Genetic delivery of the murine equivalent of bevacizumab (avastin), an anti-vascular endothelial growth factor monoclonal antibody, to suppress growth of human tumors in immunodeficient mice.
Vascular endothelial growth factor (VEGF) produced by tumor cells plays a central role in stimulating angiogenesis required for solid tumor growth. VEGF-specific antibodies inhibit tumor cell line growth in animal models and a humanized monoclonal anti-VEGF antibody (bevacizumab [Avastin]) is approved as a treatment for metastatic cancer. We hypothesized that administration of an adenoviral (Ad) vector expressing the murine monoclonal antibody equivalent of bevacizumab would suppress human tumor growth in vivo. The Ad vector (AdalphaVEGF) encodes the light chain and heavy chain cDNAs of monoclonal antibody A.4.6.1, a murine antibody that specifically recognizes human VEGF with the same antigen-binding site as bevacizumab. AdalphaVEGF efficacy in vivo was evaluated with A-673 rhabdomyosarcoma and DU 145 prostate carcinoma cells in human tumor cell xenografts in SCID mice. For both tumor models, AdalphaVEGF directed the expression of high anti-human VEGF IgG antibody titers in vivo, the numbers of mitotic nuclei and blood vessels in the tumor were significantly decreased (p < 0.05), tumor growth was suppressed (p < 0.05), and there was increased survival (p < 0.005). Thus, AdalphaVEGF, encoding a murine monoclonal antibody that is the equivalent of bevacizumab, effectively suppresses the growth of human tumors, suggesting gene therapy as an alternative to bevacizumab monoclonal antibody therapy.
Watanabe
Masaki
M
Boyer
Julie L
JL
Hackett
Neil R
NR
Qiu
Jianping
J
Crystal
Ronald G
RG
D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics* / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D009389:Neovascularization, Pathologic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab