Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy.
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.
Oh
Phil
P
Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, California 92121, USA.
Li
Yan
Y
Yu
Jingyi
J
Durr
Eberhard
E
Krasinska
Karolina M
KM
Carver
Lucy A
LA
Testa
Jacqueline E
JE
Schnitzer
Jan E
JE
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
D017305:Annexin A1; D000906:Antibodies; D008565:Membrane Proteins; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase