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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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Lung metastatic tumors after intravenous administration of DU145 tumor cell and treatment with AAVrh10αVEGF. Tumor cells (5×105) were administered intravenously into NOD/SCID mice. On the next day, AAVrh.10αVEGF or control AAVrh.10αPA, AAVrh.10EGFP or PBS was administered by the intrapleural route (1011 gc). At 18 wk, lungs were fixed, photos were taken and paraffin sections were stained. A. Gross photos of lung under various conditions. B. Hematoxylin and eosin staining. Scale bar; 5 mm.
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Figure 4: Lung metastatic tumors after intravenous administration of DU145 tumor cell and treatment with AAVrh10αVEGF. Tumor cells (5×105) were administered intravenously into NOD/SCID mice. On the next day, AAVrh.10αVEGF or control AAVrh.10αPA, AAVrh.10EGFP or PBS was administered by the intrapleural route (1011 gc). At 18 wk, lungs were fixed, photos were taken and paraffin sections were stained. A. Gross photos of lung under various conditions. B. Hematoxylin and eosin staining. Scale bar; 5 mm.

Mentions: To determine the effects of intrapleural AAVrh.10αVEGF administration on metastatic lung tumor growth, lung histopathology, lung weight and human DNA expression levels in lung were assessed. Treatment with AAVrh.10αVEGF resulted in a marked reduction of metastatic lung tumor growth as assessed by histology (Figure 4). The lung weight and human DNA expression levels in lung demonstrated a significant reduction in AAVrh.10αVEGF-treated mice relative to animals that received PBS, AAVrh.10EGFP or AAVrh.10αPA (Figure 5; p<0.05, compared with all control treated groups and similar to naive animals, P>0.09). These results indicate that the anti-VEGF-A antibody expressed from AAVrh.10αVEGF was effective in suppressing growth of metastatic lung tumor in this xenograft model.


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)

Lung metastatic tumors after intravenous administration of DU145 tumor cell and treatment with AAVrh10αVEGF. Tumor cells (5×105) were administered intravenously into NOD/SCID mice. On the next day, AAVrh.10αVEGF or control AAVrh.10αPA, AAVrh.10EGFP or PBS was administered by the intrapleural route (1011 gc). At 18 wk, lungs were fixed, photos were taken and paraffin sections were stained. A. Gross photos of lung under various conditions. B. Hematoxylin and eosin staining. Scale bar; 5 mm.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Lung metastatic tumors after intravenous administration of DU145 tumor cell and treatment with AAVrh10αVEGF. Tumor cells (5×105) were administered intravenously into NOD/SCID mice. On the next day, AAVrh.10αVEGF or control AAVrh.10αPA, AAVrh.10EGFP or PBS was administered by the intrapleural route (1011 gc). At 18 wk, lungs were fixed, photos were taken and paraffin sections were stained. A. Gross photos of lung under various conditions. B. Hematoxylin and eosin staining. Scale bar; 5 mm.
Mentions: To determine the effects of intrapleural AAVrh.10αVEGF administration on metastatic lung tumor growth, lung histopathology, lung weight and human DNA expression levels in lung were assessed. Treatment with AAVrh.10αVEGF resulted in a marked reduction of metastatic lung tumor growth as assessed by histology (Figure 4). The lung weight and human DNA expression levels in lung demonstrated a significant reduction in AAVrh.10αVEGF-treated mice relative to animals that received PBS, AAVrh.10EGFP or AAVrh.10αPA (Figure 5; p<0.05, compared with all control treated groups and similar to naive animals, P>0.09). These results indicate that the anti-VEGF-A antibody expressed from AAVrh.10αVEGF was effective in suppressing growth of metastatic lung tumor in this xenograft model.

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