Leung Kam
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Epidermal growth factor (EGF) is a 53-amino acid cytokine (6.2 kDa) that is secreted by ectodermic cells, monocytes, kidneys, and duodenal glands (1). EGF stimulates 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 a poor prognosis (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) for imaging EGFR expression on solid tumors with the use of single-photon emission computed tomography (SPECT). 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 are the smallest intact antigen-binding fragments (15 kDa) isolated from heavy-chain camelid antibodies, and they exhibit efficient and specific tumor targeting (19-21). Nanobody 7D12 was labeled with Tc at its C-terminus hexahistidine tail as a SPECT agent for imaging EGFR expression in tumors in mice (22). For use with positron emission tomography (PET), nanobody 7D12 was conjugated with the bifunctional chelate -isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS) and labeled with Ga (t, 67.7 min) to form Ga-Df-Bz-NCS-7D12 for imaging HER1 expression in tumors (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个氨基酸的细胞因子（6.2 kDa）（1）。EGF刺激表皮和上皮细胞的生长。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。EGF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在许多实体瘤细胞上过度表达，如乳腺癌、非小细胞肺癌、头颈癌和结肠癌（4 - 6）。癌细胞上HER1和HER2的高表达与不良预后相关（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，被标记为Tc-EC-C225（15, 16），用于通过单光子发射计算机断层扫描（SPECT）对实体瘤上的EGFR表达进行成像。然而，完整放射性标记mAb的药代动力学通常不理想，肝脏摄取高且血液清除缓慢，不利于成像（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。纳米抗体是从骆驼科动物重链抗体中分离出的最小完整抗原结合片段（15 kDa），它们表现出高效且特异性的肿瘤靶向性（19 - 21）。纳米抗体7D12在其C末端六组氨酸尾部用锝标记作为SPECT显像剂，用于成像小鼠肿瘤中的EGFR表达（22）。为用于正电子发射断层扫描（PET），纳米抗体7D12与双功能螯合剂 - 异硫氰酸苄基去铁胺（Df-Bz-NCS）偶联并用镓（半衰期67.7分钟）标记，形成Ga-Df-Bz-NCS-7D12用于成像肿瘤中的HER1表达（23）。
