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

Watanabe M, Boyer JL, Crystal RG - Gene Ther. (2010)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.

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.

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Organ distribution of anti-VEGF-A antibody mRNA expression levels after intrapleural administration of AAVrh.10αVEGF. AAVrh.10αVEGF (1011 gc) was administered intrapleurally. At 18 wk, various organs were collected and anti-VEGF-A antibody mRNA expression levels relative to endogenous 18S rRNA were assessed by quantitative TaqMan real-time PCR (limit of detection, 0.15 relative to 18S rRNA). Data were obtained from n=2 animals per group.
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Figure 3: Organ distribution of anti-VEGF-A antibody mRNA expression levels after intrapleural administration of AAVrh.10αVEGF. AAVrh.10αVEGF (1011 gc) was administered intrapleurally. At 18 wk, various organs were collected and anti-VEGF-A antibody mRNA expression levels relative to endogenous 18S rRNA were assessed by quantitative TaqMan real-time PCR (limit of detection, 0.15 relative to 18S rRNA). Data were obtained from n=2 animals per group.

Mentions: To evaluate the organ distribution of anti-VEGF-A antibody mRNA expression levels following intrapleural AAVrh.10αVEGF administration, anti-VEGF-A antibody mRNA expression levels relative to endogenous 18S rRNA in various tissues were assessed by quantitative TaqMan real-time PCR. As expected from local administration in the pleura, anti-VEGF-A antibody mRNA was found in the diaphragm and the lung (Figure 3). Anti-VEGF-A antibody mRNA was undetectable in heart, liver, kidney or spleen. In a previous study, we similarly demonstrated that following intrapleural administration of AAVrh.10, the highest levels of transgene expression were found in thoracic structures, i.e., diaphragm, chest wall and heart33.


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

Watanabe M, Boyer JL, Crystal RG - Gene Ther. (2010)

Organ distribution of anti-VEGF-A antibody mRNA expression levels after intrapleural administration of AAVrh.10αVEGF. AAVrh.10αVEGF (1011 gc) was administered intrapleurally. At 18 wk, various organs were collected and anti-VEGF-A antibody mRNA expression levels relative to endogenous 18S rRNA were assessed by quantitative TaqMan real-time PCR (limit of detection, 0.15 relative to 18S rRNA). Data were obtained from n=2 animals per group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2921016&req=5

Figure 3: Organ distribution of anti-VEGF-A antibody mRNA expression levels after intrapleural administration of AAVrh.10αVEGF. AAVrh.10αVEGF (1011 gc) was administered intrapleurally. At 18 wk, various organs were collected and anti-VEGF-A antibody mRNA expression levels relative to endogenous 18S rRNA were assessed by quantitative TaqMan real-time PCR (limit of detection, 0.15 relative to 18S rRNA). Data were obtained from n=2 animals per group.
Mentions: To evaluate the organ distribution of anti-VEGF-A antibody mRNA expression levels following intrapleural AAVrh.10αVEGF administration, anti-VEGF-A antibody mRNA expression levels relative to endogenous 18S rRNA in various tissues were assessed by quantitative TaqMan real-time PCR. As expected from local administration in the pleura, anti-VEGF-A antibody mRNA was found in the diaphragm and the lung (Figure 3). Anti-VEGF-A antibody mRNA was undetectable in heart, liver, kidney or spleen. In a previous study, we similarly demonstrated that following intrapleural administration of AAVrh.10, the highest levels of transgene expression were found in thoracic structures, i.e., diaphragm, chest wall and heart33.

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.

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.

Show MeSH
Related in: MedlinePlus