A human monoclonal antibody 264RAD targeting αvβ6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo
A human monoclonal antibody 264RAD targeting αvβ6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo
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DOI：
10.1038/onc.2012.460
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发表时间：
2013-09-12
期刊：
影响因子：
8
通讯作者：
Barry, S. T.
中科院分区：
文献类型：
--
作者：
Eberlein, C.;Kendrew, J.;Barry, S. T.
α v β 6整合素在多种上皮肿瘤中表达上调，并被认为在调节肿瘤生长中发挥作用。在这里，我们描述了一种人类治疗性抗体264RAD，它结合并抑制α v β 6整合素的功能。264RAD与人、小鼠和食蟹猴α v β 6交叉反应，抑制与所有配体的结合，包括tgf - β的潜伏期相关肽。对一系列整合素的筛选表明，264RAD也结合并抑制相关的整合素α v β 8，但不抑制整合素α 5 β 1、α v β 3、α v β 5和α 4 β 1。在体外Matrigel侵袭实验中，264RAD抑制VB6和Detroit 562细胞的侵袭，并抑制α v β 6介导的Calu-3细胞中基质金属蛋白酶-9的产生。在肿瘤细胞-成纤维细胞共培养实验中，它通过阻止NCI-H358肿瘤细胞对tgf - β的局部激活来抑制tgf - β介导的真皮皮肤成纤维细胞的激活。体内264RAD显示出剂量依赖性抑制底特律562肿瘤生长，当剂量为20 mg/kg每周一次时，已建立的肿瘤消退。与264RAD相关的生长减少与Ki67和phospho-ERK的剂量依赖性抑制以及肿瘤细胞中α v β 6表达的减少有关，同时还与间质成纤维细胞中纤维连接蛋白和α平滑肌肌动蛋白表达的减少有关。264RAD还能减少原位4T1肿瘤的生长和转移。在20 mg/kg的剂量下，原发肿瘤的生长和肺转移灶的数量都减少了。数据支持264RAD是α v β 6整合素的有效抑制剂，对α v β 8整合素具有一定的活性，可以减少肿瘤的生长和转移。
alpha v beta 6 integrin expression is upregulated on a wide range of epithelial tumours, and is thought to play a role in modulating tumour growth. Here we describe a human therapeutic antibody 264RAD, which binds and inhibits alpha v beta 6 integrin function. 264RAD cross-reacts with human, mouse and cynomolgus monkey alpha v beta 6, and inhibits binding to all ligands including the latency-associated peptide of TGF-beta. Screening across a range of integrins revealed that 264RAD also binds and inhibits the related integrin alpha v beta 8, but not the integrins alpha 5 beta 1, alpha v beta 3, alpha v beta 5 and alpha 4 beta 1. In vitro 264RAD inhibited invasion of VB6 and Detroit 562 cells in a Matrigel invasion assay and alpha v beta 6 mediated production of matrix metalloproteinase-9 in Calu-3 cells. It inhibited TGF-beta-mediated activation of dermal skin fibroblasts by preventing local activation of TGF-beta by NCI-H358 tumour cells in a tumour cell - fibroblast co-culture assay. In vivo 264RAD showed dose-dependent inhibition of Detroit 562 tumour growth, regressing established tumours when dosed at 20 mg/kg once weekly. The reduction in growth associated with 264RAD was related to a dose-dependent inhibition of Ki67 and phospho-ERK and a reduction of alpha v beta 6 expression in the tumour cells, coupled to a reduction in fibronectin and alpha smooth muscle actin expression in stromal fibroblasts. 264RAD also reduced the growth and metastasis of orthotopic 4T1 tumours. At 20 mg/kg growth of both the primary tumour and the number of metastatic deposits in lung were reduced. The data support the conclusion that 264RAD is a potent inhibitor of alpha v beta 6 integrin, with some activity against alpha v beta 8 integrin, that reduces both tumour growth and metastasis.