Leung Kam
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Epidermal growth factor (EGF) is a 53-amino-acid growth factor (6.2 kDa) that is secreted by ectodermic cells, monocytes, kidneys, and duodenal glands (1). EGF stimulates the growth of epidermal and epithelial cells. EGF and at least seven other growth factors and their transmembrane receptor kinases play important roles in cell proliferation, survival, adhesion, migration, and differentiation. The EGF receptor (EGFR) family consists of four transmembrane receptors, including EGFR (HER1/erbB-1), HER2 (erbB-2/neu), HER3 (erbB-3), and HER4 (erbB-4) (2). HER1, HER3, and HER4 comprise three major functional domains: an extracellular ligand-binding domain, a hydrophobic transmembrane domain, and a cytoplasmic tyrosine kinase domain. No ligand has been clearly identified for HER2; however, HER2 can be activated as a result of ligand binding to other HER receptors with the formation of receptor homodimers and/or heterodimers (3). HER1 as well as HER2 are overexpressed on many solid tumor cells such as breast, non–small-cell lung, head and neck, and colon cancers (4-6). The high levels of HER1 and HER2 expression on cancer cells are associated with poor patient prognosis because high levels are related to increased proliferation (7-10). Trastuzumab, a humanized immunoglobulin G (IgG) monoclonal antibody (mAb) against the extracellular domain of recombinant HER2 (11), was labeled as In-trastuzumab (12-14). C225, an anti-EGFR (HER1), mouse-human chimeric, IgG mAb, also known as erbitux and cetuximab, was labeled as Tc-EC-C225 (15, 16) and Cu-DOTA-cetuximab for imaging EGFR expression on solid tumors with the use of single-photon emission computed tomography (SPECT) and positron emission tomography (PET), respectively. However, the pharmacokinetics of the intact radiolabeled mAb, with high liver uptake and slow blood elimination, are generally not ideal for imaging (17, 18). Smaller antibody fragments, such as scFv, Fab, or F(ab'), have better imaging pharmacokinetics because they are rapidly excreted by the kidneys. Nanobodies (15 kDa) and affibodies (50 kDa) exhibit efficient and specific tumor targeting but with high kidney accumulation (19-21). An engineered fibronectin scaffold with EGFR-binding domain (Fn, 10 kDa) was radiolabeled with Cu 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugation to form Cu-DOTA-Fn as a PET probe for imaging of EGFR in tumor-bearing nude mice (22). Fn does not contain the integrin binding sequence of Arg-Gly-Asp (RGD) (23).
表皮生长因子（EGF）是一种由外胚层细胞、单核细胞、肾脏和十二指肠腺分泌的含53个氨基酸的生长因子（6.2 kDa）（1）。EGF刺激表皮细胞和上皮细胞的生长。EGF以及至少其他七种生长因子及其跨膜受体激酶在细胞增殖、存活、黏附、迁移和分化中发挥重要作用。表皮生长因子受体（EGFR）家族由四种跨膜受体组成，包括EGFR（HER1/erbB-1）、HER2（erbB-2/neu）、HER3（erbB-3）和HER4（erbB-4）（2）。HER1、HER3和HER4包含三个主要功能结构域：细胞外配体结合结构域、疏水跨膜结构域和细胞质酪氨酸激酶结构域。尚未明确鉴定出HER2的配体；然而，HER2可因配体与其他HER受体结合并形成受体同二聚体和/或异二聚体而被激活（3）。HER1以及HER2在许多实体瘤细胞如乳腺癌、非小细胞肺癌、头颈癌和结肠癌中过表达（4 - 6）。癌细胞上HERl和HER2的高表达与患者预后不良相关，因为高水平与增殖增加有关（7 - 10）。曲妥珠单抗是一种针对重组HER2细胞外结构域的人源化免疫球蛋白G（IgG）单克隆抗体（mAb）（11），曾被标记为In - 曲妥珠单抗（12 - 14）。C225是一种抗EGFR（HER1）的鼠 - 人嵌合IgG mAb，也称为爱必妥和西妥昔单抗，分别被标记为Tc - EC - C225（15, 16）和Cu - DOTA - 西妥昔单抗，用于通过单光子发射计算机断层扫描（SPECT）和正电子发射断层扫描（PET）对实体瘤中的EGFR表达进行成像。然而，完整放射性标记mAb的药代动力学，肝脏摄取高且血液清除缓慢，通常对于成像并不理想（17, 18）。较小的抗体片段，如单链抗体（scFv）、Fab或F(ab')，具有更好的成像药代动力学，因为它们可被肾脏快速排泄。纳米抗体（15 kDa）和亲和体（50 kDa）表现出高效且特异性的肿瘤靶向性，但肾脏蓄积较高（19 - 21）。一种带有EGFR结合结构域的工程化纤连蛋白支架（Fn，10 kDa）通过与铜 - 1,4,7,10 - 四氮杂环十二烷 - 1,4,7,10 - 四乙酸（DOTA）偶联进行放射性标记，形成Cu - DOTA - Fn作为PET探针，用于在荷瘤裸鼠中对EGFR进行成像（22）。Fn不包含精氨酸 - 甘氨酸 - 天冬氨酸（RGD）的整合素结合序列（23）。
