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新型人源抗 VEGF 抗体 MIL60 的强效抗血管生成和抗肿瘤活性。

Potent anti-angiogenesis and anti-tumor activity of a novel human anti-VEGF antibody, MIL60.

机构信息

1] Laboratory of Immunology, Institute of Basic Medical Sciences, Beijing, China [2] Department of Pathogens and Immunology, Logistics College of Chinese People's Armed Police Forces, Tianjin, China.

Department of Ophthalmology, General Hospital of People's Liberation Army, Beijing, China.

出版信息

Cell Mol Immunol. 2014 May;11(3):285-93. doi: 10.1038/cmi.2014.6. Epub 2014 Mar 10.

Abstract

Angiogenesis is crucial for tumor development, growth and metastasis. Vascular endothelial growth factor (VEGF) has been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis, and blocking the activity of VEGF can starve tumors. Avastin, which is a humanized anti-VEGF antibody, has been successfully applied in clinics since 2004. However, the price of Avastin is extremely high for Chinese people. Here, we report a novel human anti-VEGF neutralizing antibody, MIL60, which shows an affinity comparable to that of Avastin (the KD value of MIL60 was 44.5 pM, while that of Avastin was 42.7 pM). MIL60 displays favorable actions in inhibiting VEGF-triggered endothelial cell proliferation (the IC50 value of MIL60 was 31±6.4 ng/ml and that of Avastin was 47±8.1 ng/ml), migration (8 µg/ml or 0.8 µg/ml MIL60 versus the control: P<0.05) and tube formation (2 µg/ml or 0.2 µg/ml MIL60 versus the control: P<0.05) via the VEGFR2 signaling pathway. Moreover, MIL60 was shown to inhibit tumor growth and angiogenesis in vivo in xenograft models of human colon carcinoma and ovarian cancer using immunotherapy and immunohistochemistry analysis (MIL60 versus N.S.: P=0.0007; Avastin versus N.S.: P=0.00046). These data suggest that MIL60 is a potential therapeutic, anti-angiogenic agent. Our work provides a novel anti-VEGF antibody, which can be considered an anti-tumor antibody candidate and a new option for patients with various cancers.

摘要

血管生成对于肿瘤的发展、生长和转移至关重要。血管内皮生长因子(VEGF)通过刺激肿瘤相关血管生成促进实体瘤的生长和转移,而阻断 VEGF 的活性可以使肿瘤饥饿。自 2004 年以来,阿瓦斯汀(一种人源化抗 VEGF 抗体)已成功应用于临床。然而,对于中国人来说,阿瓦斯汀的价格非常高。在这里,我们报告了一种新型的人源抗 VEGF 中和抗体 MIL60,其亲和力可与阿瓦斯汀相媲美(MIL60 的 KD 值为 44.5 pM,而阿瓦斯汀的 KD 值为 42.7 pM)。MIL60 显示出抑制 VEGF 触发的内皮细胞增殖(MIL60 的 IC50 值为 31±6.4 ng/ml,阿瓦斯汀的 IC50 值为 47±8.1 ng/ml)、迁移(8 µg/ml 或 0.8 µg/ml MIL60 与对照组相比:P<0.05)和管形成(2 µg/ml 或 0.2 µg/ml MIL60 与对照组相比:P<0.05)的有利作用通过 VEGFR2 信号通路。此外,通过免疫治疗和免疫组织化学分析,MIL60 被证明在人结肠癌和卵巢癌异种移植模型中抑制体内肿瘤生长和血管生成(MIL60 与 N.S.:P=0.0007;阿瓦斯汀与 N.S.:P=0.00046)。这些数据表明,MIL60 是一种潜在的治疗性抗血管生成药物。我们的工作提供了一种新型的抗 VEGF 抗体,可作为抗肿瘤抗体候选物,为各种癌症患者提供了新的选择。

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