Subtractive Proteomic Mapping of the Endothelial Surface in Lung and Solid Tumours for Tissue-Specific Therapy

Nature. 2004 Jun 10;429(6992):629-35. doi: 10.1038/nature02580.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aminopeptidases / immunology
  • Aminopeptidases / metabolism
  • Animals
  • Annexin A1 / immunology
  • Annexin A1 / metabolism
  • Antibodies / administration & dosage
  • Antibodies / immunology
  • Antibodies / therapeutic use
  • Computational Biology
  • Drug Delivery Systems / methods
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Gene Expression Profiling*
  • Humans
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / radiotherapy
  • Lung Neoplasms / therapy*
  • Mass Spectrometry
  • Membrane Proteins / metabolism
  • Models, Biological
  • Organ Specificity
  • Proteomics*
  • Radioimmunotherapy / methods*
  • Rats
  • Survival Rate

Substances

  • Annexin A1
  • Antibodies
  • Membrane Proteins
  • Aminopeptidases
  • X-Pro aminopeptidase