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Therapeutic antibodies targeting angiomotin inhibit angiogenesis in vivo

Tetyana Levchenko^*,1, Niina Veitonmäki^*,,1, Andrea Lundkvist, Holger Gerhardt, Yue Ming, Kristina Berggren, Anders Kvanta, Roland Carlsson and Lars Holmgren^*,2

^* Department of Oncology and Pathology, Cancer Centre Karolinska, and

Department of Clinical Neuroscience, Section of Ophthalmology and Vision, Karolinska Institute, St. Erik’s Eye Hospital, Stockholm, Sweden;

Vascular Biology Laboratory, Cancer Research UK, London, UK; and

BioInvent International AB, Sölvegatan 41, Lund, Sweden

²Correspondence: Department of Oncology and Pathology, CCK, Cancer Centre Karolinska, Karolinska Institute, SE 17176, Stockholm, Sweden. E-mail: lars.holmgren{at}ki.se

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, T., Veitonmäki, N, Lundkvist, A., Gerhardt, H., Ming, Y., Berggren, K., Kvanta, A., Carlsson, R., Holmgren, L. Therapeutic antibodies targeting angiomotin inhibit angiogenesis in vivo.

Key Words: angiostatin • neoplasia • vascular/ocular disease • migration