title: Effects of the combination of TRC105 and bevacizumab on endothelial cell biology.
abstract: Endoglin, or CD105, is a cell membrane glycoprotein that is overexpressed on proliferating endothelial cells (EC), including those found in malignancies and choroidal neovascularization. Endoglin mediates the transition from quiescent endothelium, characterized by the relatively dominant state of Smad 2/3 phosphorylation, to active angiogenesis by preferentially phosphorylating Smad 1/5/8. The monoclonal antibody TRC105 binds endoglin with high avidity and is currently being tested in phase 1b and phase 2 clinical trials. In this report, we evaluated the effects of TRC105 on primary human umbilical vascular endothelial cells (HUVEC) as a single agent and in combination with bevacizumab. As single agents, both TRC105 and bevacizumab efficiently blocked HUVEC tube formation, and the combination of both agents achieved even greater levels of inhibition. We further assessed the effects of each drug on various aspects of HUVEC function. While bevacizumab was observed to inhibit HUVEC viability in nutrient-limited medium, TRC105 had little effect on HUVEC viability, either alone or in combination with bevacizumab. Additionally, both drugs inhibited HUVEC migration and induced apoptosis. At the molecular level, TRC105 treatment of HUVEC lead to decreased Smad 1/5/8 phosphorylation in response to BMP-9, a primary ligand for endoglin. Together, these results indicate that TRC105 acts as an effective anti-angiogenic agent alone and in combination with bevacizumab.
authors.affiliation: Department of Medicine, Duke University Medical Center, Box 2631, Durham, NC, 27710, USA.
authors.forename: Yingmiao
authors.initials: Y
authors.lastname: Liu
authors.forename: Hongyu
authors.initials: H
authors.lastname: Tian
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Blobe
authors.forename: Charles P
authors.initials: CP
authors.lastname: Theuer
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Nixon
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000068258:Bevacizumab; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D051785:Smad Proteins; D000068258:Bevacizumab; C579557:carotuximab