title: Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy.
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 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.
authors.affiliation: Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, California 92121, USA.
authors.forename: Phil
authors.initials: P
authors.lastname: Oh
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jingyi
authors.initials: J
authors.lastname: Yu
authors.forename: Eberhard
authors.initials: E
authors.lastname: Durr
authors.forename: Karolina M
authors.initials: KM
authors.lastname: Krasinska
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Carver
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Testa
authors.forename: Jan E
authors.initials: JE
authors.lastname: Schnitzer
mesh_terms: D000626:Aminopeptidases / Q000276:immunology / Q000378:metabolism; D000818:Animals; D017305:Annexin A1 / Q000276:immunology / Q000378:metabolism; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D019295:Computational Biology; D016503:Drug Delivery Systems / Q000379:methods; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000532:radiotherapy / Q000628:therapy*; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D009928:Organ Specificity; D040901:Proteomics; D016499:Radioimmunotherapy / Q000379:methods*; D051381:Rats; D015996:Survival Rate
chemical_list: D017305:Annexin A1; D000906:Antibodies; D008565:Membrane Proteins; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase