Genetic delivery of bevacizumab to suppress vascular endothelial growth factor-induced high-permeability pulmonary edema.

Publication Type	Academic Article
Authors	Watanabe M, Boyer J, Crystal R
Journal	Hum Gene Ther
Volume	20
Issue	6
Pagination	598-610
Date Published	06/01/2009
ISSN	1557-7422
Keywords	Antibodies, Monoclonal, Gene Transfer Techniques, Pulmonary Edema
Abstract	High-permeability pulmonary edema causing acute respiratory distress syndrome is associated with high mortality. Using a model of intratracheal adenovirus (Ad)-mediated overexpression of human vascular endothelial growth factor (VEGF)-A(165) in mouse lung to induce alveolar permeability and consequent pulmonary edema, we hypothesized that systemic administration of a second adenoviral vector expressing an anti-VEGF antibody (AdalphaVEGFAb) would protect the lung from pulmonary edema. Pulmonary edema was induced in mice by intratracheal administration of AdVEGFA165. To evaluate anti-VEGF antibody therapy, the mice were treated intravenously with AdalphaVEGFAb, an adenoviral vector encoding the light and heavy chains of an anti-human VEGF antibody with the bevacizumab (Avastin) antigen-binding site. Lung VEGF-A(165) and phosphorylated VEGF receptor (VEGFR)-2 levels, histology, lung wet-to-dry weight ratios, and bronchoalveolar lavage fluid (BALF) levels of total protein were assessed. Administration of AdalphaVEGFAb to mice decreased AdVEGFA165-induced levels of human VEGF-A(165) and phosphorylated VEGFR-2 in the lung. Histological analysis of AdalphaVEGFAb-treated mice demonstrated a reduction of edema fluid in the lung tissue that correlated with a reduction of lung wet-to-dry ratios and BALF total protein levels. Importantly, administration of AdalphaVEGFAb 48 hr after induction of pulmonary edema with AdVEGFA165 was effective in suppressing pulmonary edema. Administration of an adenoviral vector encoding an anti-VEGF antibody that is the equivalent of bevacizumab effectively suppresses VEGF-A(165)-induced high-permeability pulmonary edema, suggesting that anti-VEGF antibody therapy may represent a novel therapy for high-permeability pulmonary edema.
DOI	10.1089/hum.2008.169
PubMed ID	19254174
PubMed Central ID	PMC2828641