Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: Implications for cancer immunotherapy
Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: Implications for cancer immunotherapy
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DOI：
10.1073/pnas.0409610102
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发表时间：
2005-02-08
影响因子：
11.1
通讯作者：
Yarden, Y
中科院分区：
文献类型：
--
作者：
Friedman, LM;Rinon, A;Yarden, Y
针对受体酪氨酸激酶如EGF受体/ErbB-1和HER 2/ErbB-2的mAb抑制某些癌细胞的致瘤性生长，但是尽管这种Ab的重组版本已经用于肿瘤病房，但免疫治疗的潜在机制仍然未知。我们报告说，抗EGF受体抗体促进缓慢的内吞过程不同的快速EGF诱导的受体内化。结合不同表位的mAb显著加速受体降解。此外，mAb组合在体外抑制HER 2信号传导和动物肿瘤发生方面比单一Ab更有效。我们提出了一个模型，将免疫治疗的功效归因于在细胞表面形成的Ab受体晶格的大小，这决定了内吞清除的速率和信号阻断的程度。
mAbs to receptor tyrosine kinases such as EGF receptor/ErbB-1 and HER2/ErbB-2 inhibit the tumorigenic growth of certain cancer cells, but although recombinant versions of such Abs are already used in oncology wards, the mechanism underlying immunotherapy remains unknown. We report that anti-EGF receptor Abs promote a slow endocytic process distinct from the rapid EGF-induced receptor internalization. Combining mAbs that engage distinct epitopes significantly accelerates receptor degradation. In addition, mAb combinations are more effective than single Abs in inhibiting HER2 signaling in vitro and tumorigenesis in animals. We present a model attributing efficacy of immunotherapy to the size of Ab-receptor lattices formed at the cell surface, which dictates the rate of endocytic clearance and extent of signaling blockade.