Chopra Arvind
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894
The biological characteristics, activating ligands, functions, and signal transduction pathways of the various transmembrane epidermal growth factor receptors (EGFRs) are described elsewhere (1-3). The EGFRs are known to regulate the growth, survival, differentiation, and migration of cells through the activation of an associated intracellular tyrosine kinase (TK) signaling pathway, and they are overexpressed in many malignant epithelial tumors (2, 3). Overexpression of the EGFR in tumors has been attributed to cellular amplification of the receptor gene, and this phenomenon may result in the production of a mutated receptor in the cell (2, 4). In addition, overexpression of the EGFR in tumors usually indicates a poor clinical prognosis for a cancer patient (4). The most common mutation observed in the receptor is the deletion of an extracellular domain segment of the EGFR, including the ligand-binding region, and this generates a variant known as EGFRvIII or de2-7 EGFR (2, 4). The generation, structure, functions, and role of EGFRvIII in tumor malignancy was reviewed by Gan et al. (5). Although EGFRvIII is nonresponsive to a ligand due to the absence of a ligand-binding site, it is constitutively active with a constantly operating downstream TK signal transduction pathway that appears to promote the development of a neoplastic phenotype, particularly for glioblastoma and to some extent for other cancers such as those of the prostate and the breast (2, 6). Because the EGFR promotes and helps maintain transformed cells, several anti-EGFR antibodies that inhibit the activity of this receptor and small molecule drugs that block the downstream TK signaling pathway were developed and have been approved by the United States Food and Drug Administration for the treatment of certain cancers (2). The antibodies are designed to target the extracellular domain of the receptor, block ligand binding, and inhibit activation of the TK signal transduction pathway, which leads to downregulation of the EGFR on the cell surface. However, because EGFRvIII lacks the ligand-binding region on the extracellular domain, these antibodies cannot obstruct the constitutive mutant receptor activity (2). Hence, a monoclonal antibody (mAb), designated mAb806 and specifically targets the EGFRvIII, was generated and has been characterized in preclinical studies (7, 8). Subsequently, a chimeric form of the mAb (chAb), designated ch806, was developed and evaluated in a phase I clinical trial involving patients with cancerous tumors that overexpressed the EGFRvIII. Results from this trial indicated that ch806 can be a suitable biotherapeutic agent to treat cancers (4). Various studies performed with mAb806 or ch806 are described in separate chapters of MICAD. Studies are also in progress with another anti-EGFRvIII mAb, L8A4, to develop a radioimmunotherapeutic (RIT) agent for the treatment of cancer (9, 10). In a recent study, the use of acyclic ([()-2-amino-3-(4-isothiocyanatophenyl)propyl]--(,)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A''-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylene-triaminepentaacetic acid (1B4M-DTPA) as well as the macrocyclic ligands ()-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and α-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (MeO-DOTA) was evaluated for the labeling of L8A4 with Lu, which was considered suitable to generate an RIT agent against cancer (10). The characteristics of the various Lu-labeled conjugates of L8A4 ([Lu]-CHX-A''-DTPA-L8A4, [Lu]-1B4M-DTPA-L8A4, [Lu]-C-DOTA-L8A4, and [Lu]-MeO-DOTA-L8A4) were compared to the characteristics of L8A4 labeled with -succinimidyl 4-guanidinomethyl-3-[I]iodobenzoate ([I]SGMIB-L8A4) under (9) and (10) conditions. This chapter describes results obtained from the and the biodistribution studies performed with [Lu]-C-DOTA-L8A4 in athymic mice bearing subcutaneous U87MG.∆EGFR cell glioma xenograft tumors. Results obtained with [I]SGMIB-L8A4, [Lu]-1B4M-DTPA-L8A4, [Lu]-CHX-A''-DTPA-L8A4 , and [Lu]-MeO-DOTA-L8A4 are presented in separate chapters of MICAD (www.micad.nih.gov) (11-14).
