How Industry Is Approaching the Search for New Diagnostic Markers and Biomarkers*

In the diagnostic and the pharmaceutical industry there is a constant need for new diagnostic markers and biomarkers with improved sensitivity and specificity. During the last 5 years, only a few novel diagnostic markers have been introduced into the market. Proteomics technologies are now offering unique chances to identify new candidate markers. Before a marker can be introduced into the market, three successive developmental phases have to be completed: the discovery phase, in which a variety of proteomics technologies are applied to identify marker candidates; the prototype developmental phase, in which immunological assays are established and validated in defined sample collectives; and finally the product development phase, with assay formats suitable for automated platforms. The hurdles that a potential candidate marker has to pass in each developmental phase before reaching the market are considerable. The costs are increasing from phase to phase, and in industry a number of questions concerning the medical need and the potential return on investment have to be answered before a proteomics discovery project is started. In this review, we will cover aspects of all three developmental phases including the repertoire of discovery tools for protein separation as well as giving an outline of modern principles of mass spectrometry for the identification of proteins.

[1]  B. Séraphin,et al.  The tandem affinity purification (TAP) method: a general procedure of protein complex purification. , 2001, Methods.

[2]  E. Petricoin,et al.  Use of proteomic patterns in serum to identify ovarian cancer , 2002, The Lancet.

[3]  Mark C. Field,et al.  Isolation and characterization of subnuclear compartments from Trypanosoma brucei. Identification of a major repetitive nuclear lamina component. , 2001, The Journal of biological chemistry.

[4]  L M Schuman,et al.  Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. , 1993, The New England journal of medicine.

[5]  L. Huber,et al.  Organelle proteomics: implications for subcellular fractionation in proteomics. , 2003, Circulation research.

[6]  R. Caprioli,et al.  Molecular imaging of biological samples: localization of peptides and proteins using MALDI-TOF MS. , 1997, Analytical chemistry.

[7]  C. Gray,et al.  Enrichment and purification of proteins of Haemophilus influenzae by chromatofocusing. , 1998, Journal of chromatography. A.

[8]  H. Langen,et al.  Reference map of the low molecular mass proteins of Haemophilus influenzae , 1998, Electrophoresis.

[9]  J. Welsh,et al.  Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[10]  William S Hancock,et al.  Targeted proteomics of low-level proteins in human plasma by LC/MSn: using human growth hormone as a model system. , 2002, Journal of proteome research.

[11]  P. Haney,et al.  SwellGel: a sample preparation affinity chromatography technology for high throughput proteomic applications. , 2003, Protein expression and purification.

[12]  J. Yates,et al.  Large-scale analysis of the yeast proteome by multidimensional protein identification technology , 2001, Nature Biotechnology.

[13]  P. Righetti,et al.  Assessment of protein expression by means of 2-D gel electrophoresis with and without mass spectrometry. , 2003, Mass spectrometry reviews.

[14]  N. Cairns,et al.  Enrichment of human brain proteins by heparin chromatography , 1999, Electrophoresis.

[15]  D. Johnson,et al.  Isolation of albumin from whole human plasma and fractionation of albumin-depleted plasma. , 1976, The Biochemical journal.

[16]  Jennifer M. Campbell,et al.  De novo sequencing of peptides using MALDI/TOF-TOF , 2002, Journal of the American Society for Mass Spectrometry.

[17]  M. Schrader,et al.  Peptidomics technologies for human body fluids. , 2001, Trends in biotechnology.

[18]  M. Karas,et al.  Mass spectrometry of peptides and proteins by matrix-assisted ultraviolet laser desorption/ionization. , 1990, Methods in enzymology.

[19]  N. Anderson,et al.  The Human Plasma Proteome , 2002, Molecular & Cellular Proteomics.

[20]  C. Gray,et al.  Two‐dimensional map of Haemophilus influenzae following protein enrichment by heparin chromatography , 1997, Electrophoresis.

[21]  K. Bennett,et al.  Subproteomics: Identification of plasma membrane proteins from the yeast Saccharomyces cerevisiae , 2002, Proteomics.

[22]  W. Hancock,et al.  The challenges of developing a sound proteomics strategy , 2002, Proteomics.

[23]  P. O’Farrell.  High resolution two-dimensional electrophoresis of proteins. , 1975, The Journal of biological chemistry.

[24]  D. Pappin,et al.  The potential use of laser capture microdissection to selectively obtain distinct populations of cells for proteomic analysis — Preliminary findings , 1999, Electrophoresis.

[25]  C. Dass,et al.  Mass spectrometric quantification of endogenous beta-endorphin. , 1991, Biological mass spectrometry.

[26]  M. Zweig,et al.  Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. , 1993, Clinical chemistry.

[27]  M. Mann,et al.  Electrospray ionization for mass spectrometry of large biomolecules. , 1989, Science.

[28]  S. Weinberger,et al.  Current developments in SELDI affinity technology. , 2004, Mass spectrometry reviews.

[29]  R. Banks,et al.  Laser capture microdissection and proteomics: Possibilities and limitation , 2001, Proteomics.

[30]  J. V. Van Beeumen,et al.  Automated nanoflow liquid chromatography/tandem mass spectrometric identification of proteins from Shewanella putrefaciens separated by two-dimensional polyacrylamide gel electrophoresis. , 2001, Rapid communications in mass spectrometry : RCM.

[31]  S. Weinberger,et al.  Recent advancements in surface‐enhanced laser desorption/ionization‐time of flight‐mass spectrometry , 2000, Electrophoresis.

[32]  M. Fountoulakis,et al.  Enrichment of low-copy-number gene products by hydrophobic interaction chromatography. , 1999, Journal of chromatography. A.

[33]  D. Desiderio,et al.  Fast atom bombardment mass spectrometric quantitative analysis of methionine-enkephalin in human pituitary tissues. , 1990, Analytical chemistry.

[34]  Yu Shyr,et al.  Proteomic patterns of tumour subsets in non-small-cell lung cancer , 2003, The Lancet.

[35]  Werner Zolg,et al.  Quantification of C‐reactive protein in the serum of patients with rheumatoid arthritis using multiple reaction monitoring mass spectrometry and 13C‐labeled peptide standards , 2004, Proteomics.

[36]  J. Yates,et al.  Shotgun Proteomics and Biomarker Discovery , 2002, Disease markers.

[37]  Mathias Dreger,et al.  Subcellular proteomics , 2021, Nature Reviews Methods Primers.

[38]  W. Colburn,et al.  Biomarkers in Drug Discovery and Development: From Target Identification through Drug Marketing , 2003, Journal of clinical pharmacology.

[39]  J. Ferlay,et al.  Globocan 2000 : cancer incidence, mortality and prevalence worldwide , 2001 .