Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy

• Published in: Nature 2004-06, Vol.429 (6992), p.629-635
• Main Authors: Schnitzer, Jan E, Oh, Phil, Li, Yan, Yu, Jingyi, Durr, Eberhard, Krasinska, Karolina M, Carver, Lucy A, Testa, Jacqueline E
• Format: Article
• Language: English
• Subjects: Aminopeptidases - immunology; Aminopeptidases - metabolism; Animals; Annexin A1 - immunology; Annexin A1 - metabolism; Antibodies - administration & dosage; Antibodies - immunology; Antibodies - therapeutic use; Antineoplastic agents; Bioinformatics; Biological and medical sciences; Cells; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Computational Biology; Drug Delivery Systems - methods; Drug therapy; Endothelial Cells - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Fractionation; Gene Expression Profiling; Humanities and Social Sciences; Humans; Immunotherapy; Lung Neoplasms - blood supply; Lung Neoplasms - metabolism; Lung Neoplasms - radiotherapy; Lung Neoplasms - therapy; Lungs; Mass Spectrometry; Medical imaging; Medical research; Medical sciences; Membrane Proteins - metabolism; Models, Biological; multidisciplinary; Organ Specificity; Pharmacology. Drug treatments; Proteins; Proteomics; Radioimmunotherapy - methods; Rats; Science; Science (multidisciplinary); Survival Rate; Tissues; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature02580

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 γ-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.