Preclinical evaluation of an anti-alpha5beta1 integrin antibody as a novel anti-angiogenic agent.

血管生成 化学 体内 体外 血管内皮生长因子 癌症研究 抗体 纤维连接蛋白 细胞生物学 药理学 生物化学 免疫学 生物 细胞外基质 血管内皮生长因子受体 生物技术
作者
Vanitha Ramakrishnan,Vinay Bhaskar,Debbie A. Law,Melanie Wong,Robert B. DuBridge,Danna Breinberg,Christopher O'Hara,David B. Powers,Gao Liu,Jennifer Grove,Peter Hevezi,Kellie M Cass,Susan A. Watson,Ferdinand Evangelista,Rick Powers,B. Finck,M. Wills,Ingrid W. Caras,Yuni Fang,Donald F. McDonald,Dale E. Johnson,Richard M. Murray,Ursula Jeffry
出处
期刊:PubMed 卷期号:5 (4): 273-86 被引量:27
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摘要

Integrin alpha5beta1, the principal fibronectin receptor, is an important survival factor, playing a key role in angiogenesis. Angiogenesis is critical for tumor growth, and anti-angiogenic therapies have met clinical success. To validate the therapeutic potential of an anti-alpha5beta1 strategy, we generated volociximab (M200) a chimeric human IgG4 version of the alpha5beta1 function-blocking murine antibody IIA1; and F200, the Fab derivative. Volociximab, F200 and IIA1 showed similar activity by ELISA (EC50= 0.2nM), Biacore (Kd= 0.1-0.4nM) and inhibition of fibronectin binding (IC50= 2-3nM). The inhibitory potential of alpha5beta1 antibodies was compared to HuMV833, an anti-VEGF antibody. Both volociximab and HuMV833 inhibited HUVEC proliferation (IC50 of volociximab = 0.2-0.5nM; IC50 of HuMV833 = 45nM). However, IIA1, volociximab and F200 were also potent inhibitors of an in vitro model of angiogenesis (HUVEC tube formation assay), unlike HuMV833. Additionally, volociximab inhibited in vitro tube formation induced by VEGF and/or bFGF, suggesting a mechanism of action independent of growth factor stimulus. In fact, inhibition of alpha5beta1 function by volociximab induced apoptosis of actively proliferating, but not resting, endothelial cells. Volociximab does not cross-react with rodent alpha5beta1, therefore in vivo validation of an anti-alpha5beta1 approach was conducted in a cynomolgus model of choroidal revascularization. Volociximab and F200 were potent inhibitors of neovessel formation in this model. These data demonstrate that volociximab has therapeutic potential in diseases in which new vessel formation is a component of the pathology.

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