Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Protein Eng Des Sel. 2012 Feb;25(2):47-57. doi: 10.1093/protein/gzr056. Epub 2011 Dec 9.
No single engineered protein has been shown previously to robustly downregulate epidermal growth factor receptor (EGFR), a validated cancer target. A panel of fibronectin-based domains was engineered to bind with picomolar to nanomolar affinity to multiple epitopes of EGFR. Monovalent and homo- and hetero-bivalent dimers of these domains were tested for EGFR downregulation. Selected orientations of non-competitive heterodimers decrease EGFR levels by up to 80% in multiple cell types, without activating receptor signaling. These heterodimers inhibit autophosphorylation, proliferation and migration, and are synergistic with the monoclonal antibody cetuximab in these activities. These small (25 kDa) heterodimers represent a novel modality for modulating surface receptor levels.
以前没有任何一种工程蛋白被证明能够有效地下调表皮生长因子受体 (EGFR)，EGFR 是一个经过验证的癌症靶点。设计了一组基于纤维连接蛋白的结构域，以皮摩尔到纳摩尔的亲和力与 EGFR 的多个表位结合。这些结构域的单价和同型及异型二聚体被测试用于 EGFR 的下调。非竞争异二聚体的选定取向可使多种细胞类型中的 EGFR 水平降低多达 80%，而不会激活受体信号。这些异二聚体抑制受体的自动磷酸化、增殖和迁移，并且与单克隆抗体西妥昔单抗在这些活性中具有协同作用。这些小的（25 kDa）异二聚体代表了一种调节表面受体水平的新方法。
