AAVrh.10-mediated genetic delivery of bevacizumab to the pleura to provide local anti-VEGF to suppress growth of metastatic lung tumors. Academic Article uri icon

Overview

MeSH

  • Animals
  • Antibodies, Monoclonal, Humanized
  • Bevacizumab
  • Cell Line, Tumor
  • Gene Transfer Techniques
  • Genetic Vectors
  • Humans
  • Mice
  • Mice, SCID
  • Neoplasm Metastasis
  • Pleura
  • RNA, Messenger

MeSH Major

  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal
  • Carcinoma, Non-Small-Cell Lung
  • Dependovirus
  • Genetic Therapy
  • Lung Neoplasms
  • Vascular Endothelial Growth Factor A

abstract

  • Vascular endothelial growth factor (VEGF) produced by tumor cells has 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 weeks. 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.10alphaVEGF encodes the light chain and heavy chain complementary DNAs 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 severe combined immunodeficient mice by intravenous administration of human DU145 prostate carcinoma cells. Intrapleural administration of AAVrh.10alphaVEGF directed long-term expression of the anti-human VEGF-A antibody in lung, as shown by sustained, high-level anti-human VEGF titers in lung epithelial lining fluid for 40 weeks, which was the duration of the study. In the AAVrh.10alphaVEGF-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 the 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.

publication date

  • August 2010

has subject area

  • Angiogenesis Inhibitors
  • Animals
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Bevacizumab
  • Carcinoma, Non-Small-Cell Lung
  • Cell Line, Tumor
  • Dependovirus
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors
  • Humans
  • Lung Neoplasms
  • Mice
  • Mice, SCID
  • Neoplasm Metastasis
  • Pleura
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2921016

Digital Object Identifier (DOI)

  • 10.1038/gt.2010.87

PubMed ID

  • 20596059

Additional Document Info

start page

  • 1042

end page

  • 1051

volume

  • 17

number

  • 8