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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling
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Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling

机译：组合抗体治疗通过抑制内体循环而下调表皮生长因子受体

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摘要

Due to its common dysregulation in epithelial-based cancers and extensive characterization of its role in tumor growth, epidermal growth factor receptor (EGFR) is a highly validated target for antic-ancer therapies. There has been particular interest in the development of monoclonal antibodies (mAbs) targeting EGFR, resulting in two approved mAb-based drugs and several others in clinical trials. It has recently been reported that treatment with combinations of noncompetitive mAbs can induce receptor clustering, leading to synergistic receptor down-regulation. We elucidate three key aspects of this phenomenon. First, we show that highly potent combinations consisting of two noncompetitive mAbs that target EGFR domain 3 reduce surface receptor levels by up to 80% with a half-time of 0.5-5 h in both normal and transformed human cell lines to an extent inversely proportional to receptor density. Second, we find the mechanism underlying down-regulation to be consistent with recycling inhibition. Third, in contrast to the agonism associated with ligand-induced down-regulation, we demonstrate that mAb-induced down-regulation does not activate EGFR or its downstream effectors and it leads to synergistic reduction in migration and proliferation of cells that secrete autocrine ligand. These new insights will aid in ongoing rational design of EGFR-targeted antibody therapeutics.
机译：由于表皮生长因子受体（EGFR）在基于上皮的癌症中常见的失调和对其在肿瘤生长中的作用的广泛表征，因此是抗癌药物治疗的高度验证的靶标。靶向EGFR的单克隆抗体（mAb）的开发引起了人们的特别兴趣，从而产生了两种批准的基于mAb的药物以及其他几种在临床试验中的药物。最近有报道说，用非竞争性mAb组合治疗可诱导受体聚集，导致受体协同下调。我们阐明了这种现象的三个关键方面。首先，我们显示了由两种靶向EGFR域3的非竞争性mAb组成的强效组合，在正常和转化的人类细胞系中，半衰期为0.5-5 h时，表面受体水平最多可降低80％，成反比受体密度。第二，我们发现下调的机制与回收抑制相一致。第三，与配体诱导的下调相关的激动作用相反，我们证明了mAb诱导的下调不激活EGFR或其下游效应子，并且导致分泌自分泌配体的细胞的迁移和增殖协同降低。这些新见解将有助于正在进行的针对EGFR的抗体治疗药物的合理设计。

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  • 作者

    Jamie B. Spangler; rnJason R. Neil; rnSivan Abramovitch; rnYosef Yarden; rnForest M. White; Douglas A. Lauffenburger; rnK. Dane Wittrup;

  • 作者单位

    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;

    rnDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;

    rnDepartment of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel;

    rnDepartment of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel;

    rnDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;

    rnDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;

    rnDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 Massachusetts Institute of Technology, 77 Massachusetts Avenue, E19-551, Cambridge, MA 02139;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    ErbB; monoclonal antibody; tyrosine kinase; trafficking;

    机译：ErbB;单克隆抗体;酪氨酸激酶贩运;

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