Leung Kam
National Center for Biotechnology Information, NLM, NIH
Epidermal growth factor (EGF) is a growth factor composed of 53 amino acids (6.2 kDa), and it 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: 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 and 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 patient prognosis because high levels are related to increased proliferation (7-10). Trastuzumab is a humanized 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 mAbs, 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 based on the 58-amino-acid -domain residues from one of the IgG-binding domains of staphylococcal protein A (10). Affibody molecules exhibit high binding affinity to HER2, with values of <100 pM. Various radiolabeled Affibody molecules have been studied in terms of their ability to image HER2 in tumors [PubMed]. A cysteine molecule was introduced at the C-terminus of Affibody molecules for site-specific coupling with the chelator 1,4,7,10-tetraazacyclododecane-1,4,7-tris-acetic acid-10-maleimidoethylacetamide (MMA-DOTA) for In labeling. In-[MMA-DOTA-Cys]-Z (In-DOTA-Z) has been evaluated as a single-photon emission computed tomography (SPECT) agent in nude mice bearing human colon adenocarcinoma tumors (17). Altai et al. (18) prepared [In-1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid-10-maleimidoethylacetamide-Cys]-Affibody Z ([In-MMA-NODAGA-Cys]-Z) for SPECT imaging of HER2 expression.
表皮生长因子（EGF）是一种由53个氨基酸组成（6.2 kDa）的生长因子，由外胚层细胞、单核细胞、肾脏和十二指肠腺分泌（1）。EGF刺激表皮和上皮细胞生长。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、迁移和分化中起重要作用。EGF受体（EGFR）家族由四种跨膜受体组成：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和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的高表达与患者预后不良相关，因为高表达与增殖增加有关（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IgG单克隆抗体（mAb），亲和常数（）为0.1 nM（11）。铟标记曲妥珠单抗、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通常不理想，肝脏摄取高且血液清除缓慢，不利于成像。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的一个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HER2重组亲和配体（亲和体分子）（10）。亲和体分子对HER2表现出高结合亲和力，解离常数<100 pM。已对各种放射性标记的亲和体分子在肿瘤中成像HER2的能力进行了研究[PubMed]。在亲和体分子的C末端引入了一个半胱氨酸分子，用于与螯合剂1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸-10-马来酰亚胺基乙酰胺（MMA-DOTA）进行位点特异性偶联以进行铟标记。铟-[MMA-DOTA-半胱氨酸]-Z（铟-DOTA-Z）已在荷人结肠腺癌肿瘤的裸鼠中作为单光子发射计算机断层扫描（SPECT）剂进行了评估（17）。阿尔泰等人（18）制备了[铟-1,4,7-三氮杂环壬烷，1-戊二酸-4,7-乙酸-10-马来酰亚胺基乙酰胺-半胱氨酸]-亲和体Z（[铟-MMA-NODAGA-半胱氨酸]-Z）用于HER2表达的SPECT成像。
