文章：

比较抗体和小分子治疗癌症

Comparing antibody and small-molecule therapies for cancer

原文发布日期：2006-09-01

DOI: 10.1038/nrc1913

类型: Review Article

开放获取: 否

要点：

1. The concept of specific molecular targeting has been applied to the development of innovative cancer-treatment strategies. At present, two main approaches are available for use in clinical practice: therapeutic monoclonal antibodies (mAbs) and small-molecule agents.
2. We focus on the ErbB receptor family, particularly epidermal growth factor receptor (EGFR, also known as ERBB1) as an example of a target in our comparison of mAbs and small-molecule inhibitors. Cetuximab, a mAb, and gefitinib and erlotinib, which are small-molecule inhibitors, differ markedly in their basic properties and their underlying mechanisms of action.
3. The presence of activating mutations within the ATP-binding cleft of the EGFR kinase domain is associated with the sensitivity of non-small-cell lung cancer (NSCLC) to gefitinib, but not to cetuximab. By contrast, cetuximab shows a clinical benefit for colorectal cancers that overexpress EGFR in a manner independent of EGFR mutations. In malignant glioma, the sensitivity to gefitinib is closely related to deletions within the ectodomain of EGFR. In contrast to these drug-sensitivity mutations, the appearance of the T790M mutation confers resistance to gefitinib in NSCLC.
4. There are unique immune-effector mechanisms that are only triggered by therapeutic mAbs, such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and complement-dependent cell-mediated cytotoxicity. By contrast, the effects of small-molecule agents are not directly linked to the activation of an immune response against tumour cells.
5. In general, mild adverse effects such as dermatological complications are commonly observed with these two classes of EGFR inhibitors. Although interstitial lung diseases or diarrhoea are more commonly associated with small-molecule therapies, therapeutic murine mAbs or chimeric mAbs can cause immunogenicity, leading to the production of human anti-mouse antibodies or human antichimeric antibodies, respectively.
6. It has been shown that mAbs such as trastuzumab and cetuximab exert synergistic anti-tumour effects in combination with chemotherapeutic agents more frequently than small-molecule inhibitors.
7. The combination of distinct classes of EGFR inhibitors could not only increase their efficacy, but also contribute to overcoming resistance to one class of EGFR inhibitor.
8. Further investigation into the distinct properties of these two classes of targeted agents should not only contribute to the development of new targeted agents but also provide an optimal therapeutic strategy for cancer treatment, thereby leading to the improvement of dual-targeted or multi-targeted therapy.

要点翻译：

1. 特异性分子靶向概念已应用于创新癌症治疗策略的开发。目前临床实践中主要采用两大方法：治疗性单克隆抗体和小分子药物。
2. 我们以ErbB受体家族（特别是表皮生长因子受体EGFR，亦称ERBB1）为靶点范例，对比单克隆抗体与小分子抑制剂的特性。西妥昔单抗（单克隆抗体）与吉非替尼、厄洛替尼（小分子抑制剂）在基本特性和作用机制上存在显著差异。
3. EGFR激酶结构域ATP结合裂隙中的激活突变与非小细胞肺癌对吉非替尼的敏感性相关，而与西妥昔单抗无关。相比之下，西妥昔单抗对过度表达EGFR的结直肠癌具有临床疗效，且该疗效与EGFR突变状态无关。在恶性胶质瘤中，对吉非替尼的敏感性与EGFR胞外结构域缺失密切相关。与这些药物敏感性突变相反，T790M突变的出现会导致非小细胞肺癌对吉非替尼产生耐药性。
4. 治疗性单克隆抗体可触发独特的免疫效应机制，如抗体依赖性细胞毒性、补体依赖性细胞毒性和补体依赖性细胞介导的细胞毒性。而小分子药物的作用与激活抗肿瘤免疫反应无直接关联。
5. 总体而言，这两类EGFR抑制剂通常会引起轻度不良反应（如皮肤并发症）。虽然间质性肺病或腹泻更常见于小分子药物治疗，但鼠源或嵌合单克隆抗体可能引发免疫原性，分别导致人抗鼠抗体或人抗嵌合抗体的产生。
6. 研究显示，曲妥珠单抗和西妥昔单抗等单克隆抗体与化疗药物联用产生的协同抗肿瘤效应，较小分子抑制剂更为常见。
7. 不同类别EGFR抑制剂的联合应用不仅能增强疗效，还有助于克服对某类EGFR抑制剂的耐药性。
8. 深入探究这两类靶向药物的独特属性，不仅有助于开发新型靶向药物，更能为癌症治疗提供最优策略，从而推动双靶点或多靶点治疗方案的完善。

英文摘要：

The 'magic bullet' concept of specifically targeting cancer cells at the same time as sparing normal tissues is now proven, as several monoclonal antibodies and targeted small-molecule compounds have been approved for cancer treatment. Both antibodies and small-molecule compounds are therefore promising tools for target-protein-based cancer therapy. We discuss and compare the distinctive properties of these two therapeutic strategies so as to provide a better view for the development of new drugs and the future direction of cancer therapy.

摘要翻译： 

“魔弹”概念——即特异性杀伤癌细胞的同时保护正常组织——现已得到证实，多种单克隆抗体和靶向小分子化合物已获批用于癌症治疗。因此，抗体和小分子化合物都是基于靶蛋白的癌症治疗中极具前景的工具。我们讨论并比较这两种治疗策略的独特性质，以期为开发新药和癌症治疗的未来方向提供更清晰的视角。

原文链接：

Comparing antibody and small-molecule therapies for cancer