Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody
Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody
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DOI：
10.1158/1535-7163.mct-05-0048
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发表时间：
2005-08-01
影响因子：
5.7
通讯作者：
Pachter, JA
中科院分区：
文献类型：
--
作者：
Wang, Y;Hailey, J;Pachter, JA
胰岛素样生长因子-I受体(IGF-IR)在肿瘤细胞的生长和存活中起重要作用。在配体的刺激下，受体酪氨酸激酶IGF-IR磷酸化IRS-1和Shc两个主要底物上的酪氨酸残基，随后通过Ras/丝裂原激活的蛋白激酶和磷脂酰肌醇3-激酶/AKT通路发出信号。在这里，我们描述了一种全人抗IGF-IR单抗19D12的特征，它可以抑制IGF-IR/IGF-IR同源二聚体和IGF-IR/Ins受体异构体的IGF结合和自磷酸化。19D12不识别胰岛素受体同源二聚体。除了抑制胰岛素样生长因子-IR的自磷酸化，191312还抑制胰岛素样生长因子-1的磷酸化和下游主要信号分子AKT和细胞外信号调节蛋白1/2的激活。此外，该抗体下调总的胰岛素样生长因子-IR蛋白水平，并在分离的人自然杀伤细胞存在的情况下，在体外对非小细胞腺癌细胞株表现出抗体依赖的细胞毒活性。191312与受体结合紧密，其亲和力为3.8pmol/L。在细胞培养中，191312抑制各种肿瘤细胞系的增殖和软琼脂生长。在体内，19D12抑制了侵袭性很强的人卵巢肿瘤异种移植模型A2780的肿瘤生长。这些数据支持该抗IGF-IR单抗作为一种有前途的抗癌药物的发展。
Insulin-like growth factor-I receptor (IGF-IR) plays an important role in tumor cell growth and survival. On ligand stimulation, IGF-IR, a receptor tyrosine kinase, phosphorylates tyrosine residues on two major substrates, IRS-1 and Shc, which subsequently signal through the Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways. Here, we describe the characterization of a fully human anti-IGF-IR monoclonal antibody 19D12 that inhibits IGF binding and autophosphorylation of both IGF-IR/IGF-IR homodimers and IGF-IR/insulin receptor heterodinners. 19D12 does not recognize insulin receptor homodimers. In addition to inhibiting IGF-IR autophosphorylation, 191312 also inhibits IRS-1 phosphorylation and activation of the major downstream signaling molecules AKT and extracellular signal-regulated kinase 1/2. Furthermore, the antibody down-regulates the total IGF-IR protein level and can exhibit antibody-dependent cellular cytotoxicity activity against a non-small cell adenocarcinoma cell line in vitro in the presence of isolated human natural killer cells. 191312 binds tightly to the receptor, with an affinity of 3.8 pmol/L as measured by KinExA. In cell culture, 191312 inhibits proliferation and soft agar growth of various tumor cell lines. In vivo, 19D12 inhibits the tumor growth of a very aggressive human ovarian tumor xenograft model A2780. These data support the development of this anti-IGF-IR monoclonal antibody as a promising anticancer agent.