AAVrh.10-mediated Genetic Delivery of Bevacizumab to the Pleura to Provide Local Anti-VEGF to Suppress Growth of Metastatic Lung Tumors

Vascular endothelial growth factor (VEGF) produced by tumor cells plays a central role in stimulating angiogenesis required for tumor growth. Humanized monoclonal anti-VEGF antibody (bevacizumab, Avastin(®)), approved as a treatment for non-squamous, non-small cell lung cancer, requires administration every 3 wk. We hypothesized that an intrapleural administration of an adeno-associated virus (AAV) vector expressing an anti-VEGF-A antibody equivalent of bevacizumab would result in sustained anti-VEGF-A localized expression within the lung and suppress metastatic tumor growth. The AAV vector AAVrh.10αVEGF encodes the light chain and heavy chain cDNAs of monoclonal antibody A.4.6.1, a murine antibody that specifically recognizes human VEGF-A with the same antigen-binding site as bevacizumab. A metastatic lung tumor model was established in SCID mice by intravenous administration of human DU145 prostate carcinoma cells. Intrapleural administration of AAVrh.10αVEGF directed long term expression of the anti-human VEGF-A antibody in lung, as demonstrated by sustained, high level anti-human VEGF titers in lung epithelial lining fluid for 40 wk, the duration of the study. In the AAVrh.10αVEGF-treated animals, tumor growth was significantly suppressed (p<0.05), the numbers of blood vessels and mitotic nuclei in the tumor was decreased (p<0.05), and there was increased survival (p<0.05). Thus, intrapleural administration of an AAVrh.10 vector encoding a murine monoclonal antibody equivalent of bevacizumab, effectively suppresses the growth of metastatic lung tumors, suggesting AAV-mediated gene transfer to the pleura to deliver bevacizumab locally to the lung as a novel alternative platform to conventional monoclonal antibody therapy.