A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenografts
A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenografts
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DOI：
10.1002/ijc.20543
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发表时间：
2005-01-10
影响因子：
6.4
通讯作者：
Corvaia, N
中科院分区：
文献类型：
--
作者：
Goetsch, L;Gonzalez, A;Corvaia, N
胰岛素样生长因子受体I(IGF-IR)与其配体相互作用可诱导细胞增殖、转化和阻断细胞的凋亡功能。IGF-IR在多种肿瘤细胞上过度表达，阻断IGF-IR对抗癌治疗具有重要意义。我们已经产生了人源化的抗IGF-IR抗体h7C10，它可以在体外阻断IGF-I和IGF-II诱导的MCF-7乳腺癌细胞的增殖。对IGF-I转导级联的分析表明，人源化的抗IGF-IR抗体及其亲本形式阻断了IGF-I诱导的酪氨酸磷酸化，包括IGF-I的β链和IRS-1酪氨酸磷酸化。这可能会导致细胞周期停滞，从而抑制生长。用H7C10或其亲本形式7C10处理荷人乳腺癌细胞(MCF-7)或非小细胞肺癌细胞(A549)的裸鼠，可显著抑制肿瘤生长。当小鼠接受抗IGF-IR抗体与化疗药物长春瑞滨或抗表皮生长因子受体(EGFR)抗体联合治疗时，观察到几乎完全抑制了A549肿瘤的生长，225。在A549的体内原位模型中，联合治疗显著延长了小鼠的寿命；抗IGF-IR抗体和抗EGFR抗体的联合治疗优于长春瑞滨联合治疗。目前的结果表明，人源化的抗IGF-IR抗体h7C10与化疗药物或针对其他生长因子受体(如表皮生长因子受体)的抗体结合时，具有巨大的癌症治疗潜力。
Interaction of insulin-like growth factor receptor I (IGF-IR) with its ligands has been reported to induce cell proliferation, transformation and blockade of cell apoptotic functions. IGF-IR is over-expressed on numerous tumor cell types and its blockade could be of importance for anti-cancer therapy. We have generated a humanized anti-IGF-IR antibody h7C10 that blocks in vitro IGF-I and IGF-II-induced cell proliferation of MCF-7 breast cancer cells. Analysis of the IGF-I transduction cascade demonstrated that the humanized anti-IGF-IR antibody and its murine parental form block IGF-I-induced tyrosine phosphorylation, both its beta-chain and IRS-1 tyrosine phosphorylation. This presumably leads to cell cycle arrest and, consequently, growth inhibition. Treatment of nude mice bearing either human breast cancer cells (MCF-7) or non small lung cancer cells (A549) with h7C10, or its murine parental form 7C10, inhibited significantly tumor growth. An almost complete inhibition of A549 tumor growth was observed when mice were treated with the anti-IGF-IR antibody combined with either a chemotherapeutic agent, Vinorelbine or an anti-epidermal growth factor receptor (EGFR) antibody, 225. Combined therapy prolonged significantly the life span of mice in an orthotopic in vivo model of A549; the combination of the anti-IGF-IR antibody with an anti-EGFR antibody was superior to the Vinorelbine combination. The present resulis indicate that the humanized anti-IGF-IR antibody h7C10 has a great potential for cancer therapy when combined with either a chemotherapeutic agent or an antibody that targets other growth factor receptors, such as the epidermal growth factor receptor.