文章：

抗癌治疗中的配体靶向疗法

Ligand-targeted therapeutics in anticancer therapy

原文发布日期：2002-10-01

DOI: 10.1038/nrc903

类型: Review Article

开放获取: 否

要点：

1. Ligand-targeted therapeutics (LTTs) are a successful means of improving the selective toxicity of anticancer therapeutics. A radioimmunotherapy, an immunotoxin and an immunoconjugate have received clinical approval and over 100 ligand-targeted therapeutics are currently in clinical trials.
2. Recent advances in antibody engineering have allowed humanized or fully human antibody fragments to be made, which will reduce problems with immune responses against mouse antibodies. Phage-display techniques allow the selection of new targeting moieties that have high affinity for the selected target.
3. The choice of targeting ligand can be crucial to the success of targeting applications. Variables that must be considered include the degree of receptor expression; whether the ligand is internalized or not; choice of antibody, antibody fragments or non-antibody ligands; and binding affinity of the ligand.
4. New approaches to LTTs include the use of crosslinked antibody fragments, bispecific antibodies and fusion proteins that carry both the targeting moiety and the therapeutic moiety in the same molecule.
5. The principles of LTTs can also be applied to microreservoir systems such as liposomes and polymers. Targeting of microreservoir systems can significantly increase the number of therapeutic molecules that can be delivered per targeting molecule and can allow sustained release of the therapy over time.
6. More basic research needs to be done to understand how to optimize factors such as drug-release rates and pharmacokinetics and biodistribution, and also to understand the mechanisms behind some of the side effects that are caused by some classes of LTTs.
7. Important issues that need to be addressed include what are the best ways to test LTTs in the clinic, given that they might have their best responses in an adjuvant setting, and how to resolve non-clinical considerations that surround the complex intellectual-property rights in this field.
8. The principles of LTTs can also be applied to the targeted delivery of gene medicines such as antisense oligonucleotides.

要点翻译：

1. 配体靶向治疗药物（LTTs）是提高抗癌治疗选择性毒性的有效手段。目前已有一种放射免疫疗法、一种免疫毒素和一种免疫偶联药物获得临床批准，超过100种配体靶向治疗药物正处于临床试验阶段。
2. 抗体工程技术的最新进展使得人源化或全人源抗体片段得以制备，这将减少针对鼠源抗体产生免疫反应的问题。噬菌体展示技术能够筛选出对选定靶点具有高亲和力的新型靶向分子。
3. 靶向配体的选择对靶向应用的成功至关重要。需要考虑的变量包括：受体表达程度；配体是否会被内化；抗体、抗体片段或非抗体配体的选择；以及配体的结合亲和力。
4. 配体靶向治疗的新策略包括使用交联抗体片段、双特异性抗体以及将靶向部分与治疗部分整合于同一分子的融合蛋白。
5. 配体靶向治疗的原理同样适用于微储库系统（如脂质体和聚合物）。微储库系统的靶向能显著提高单个靶向分子可递送的治疗分子数量，并能实现药物的持续释放。
6. 需要开展更多基础研究以优化药物释放速率、药代动力学和生物分布等因素，并理解某些类别配体靶向治疗药物引发副作用的机制。
7. 亟待解决的重要问题包括：鉴于这类药物可能在辅助治疗环境中发挥最佳效果，如何确定最佳的临床检测方法；以及如何解决该领域复杂的知识产权相关的非临床问题。
8. 配体靶向治疗的原理还可应用于基因药物（如反义寡核苷酸）的靶向递送。

英文摘要：

Cytotoxic chemotherapy or radiotherapy of cancer is limited by serious, sometimes life-threatening, side effects that arise from toxicities to sensitive normal cells because the therapies are not selective for malignant cells. So how can selectivity be improved? One strategy is to couple the therapeutics to antibodies or other ligands that recognize tumour-associated antigens. This increases the exposure of the malignant cells, and reduces the exposure of normal cells, to the ligand-targeted therapeutics.

摘要翻译： 

细胞毒性化疗或放疗治疗癌症受到严重、有时甚至危及生命的副作用限制，这些副作用源于对敏感正常细胞的毒性，因为治疗对恶性细胞并无选择性。那么，如何提高选择性？一种策略是将治疗药物与识别肿瘤相关抗原的抗体或其他配体结合。这样可以增加恶性细胞对治疗药物的暴露，同时减少正常细胞的暴露。

原文链接：

Ligand-targeted therapeutics in anticancer therapy