Watanabe Masaki, Boyer Julie L, Hackett Neil R, Qiu Jianping, Crystal Ronald G
Hum Gene Ther. 2008 Mar;19(3):300-10. doi: 10.1089/hum.2007.109.
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.
肿瘤细胞产生的血管内皮生长因子（VEGF）在刺激实体瘤生长所需的血管生成中起核心作用。VEGF特异性抗体在动物模型中可抑制肿瘤细胞系生长，一种人源化抗VEGF单克隆抗体（贝伐单抗[阿瓦斯汀]）已被批准用于治疗转移性癌症。我们假设，给予表达与贝伐单抗等效的鼠单克隆抗体的腺病毒（Ad）载体将在体内抑制人类肿瘤生长。该Ad载体（AdalphaVEGF）编码单克隆抗体A.4.6.1的轻链和重链cDNA，这是一种鼠抗体，它能以与贝伐单抗相同的抗原结合位点特异性识别人类VEGF。通过将A-673横纹肌肉瘤和DU 145前列腺癌细胞接种到SCID小鼠体内建立人肿瘤细胞异种移植模型，评估AdalphaVEGF在体内的疗效。对于这两种肿瘤模型，AdalphaVEGF在体内均可引导产生高抗人VEGF IgG抗体滴度，肿瘤中的有丝分裂核数量和血管数量显著减少（p<0.05），肿瘤生长受到抑制（p<0.05），并且生存期延长（p<0.005）。因此，编码与贝伐单抗等效的鼠单克隆抗体的AdalphaVEGF可有效抑制人类肿瘤生长，提示基因治疗可作为贝伐单抗单克隆抗体治疗的替代方法。
