists of at least six isoforms of various numbers of amino acids (121, 145, 165, 183, 189, and 206 amino acids) produced through alternative splicing (1). VEGF121, VEGF165, and VEGF189 are the forms secreted by most cell types and are active as homodimers linked by disulfide bonds. VEGF121 does not bind to heparin like the other VEGF species do (2). VEGF is a potent angiogenic factor that induces proliferation, sprouting, migration, and tube formation of endothelial cells. There are three high-affinity tyrosine kinase VEGF receptors (VEGFR-1, Flt-1; VEGFR-2, KDR/Flt-1; and VEGFR-3, Flt-4) on endothelial cells. Several types of non-endothelial cells such as hematopoietic stem cells, melanoma cells, monocytes, osteoblasts, and pancreatic β cells also express VEGF receptors (1).
VEGF is overexpressed in various tumor cells and tumor-associated endothelial cells (3). Inhibition of VEGF receptor function has been shown to inhibit pathological angiogenesis as well as tumor growth and metastasis (4, 5). Radiolabeled VEGF has been developed as a single-photon emission computed tomography tracer for imaging solid tumors and angiogenesis in humans (6-8). However, several studies have shown that cancer treatments (photodynamic therapy, radiotherapy, and chemotherapy) can lead to increased tumor VEGF expression and subsequently to more aggressive disease (9, 10). Therefore, it is important to measure VEGF levels in the tumors to design better anti-cancer treatment protocols. Bevacizumab is a humanized antibody against VEGF-A (11). It binds to all VEGF isoforms. Bevacizumab is approved for clinical use in metastatic colon carcinoma and non-small cell lung cancer (12). Stollman et al. (13) prepared 111In-diethylenetriamine pentaacetic acid-bevacizumab (111In-DTPA-bevacizumab) for imaging VEGF expression in nude mice bearing LS174T human colon carcinoma xenografts.
[PubMed]
Isothiocyanate-benzyl-DTPA and bevacizumab (1:1 molar ratio) were incubated in sodium borate buffer (pH 9) for 20 h at 37°C (13). DTPA-Bevacizumab was isolated from the incubation mixture with column chromatography. DTPA-Bevacizumab (0.05 mg) in 0.15 M ammonium acetate buffer (pH 5.25) was mixed with 18.5 MBq (0.5 mCi) of 111InCl3. The mixture was incubated for 30 min at room temperature. 111In-DTPA-Bevacizumab was purified with column chromatography with a specific activity of 15.2 MBq/nmol (0.41 mCi/nmol) and a radiochemical purity of >97%. Nagengast et al. (14) reported a similar synthesis of 111In-DTPA-bevacizumab with a labeling yield of 96.6% and a specific activity of 7.6 MBq/nmol (0.2 mCi/nmol). There were two to three chelators per antibody. 111In-DTPA-Bevacizumab was stable for 7 d at 4°C in ammonium acetate and at 37°C in serum. 111In-DTPA-bevacizumab resulted in 56.9 ± 0.7% binding to immobilized VEGF. Bevacizumab and 111In-DTPA-bevacizumab (1:1) blocked binding by 50%.
[PubMed]
Stollman et al. (13) performed a dose escalation study of 111In-DTPA-bevacizumab (1, 3, 10, 30, 100, 300, and 1,000 µg/mouse) in mice bearing VEGF-expressing LS174 tumors. Muscle, tumor, and blood radioactivity levels (in percent of injected dose per gram (% ID/g)) were assessed at 3 d after injection. There were no dose-related effects in the blood (10–12% ID/g) and muscle (2–3% ID/g). On the other hand, there was an inverse correlation between antibody dose and accumulation of radioactivity in the tumor. The highest tumor accumulation (20–25% ID/g) was observed with 1 and 3 µg of 111In-DTPA-bevacizumab. The lowest tumor accumulation (<3% ID/g) was observed at 300 and 1,000 µg, indicating binding to a saturable site. Subsequent biodistribution studies were performed with 2 µg/mouse at 1, 3, and 6 d after injection. The organ with the highest accumulation of 111In-DTPA-bevacizumab was the lung (~8% ID/g) with accumulation of <3% ID/g in the liver, intestine, spleen, and kidneys at 3 d after injection. The tumor/muscle ratio was >10. Co-injection of excess bevacizumab resulted in a significant decrease in radioactivity concentration in the tumors (<3% ID/g, P < 0.005). Little inhibition was observed in the other organs. LS174 tumors, which were found to express VEGF-A mRNA, could be clearly visualized on planar scintigraphic images at 1, 3, and 7 d after injection. Nagengast et al. (14) observed a similar biodistribution pattern in mice bearing human SKOV-3 ovarian tumor xenografts with 100 ug 111In-DTPA-bevacizumab. The tumor accumulation was 6.17% ID/g at 3 d after injection.
[PubMed]
Scheer et al. (15) performed whole-body single-photon emission computed tomography and computed tomography scans in 12 patients with colorectal liver metastases after intravenous injection of ~200 MBq (5.4 mCi) 111In-bevacizumab at 10 min and 7 d after injection. Enhanced uptake of 111In-bevacizumab in the liver metastases was detected in 9 of the 12 patients. The level of antibody accumulation in these lesions varied considerably. There was no correlation between the level of 111In-bevacizumab accumulation and the level of VEGF-A expression in the tumor sections as determined with in situ hybridization and ELISA.
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