Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF
Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF
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DOI：
10.1074/jbc.m508199200
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发表时间：
2006-01-13
影响因子：
4.8
通讯作者：
Fuh, G
中科院分区：
文献类型：
--
作者：
Liang, WC;Wu, XM;Fuh, G
为了充分评估 VEGF-A 在肿瘤血管生成中的作用，需要能够阻断所有血管内皮生长因子 (VEGF) 来源的抗体。选择性靶向肿瘤来源的 VEGF 忽略了宿主基质 VEGF 的贡献。其他策略，例如直接靶向 VEGF 受体或使用受体诱饵，不仅会抑制 VEGF-A，还会抑制 VEGF 同系物（例如胎盘生长因子、VEGF-B 和 VEGF-C），这些同源物可能在血管生成中发挥作用。在这里，我们报告了从合成抗体噬菌体文库中鉴定出的新型抗 VEGF 抗体 B20 和 G6，它们在体外阻断人和鼠 VEGF 作用。他们的亲和力增强的变体完全抑制骨骼肌、结直肠和胰腺来源的小鼠中的三种人类肿瘤异种移植物（A673、HM-7和HPAC）。阿瓦斯汀仅抑制肿瘤来源的人 VEGF，其抑制 HM-7 和 A673 生长的效果类似于 90%，但抑制 HPAC 生长的效果小于 50%。事实上，HPAC 肿瘤比其他肿瘤含有更多的宿主间质侵袭和间质衍生的 VEGF。因此，基质 VEGF 的功能贡献在肿瘤之间差异很大，并且肿瘤和基质衍生的 VEGF 的系统阻断足以抑制肿瘤异种移植物的生长。
To fully assess the role of VEGF-A in tumor angiogenesis, antibodies that can block all sources of vascular endothelial growth factor (VEGF) are desired. Selectively targeting tumor-derived VEGF overlooks the contribution of host stromal VEGF. Other strategies, such as targeting VEGF receptors directly or using receptor decoys, result in inhibiting not only VEGF-A but also VEGF homologues (e.g. placental growth factor, VEGF-B, and VEGF-C), which may play a role in angiogenesis. Here we report the identification of novel anti-VEGF antibodies, B20 and G6, from synthetic antibody phage libraries, which block both human and murine VEGF action in vitro. Their affinity-improved variants completely inhibit three human tumor xenografts in mice of skeletal muscle, colorectal, and pancreatic origins (A673, HM-7, and HPAC). Avastin, which only inhibits the tumor-derived human VEGF, is similar to 90% effective at inhibiting HM-7 and A673 growth but is < 50% effective at inhibiting HPAC growth. Indeed, HPAC tumors contain more host stroma invasion and stroma-derived VEGF than other tumors. Thus, the functional contribution of stromal VEGF varies greatly among tumors, and systemic blockade of both tumor and stroma-derived VEGF is sufficient for inhibiting the growth of tumor xenografts.