Leung Kam
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
MET is a proto-oncogene protein, also known as c-Met or hepatocyte growth factor (HGF) receptor (HGFR) (1). MET is a membrane receptor with tyrosine kinase activity that is essential for embryonic development and wound healing. MET is normally expressed by stem cells, progenitor cells, and cells of epithelial origin, whereas expression of HGF, which is the only known ligand of MET, is restricted to cells of mesenchymal origin. Upon HGF stimulation, MET induces several biological responses that lead to invasive growth (2). Abnormal MET activation in cancer correlates with poor prognosis because deregulated MET triggers tumor growth, induces angiogenesis, and activates metastasis (3). MET and HGF are overexpressed in many types of human malignancies, including kidney, liver, stomach, breast, and brain cancers (2, 4, 5). Inhibition of MET function has been shown to inhibit pathological angiogenesis as well as tumor growth and metastasis (6). On the other hand, targeting HGF instead of the HGF receptor may also be beneficial to patients by blocking binding of HGF to MET. Monoclonal antibody DN30 (150 kDa) is directed against the extracellular domain of MET, with a of 2.64 nM (6). Inhibition of HGFR function with DN30 has been shown to inhibit pathological angiogenesis as well as tumor growth and metastasis. Perk et al. (7) prepared Zr--succinyldesferrioxamine-DN30 (Zr-DN30) for imaging MET expression in tumors, showing tumor accumulation corresponding to MET expression levels. However, DN30 is a partial agonist with partial biological responses. Onartuzumab is a MET-selective humanized 1-armed monoclonal antibody (100 kDa) with anti-proliferation, anti-angiogenic, and pro-apoptotic properties against tumor growth in mouse tumor models (8). Onartuzumab is a pure antagonist with monovalent binding to MET. For use with positron emission tomography (PET), onartuzumab was conjugated with the bifunctional chelate -isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS) and labeled with Zr to form Zr-Df-onartuzumab for imaging MET expression in tumors (9).
MET是一种原癌基因蛋白，也被称为c-Met或肝细胞生长因子（HGF）受体（HGFR）（1）。MET是一种具有酪氨酸激酶活性的膜受体，对胚胎发育和伤口愈合至关重要。MET通常由干细胞、祖细胞和上皮来源的细胞表达，而HGF（MET唯一已知的配体）的表达则局限于间充质来源的细胞。在HGF刺激下，MET诱导多种导致侵袭性生长的生物学反应（2）。癌症中MET的异常激活与预后不良相关，因为失调的MET会触发肿瘤生长、诱导血管生成并激活转移（3）。MET和HGF在多种人类恶性肿瘤中过度表达，包括肾癌、肝癌、胃癌、乳腺癌和脑癌（2、4、5）。已证明抑制MET功能可抑制病理性血管生成以及肿瘤生长和转移（6）。另一方面，靶向HGF而非HGF受体也可能通过阻断HGF与MET的结合而对患者有益。单克隆抗体DN30（150 kDa）针对MET的细胞外结构域，解离常数为2.64 nM（6）。已证明用DN30抑制HGFR功能可抑制病理性血管生成以及肿瘤生长和转移。Perk等人（7）制备了Zr-琥珀酰去铁胺-DN30（Zr-DN30）用于成像肿瘤中的MET表达，显示肿瘤蓄积与MET表达水平相对应。然而，DN30是一种具有部分生物学反应的部分激动剂。奥那珠单抗是一种MET选择性人源化单臂单克隆抗体（100 kDa），在小鼠肿瘤模型中对肿瘤生长具有抗增殖、抗血管生成和促凋亡特性（8）。奥那珠单抗是一种与MET单价结合的纯拮抗剂。为用于正电子发射断层扫描（PET），奥那珠单抗与双功能螯合剂-异硫氰酸苄基-去铁胺（Df-Bz-NCS）偶联并用Zr标记，形成Zr-Df-奥那珠单抗用于成像肿瘤中的MET表达（9）。
