Monoclonal antibody against cell surface GRP78 as a novel agent in suppressing PI3K/AKT signaling, tumor growth, and metastasis.
Monoclonal antibody against cell surface GRP78 as a novel agent in suppressing PI3K/AKT signaling, tumor growth, and metastasis.
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DOI：
10.1158/1078-0432.ccr-13-1106
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发表时间：
2013-12-15
期刊：
影响因子：
--
通讯作者：
Gill PS
中科院分区：
文献类型：
--
作者：
Liu R;Li X;Gao W;Zhou Y;Wey S;Mitra SK;Krasnoperov V;Dong D;Liu S;Li D;Zhu G;Louie S;Conti PS;Li Z;Lee AS;Gill PS
ER伴侣GRP 78易位至肿瘤细胞表面并促进存活、转移和对治疗的抗性。细胞表面GRP 78的致癌功能已归因于磷酸肌醇3-激酶（PI 3 K）途径的激活。我们拟利用一种新的抗GRP 78单克隆抗体（MAb 159）来减弱PI 3 K信号通路，从而抑制肿瘤的生长和转移。对MAb 159进行了生物化学表征。在癌细胞培养物、肿瘤异种移植模型、肿瘤转移模型和自发性肿瘤模型中测试抗肿瘤活性。分析癌细胞和肿瘤组织的PI 3 K活性。MAb 159被人源化并经过验证可用于诊断和治疗应用。MAb 159特异性识别表面GRP 78，触发GRP 78内吞作用，并定位于体内肿瘤而非正常器官。MAb 159在体外和体内均抑制肿瘤细胞增殖并增强肿瘤细胞死亡。在MAb 159处理的肿瘤中，PI 3 K信号传导被抑制而没有补偿性MAPK途径活化。此外，MAb 159在自发性PTEN丢失驱动的前列腺和白血病肿瘤模型中停止或逆转肿瘤进展，并在异种移植模型中抑制肿瘤生长和转移。人源化MAb 159保留了高亲和力、肿瘤特异性定位和抗肿瘤活性，在小鼠中无毒，并具有理想的药代动力学。GRP 78特异性抗体MAb 159调节PI 3 K通路并抑制肿瘤生长和转移。人源化MAb 159将很快进入人体试验。
The ER chaperone GRP78 translocates to the surface of tumor cells and promotes survival, metastasis, and resistance to therapy. An oncogenic function of cell surface GRP78 has been attributed to the activation of phosphoinositide 3-kinase (PI3K) pathway. We intend to use a novel anti-GRP78monoclonal antibody (MAb159) to attenuate PI3K signaling and inhibit tumor growth and metastasis. MAb159 was characterized biochemically. Anti-tumor activity was tested in cancer cell culture, tumor xenograft models, tumor metastasis models, and spontaneous tumor models. Cancer cells and tumor tissues were analyzed for PI3K activity. MAb159 was humanized and validated for diagnostic and therapeutic application. MAb159 specifically recognized surface GRP78, triggered GRP78 endocytosis, and localized to tumors but not normal organs in vivo. MAb159 inhibited tumor cell proliferation and enhanced tumor cell death both in vitro and in vivo. In MAb159 treated tumors, PI3K signaling was inhibited without compensatory MAPK pathway activation. Furthermore, MAb159 halted or reversed tumor progression in the spontaneous PTEN loss driven prostate and leukemia tumor models, and inhibited tumor growth and metastasis in xenograft models. Humanized MAb159, which retains high affinity, tumor specific localization, and the anti-tumor activity, was non-toxic in mice and had desirable pharmacokinetics. GRP78 specific antibody MAb159 modulates PI3K pathway and inhibits tumor growth and metastasis. Humanized MAb159 will enter human trials shortly.