A DNA vaccine targeting angiomotin inhibits angiogenesis and suppresses tumor growth.
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.
Holmgren
Lars
L
Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institutet, SE171 76 Stockholm, Sweden.
Ambrosino
Elena
E
Birot
Olivier
O
Tullus
Carl
C
Veitonmäki
Niina
N
Levchenko
Tetyana
T
Carlson
Lena-Maria
LM
Musiani
Piero
P
Iezzi
Manuela
M
Curcio
Claudia
C
Forni
Guido
G
Cavallo
Federica
F
Kiessling
Rolf
R
D000091082:Angiomotins; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D019444:Vaccines, DNA
D000091082:Angiomotins; D000906:Antibodies; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; C423985:AMOT protein, human