Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy
Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy
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DOI：
10.1038/nature02580
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发表时间：
2004-06-10
期刊：
影响因子：
64.8
通讯作者：
Schnitzer, JE
中科院分区：
文献类型：
--
作者：
Oh, P;Li, Y;Schnitzer, JE
组织的分子复杂性和组织内大多数细胞的不可接近性限制了体内治疗剂和成像剂的组织特异性递送的关键靶标的发现。在这里，我们描述了一种假设驱动的系统生物学方法，用于识别在组织-血液界面诱导的一小部分蛋白质，这些蛋白质本质上可以被静脉注射的抗体所接近。我们使用亚细胞分离、消减蛋白质组学和生物信息学来鉴定表现出受限组织分布和明显组织调节的内皮细胞表面蛋白。使用抗体进行表达谱分析和伽马闪烁显像成像，确定了其中两种蛋白质，氨肽酶-P 和膜联蛋白 A1，分别作为肺和实体瘤中抗体的选择性体内靶标。膜联蛋白 A1 的放射免疫疗法可破坏肿瘤并提高动物存活率。这种分析策略可以绘制内皮细胞表面蛋白的组织和疾病特异性表达，以发现可用于成像和治疗的新的可接近靶点。
The molecular complexity of tissues and the inaccessibility of most cells within a tissue limit the discovery of key targets for tissue-specific delivery of therapeutic and imaging agents in vivo. Here, we describe a hypothesis-driven, systems biology approach to identifying a small subset of proteins induced at the tissue - blood interface that are inherently accessible to antibodies injected intravenously. We use subcellular fractionation, subtractive proteomics and bioinformatics to identify endothelial cell surface proteins exhibiting restricted tissue distribution and apparent tissue modulation. Expression profiling and gamma-scintigraphic imaging with antibodies establishes two of these proteins, aminopeptidase- P and annexin A1, as selective in vivo targets for antibodies in lungs and solid tumours, respectively. Radio-immunotherapy to annexin A1 destroys tumours and increases animal survival. This analytical strategy can map tissue- and disease-specific expression of endothelial cell surface proteins to uncover novel accessible targets useful for imaging and therapy.