Steps toward mapping the human vasculature by phage display

The molecular diversity of receptors in human blood vessels remains largely unexplored. We developed a selection method in which peptides that home to specific vascular beds are identified after administration of a peptide library. Here we report the first in vivo screening of a peptide library in a patient. We surveyed 47,160 motifs that localized to different organs. This large-scale screening indicates that the tissue distribution of circulating peptides is nonrandom. High-throughput analysis of the motifs revealed similarities to ligands for differentially expressed cell-surface proteins, and a candidate ligand–receptor pair was validated. These data represent a step toward the construction of a molecular map of human vasculature and may have broad implications for the development of targeted therapies.

[1]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[2]  International Human Genome Sequencing Consortium Initial sequencing and analysis of the human genome , 2001, Nature.

[3]  T. Savarese,et al.  Increased expression of the interleukin-11 receptor and evidence of STAT3 activation in prostate carcinoma. , 2001, The American journal of pathology.

[4]  K. Kinzler,et al.  Cell surface tumor endothelial markers are conserved in mice and humans. , 2001, Cancer research.

[5]  R Pasqualini,et al.  NG2 proteoglycan-binding peptides target tumor neovasculature. , 1999, Cancer research.

[6]  Erkki Ruoslahti,et al.  αv Integrins as receptors for tumor targeting by circulating ligands , 1997, Nature Biotechnology.

[7]  Erkki Ruoslahti,et al.  Anti-cancer activity of targeted pro-apoptotic peptides , 1999, Nature Medicine.

[8]  Carlos F. Barbas,et al.  Phage display: a Laboratory manual , 2014 .

[9]  J. Pober,et al.  IL-11 Activates Human Endothelial Cells to Resist Immune-Mediated Injury , 2000, The Journal of Immunology.

[10]  E. Ruoslahti,et al.  Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. , 1998, Science.

[11]  E. Boerwinkle,et al.  Thrombomodulin Ala455Val Polymorphism and Risk of Coronary Heart Disease , 2001, Circulation.

[12]  V. Reuter,et al.  Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. , 1999, Cancer research.

[13]  G. Clayman,et al.  Isolation of a peptide for targeted drug delivery into human head and neck solid tumors. , 2000, Cancer research.

[14]  Timo Sorsa,et al.  Tumor targeting with a selective gelatinase inhibitor , 1999, Nature Biotechnology.

[15]  Fulvio Magni,et al.  Enhancement of tumor necrosis factor α antitumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13) , 2000, Nature Biotechnology.

[16]  R Pasqualini,et al.  Molecular heterogeneity of the vascular endothelium revealed by in vivo phage display. , 1998, The Journal of clinical investigation.

[17]  M. Broyde The diagnosis of brain death. , 2001, The New England journal of medicine.

[18]  K. Kandror,et al.  Sortilin Is a Major Protein Component of Glut4-containing Vesicles* , 1997, The Journal of Biological Chemistry.

[19]  Erkki Ruoslahti,et al.  Membrane Dipeptidase Is the Receptor for a Lung-targeting Peptide Identified by in Vivo Phage Display* , 1999, The Journal of Biological Chemistry.

[20]  E Ruoslahti,et al.  RGD and other recognition sequences for integrins. , 1996, Annual review of cell and developmental biology.

[21]  W. Tong,et al.  Cloning, expression, genomic localization, and enzymatic activities of the mouse homolog of prostate-specific membrane antigen/NAALADase/folate hydrolase , 2001, Mammalian Genome.

[22]  K. Lyons,et al.  Bone morphogenetic protein-3 is a negative regulator of bone density , 2001, Nature Genetics.

[23]  E. Edelman,et al.  Perlecan is required to inhibit thrombosis after deep vascular injury and contributes to endothelial cell-mediated inhibition of intimal hyperplasia. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[24]  R Pasqualini,et al.  Molecular addresses in blood vessels as targets for therapy. , 2001, Current opinion in chemical biology.

[25]  W. Arap,et al.  CD13/APN is activated by angiogenic signals and is essential for capillary tube formation. , 2001, Blood.

[26]  A. Annila,et al.  Inhibition of β2Integrin–Mediated Leukocyte Cell Adhesion by Leucine–Leucine–Glycine Motif–Containing Peptides , 2001, The Journal of cell biology.

[27]  Erkki Ruoslahti,et al.  Organ targeting In vivo using phage display peptide libraries , 1996, Nature.

[28]  D. Mccormick Sequence the Human Genome , 1986, Bio/Technology.

[29]  P. Barrow,et al.  Bacteriophage therapy and prophylaxis: rediscovery and renewed assessment of potential. , 1997, Trends in microbiology.

[30]  M. Karplus,et al.  Three key residues form a critical contact network in a protein folding transition state , 2001, Nature.

[31]  M. Weitzman,et al.  Molecular adaptors for vascular-targeted adenoviral gene delivery. , 2000, Human gene therapy.

[32]  R Pasqualini,et al.  Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. , 2000, Cancer research.

[33]  Peter W. Latham,et al.  Therapeutic peptides revisited , 1999, Nature Biotechnology.

[34]  K. Kinzler,et al.  Genes expressed in human tumor endothelium. , 2000, Science.