Department of Discovery Oncology, Biogen Idec, Inc., San Diego, California 92122, USA.
Mol Cancer Ther. 2010 Sep;9(9):2593-604. doi: 10.1158/1535-7163.MCT-09-1018. Epub 2010 Aug 17.
The insulin-like growth factor-I receptor (IGF-IR) is a cell surface receptor tyrosine kinase that mediates cell survival signaling and supports tumor progression in multiple tumor types. We identified a spectrum of inhibitory IGF-IR antibodies with diverse binding epitopes and ligand-blocking properties. By binding distinct inhibitory epitopes, two of these antibodies, BIIB4 and BIIB5, block both IGF-I and IGF-II binding to IGF-IR using competitive and allosteric mechanisms, respectively. Here, we explored the inhibitory effects of combining BIIB4 and BIIB5. In biochemical assays, the combination of BIIB4 and BIIB5 improved both the potency and extent of IGF-I and IGF-II blockade compared with either antibody alone. In tumor cells, the combination of BIIB4 and BIIB5 accelerated IGF-IR downregulation and more efficiently inhibited IGF-IR activation as well as downstream signaling, particularly AKT phosphorylation. In several carcinoma cell lines, the antibody combination more effectively inhibited ligand-driven cell growth than either BIIB4 or BIIB5 alone. Notably, the enhanced tumor growth-inhibitory activity of the BIIB4 and BIIB5 combination was much more pronounced at high ligand concentrations, where the individual antibodies exhibited substantially reduced activity. Compared with single antibodies, the BIIB4 and BIIB5 combination also significantly further enhanced the antitumor activity of the epidermal growth factor receptor inhibitor erlotinib and the mTOR inhibitor rapamycin. Moreover, in osteosarcoma and hepatocellular carcinoma xenograft models, the BIIB4 and BIIB5 combination significantly reduced tumor growth to a greater degree than each single antibody. Taken together, our results suggest that targeting multiple distinct inhibitory epitopes on IGF-IR may be a more effective strategy of affecting the IGF-IR pathway in cancer.
胰岛素样生长因子-I 受体（IGF-IR）是一种细胞表面受体酪氨酸激酶，介导细胞存活信号，并支持多种肿瘤类型的肿瘤进展。我们鉴定了一系列具有不同结合表位和配体阻断特性的抑制性 IGF-IR 抗体。通过结合不同的抑制性表位，这两种抗体 BIIB4 和 BIIB5 分别通过竞争性和变构机制阻断 IGF-I 和 IGF-II 与 IGF-IR 的结合。在这里，我们探讨了联合使用 BIIB4 和 BIIB5 的抑制作用。在生化测定中，与单独使用任一抗体相比，BIIB4 和 BIIB5 的组合均提高了 IGF-I 和 IGF-II 阻断的效力和程度。在肿瘤细胞中，BIIB4 和 BIIB5 的组合加速了 IGF-IR 的下调，并更有效地抑制了 IGF-IR 的激活及其下游信号转导，特别是 AKT 磷酸化。在几种癌细胞系中，抗体组合比单独使用 BIIB4 或 BIIB5 更有效地抑制配体驱动的细胞生长。值得注意的是，在高配体浓度下，BIIB4 和 BIIB5 组合的增强肿瘤生长抑制活性更为明显，而单独使用抗体时其活性则大大降低。与单克隆抗体相比，BIIB4 和 BIIB5 的组合还显著进一步增强了表皮生长因子受体抑制剂厄洛替尼和 mTOR 抑制剂雷帕霉素的抗肿瘤活性。此外，在骨肉瘤和肝癌异种移植模型中，BIIB4 和 BIIB5 联合治疗显著降低了肿瘤生长，其效果强于每种单克隆抗体。总之，我们的研究结果表明，针对 IGF-IR 上的多个不同抑制性表位可能是一种更有效的影响癌症中 IGF-IR 通路的策略。
