Abstract
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.
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Acknowledgements
We thank A. Wempren, K. Hearn, M. Bourne, L. Randall and T. Smith for technical assistance. This research was supported by the National Institute of Health (Heart, Lung and Blood), National Cancer Institute, Sidney Kimmel, Schutz Foundation, California Tobacco-related Disease Research Program and California Breast Cancer Research Program.
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Supplementary Methods
Includes information on: materials; expression profiling in vivo of candidate proteins; rat tumor models; gamma scintigraphic imaging and biodistribution analysis. (DOC 28 kb)
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Oh, P., Li, Y., Yu, J. et al. Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy. Nature 429, 629–635 (2004). https://doi.org/10.1038/nature02580
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DOI: https://doi.org/10.1038/nature02580
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