PET imaging of tumor angiogenesis in mice with VEGF-A-targeted (86)Y-CHX-A″-DTPA-bevacizumab.
Bevacizumab is a humanized monoclonal antibody that binds to tumor-secreted vascular endothelial growth factor (VEGF)-A and inhibits tumor angiogenesis. In 2004, the antibody was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic colorectal carcinoma in combination with chemotherapy. This report describes the preclinical evaluation of a radioimmunoconjugate, (86)Y-CHX-A″-DTPA-bevacizumab, for potential use in Positron Emission Tomography (PET) imaging of VEGF-A tumor angiogenesis and as a surrogate marker for (90)Y-based radioimmunotherapy. Bevacizumab was conjugated to CHX-A″-DTPA and radiolabeled with (86)Y. In vivo biodistribution and PET imaging studies were performed on mice bearing VEGF-A-secreting human colorectal (LS-174T), human ovarian (SKOV-3) and VEGF-A-negative human mesothelioma (MSTO-211H) xenografts. Biodistribution and PET imaging studies demonstrated highly specific tumor uptake of the radioimmunoconjugate. In mice bearing VEGF-A-secreting LS-174T, SKOV-3 and VEGF-A-negative MSTO-211H tumors, the tumor uptake at 3 days postinjection was 13.6 ± 1.5, 17.4 ± 1.7 and 6.8 ± 0.7 % ID/g, respectively. The corresponding tumor uptake in mice coinjected with 0.05 mg cold bevacizumab were 5.8 ± 1.3, 8.9 ± 1.9 and 7.4 ± 1.0 % ID/g, respectively at the same time point, demonstrating specific blockage of the target in VEGF-A-secreting tumors. The LS-174T and SKOV3 tumors were clearly visualized by PET imaging after injecting 1.8-2.0 MBq (86)Y-CHX-A″-DTPA-bevacizumab. Organ uptake quantified by PET closely correlated (r(2) = 0.87, p = 0.64, n = 18) to values determined by biodistribution studies. This preclinical study demonstrates the potential of the radioimmunoconjugate, (86)Y-CHX-A″-DTPA-bevacizumab, for noninvasive assessment of the VEGF-A tumor angiogenesis status and as a surrogate marker for (90)Y-CHX-A″-DTPA-bevacizumab radioimmunotherapy.
Nayak
Tapan K
TK
Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institute of Health, Bethesda, Maryland 20892, USA. tapann@gmail.com
Garmestani
Kayhan
K
Baidoo
Kwamena E
KE
Milenic
Diane E
DE
Brechbiel
Martin W
MW
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000175:diagnosis; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics; D017879:Isothiocyanates / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000175:diagnosis; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011863:Radioimmunoassay; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D017879:Isothiocyanates; D019275:Radiopharmaceuticals; D042461:Vascular Endothelial Growth Factor A; D015021:Yttrium Radioisotopes; C467480:vascular endothelial growth factor A, mouse; C085678:N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid; D000068258:Bevacizumab; D004369:Pentetic Acid
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