A DNA Vaccine Targeting Angiomotin Inhibits Angiogenesis and Suppresses Tumor Growth

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 24; pp. 9208 - 9213
• Main Authors: Holmgren, Lars, Ambrosino, Elena, Birot, Olivier, Tullus, Carl, Veitonmäki, Niina, Levchenko, Tetyana, Carlson, Lena-Maria, Musiani, Piero, Iezzi, Manuela, Curcio, Claudia, Forni, Guido, Cavallo, Federica, Kiessling, Rolf
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13-06-2006; National Acad Sciences
• Subjects: Angiogenesis; Animals; Antibodies; Antibodies - metabolism; B lymphocytes; Biological Sciences; Cell growth; Cell Line; Cell Movement - physiology; Deoxyribonucleic acid; DNA; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - metabolism; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - immunology; Medicin och hälsovetenskap; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice; Mice, Inbred BALB C; Mice, Transgenic; Neoplasms - metabolism; Neoplasms - pathology; Neovascularization, Pathologic; Plasmids; Proteins; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; T lymphocytes; Transgenic animals; Tumors; Vaccination; Vaccines; Vaccines, DNA
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0603110103

Endogenous angiogenesis inhibitors have shown promise in preclinical trials, but clinical use has been hindered by low half-life in circulation and high production costs. Here, we describe a strategy that targets the angiostatin receptor angiomotin (Amot) by DNA vaccination. The vaccination procedure generated antibodies that detected Amot on the endothelial cell surface. Purified Ig bound to the endothelial cell membrane and inhibited endothelial cell migration. In vivo, DNA vaccination blocked angiogenesis in the matrigel plug assay and prevented growth of transplanted tumors for up to 150 days. We further demonstrate that a combination of DNA vaccines encoding Amot and the extracellular and transmembrane domains of the human EGF receptor 2 (Her-2)/neu oncogene inhibited breast cancer progression and impaired tumor vascularization in Her-2/neu transgenic mice. No toxicity or impairment of normal blood vessels could be detected. This work shows that DNA vaccination targeting Amot may be used to mimic the effect of angiostatin.