各种跨膜表皮生长因子受体（EGFR）的生物学特性、激活配体、功能和信号转导途径在其他文献中已有描述（1 - 3）。已知EGFR通过激活相关的细胞内酪氨酸激酶（TK）信号通路来调节细胞的生长、存活、分化和迁移，并且它们在许多恶性上皮肿瘤中过表达（2, 3）。肿瘤中EGFR的过表达归因于受体基因的细胞扩增，这种现象可能导致细胞中产生突变受体（2, 4）。此外，肿瘤中EGFR的过表达通常表明癌症患者的临床预后较差（4）。在受体中观察到的最常见突变是EGFR细胞外结构域片段的缺失，包括配体结合区域，这产生了一种称为EGFRvIII或de2 - 7 EGFR的变体（2, 4）。Gan等人综述了EGFRvIII在肿瘤恶性中的产生、结构、功能和作用（5）。尽管由于缺乏配体结合位点，EGFRvIII对配体无反应，但它通过持续运行的下游TK信号转导途径具有组成性活性，这似乎促进了肿瘤表型的发展，特别是对于胶质母细胞瘤，在一定程度上对于其他癌症，如前列腺癌和乳腺癌（2, 6）。由于EGFR促进并有助于维持转化细胞，因此开发了几种抑制该受体活性的抗EGFR抗体和阻断下游TK信号通路的小分子药物，并已获得美国食品药品监督管理局批准用于治疗某些癌症（2）。这些抗体旨在靶向受体的细胞外结构域，阻断配体结合，并抑制TK信号转导途径的激活，从而导致细胞表面EGFR的下调。然而，由于EGFRvIII在细胞外结构域缺乏配体结合区域，这些抗体无法阻碍组成性突变受体的活性（2）。因此，产生了一种名为mAb806的单克隆抗体（mAb），它特异性靶向EGFRvIII，并已在临床前研究中进行了表征（7, 8）。随后，开发了mAb的嵌合形式（chAb），称为ch806，并在一项涉及过表达EGFRvIII的癌性肿瘤患者的I期临床试验中进行了评估。该试验结果表明，ch806可能是一种治疗癌症的合适生物治疗剂（4）。用mAb806或ch806进行的各种研究在MICAD的不同章节中进行了描述。针对另一种抗EGFRvIII mAb L8A4开发用于治疗癌症的放射免疫治疗（RIT）剂的研究也在进行中（9, 10）。在最近的一项研究中，评估了使用无环（[()-2 - 氨基 - 3 - (4 - 异硫氰酸苯酯基)丙基] - (,)-环己烷 - 1,2 - 二胺 - 五乙酸（CHX - A'' - DTPA）和2 - (4 - 异硫氰酸苄基) - 6 - 甲基二乙三胺五乙酸（1Bv4M - DTPA）以及大环配体（）-2-(4 - 异硫氰酸苄基) - 1,4,7,10 - 四氮杂环十二烷 - 四乙酸（C - DOTA）和α-(5 - 异硫氰酸 - 2 - 甲氧基苯基) - 1,4, 7,10 - 四氮杂环十二烷 - 1,4,7,10 - 四乙酸（MeO - DOTA）用Lu标记L8A4，认为这适合生成一种抗癌RIT剂（10）。将L8A4的各种Lu标记缀合物（[Lu] - CHX - A'' - DTPA - L8A4、[Lu] - 1Bv4M - DTPA - L8A4、[Lu] - C - DOTA - L8A4和[Lu] - MeO - DOTA - L8A4）的特性与在（9）和（10）条件下用 - N - 琥珀酰亚胺基4 - 胍基甲基 - 3 - [I]碘苯甲酸酯（[I]SGMIB-L8A4）标记L8A4的特性进行了比较。本章描述了在携带皮下U87MG.∆EGFR细胞胶质瘤异种移植瘤的无胸腺小鼠中用[Lu] - C - DOTA - L8A4进行的 和生物分布研究获得的结果。用[I]SGMIB-L8A4、[Lu] - 1Bv4M - DTPA - L8A4、[Lu] - CHX - A'' - DTPA - L8A4和[Lu] - MeO - DOTA - L8A4获得的结果在MICAD（www.micad.nih.gov）的不同章节中呈现（11 - 14）。
