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 is a humanized immunoglobulin G (IgG) monoclonal antibody (mAb) against the extracellular domain of recombinant HER2 with an affinity constant () of 0.1 nM (11). In-Trastuzumab, Cy5.5-trastuzumab, and Ga-trastuzumab-F(ab') have been developed for imaging of human breast cancer (12-16); however, the pharmacokinetics of intact radiolabeled mAb, with high liver uptake and slow blood elimination, are generally not ideal for imaging. Smaller antibody fragments, such as Fab or F(ab´), have better imaging pharmacokinetics because they are rapidly excreted by the kidneys. A novel class of recombinant affinity ligands (Affibody molecules) for HER2 was constructed on the basis of a 58-amino acid -domain residue from one of the IgG-binding domains of staphylococcal protein A (17). Affibody molecules exhibit high binding affinity to HER2 with values of <50 nM. Various radiolabeled Affibody molecules have been studied with regard to their ability for imaging HER2 in tumors [PubMed]. DOTA-Z, also known as ABY-002, is a synthetic Affibody molecule that was produced for labeling with In. In-DOTA-Z has been evaluated in nude mice bearing human SKOV-3 ovarian cancer cells with the use of single-photon emission computed tomography (18). Tolmachev et al. (19) prepared Ga-DOTA-Z for positron emission tomography (PET) imaging of HER2-positive tumors.
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。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HER1和HER2的高表达与不良预后相关（7 - 10）。曲妥珠单抗是一种人源化免疫球蛋白G（IgG）单克隆抗体（mAb），针对重组HER2的细胞外结构域，亲和常数（）为0.1 nM（11）。铟 - 曲妥珠单抗、Cy5.5 - 曲妥珠单抗和镓 - 曲妥珠单抗 - F(ab')已被开发用于人类乳腺癌成像（12 - 16）；然而，完整放射性标记单克隆抗体的药代动力学，肝脏摄取高且血液清除缓慢，通常对于成像并不理想。较小的抗体片段，如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。基于葡萄球菌蛋白A的一种IgG结合结构域的58个氨基酸的 - 结构域残基构建了一类新型的针对HER2的重组亲和配体（亲和体分子）（17）。亲和体分子对HER2表现出高结合亲和力，解离常数<50 nM。已研究了各种放射性标记的亲和体分子在肿瘤中成像HER2的能力[PubMed]。DOTA - Z，也称为ABY - 002，是一种合成的亲和体分子，用于用铟标记。铟 - DOTA - Z已在携带人SKOV - 3卵巢癌细胞的裸鼠中使用单光子发射计算机断层扫描进行了评估（18）。托尔马切夫等人（19）制备了用于HER2阳性肿瘤正电子发射断层扫描（PET）成像的镓 - DOTA - Z。
