Therapeutic antibodies targeting angiomotin inhibit angiogenesis in vivo.
We have previously shown that angiomotin (Amot) mediates angiostatin inhibition of endothelial migration and tube formation in vitro. A crucial role of angiomotin in regulating endothelial cell motility is indicated by the findings that knockdown of Amot in zebrafish reduces the number of filopodia of endothelial tip cells and severely impairs the migration of intersegmental vessels. In addition, targeting angiomotin using DNA vaccination inhibits angiogenesis and tumor growth in vivo. In this report, we have generated antibodies that, similar to angiostatin, bind to angiomotin on the endothelial cell surface. These antibodies inhibited FGF-2 and vascular endothelial growth factor (VEGF) -induced endothelial migration in the Boyden chamber assay. Furthermore, the anti-Amot B06 antibody significantly reduced the number of endothelial filopodia and inhibited vessel migration during retinal angiogenesis in vivo. We also show that systemic or local treatment with this antibody inhibits pathological blood vessel formation associated with tumor growth or laser-induced choroid neovascularization of the eye. These findings provide a rationale for using angiomotin antibodies for specifically targeting endothelial migration in angiogenesis-dependent diseases.
Levchenko
Tetyana
T
Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institute, SE 17176, Stockholm, Sweden.
Veitonmäki
Niina
N
Lundkvist
Andrea
A
Gerhardt
Holger
H
Ming
Yue
Y
Berggren
Kristina
K
Kvanta
Anders
A
Carlsson
Roland
R
Holmgren
Lars
L
D000091082:Angiomotins; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000378:metabolism / Q000627:therapeutic use*; D001011:Aorta / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004727:Endothelium / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011554:Pseudopodia / Q000187:drug effects; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000627:therapeutic use; D012160:Retina / Q000166:cytology
C511047:Amot protein, mouse; D000091082:Angiomotins; D000911:Antibodies, Monoclonal; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D011994:Recombinant Proteins