October 15, 2006 (Vol. 26, No. 18)

Protein Biomarker Discovery in Plasma

Over $1 billion in annual revenue is generated from tests developed to diagnostically measure proteins in plasma. However, only a small number of proteins are routinely measured in plasma for diagnostic purposes. While the plasma proteome holds the promise of a wealth of effective protein biomarkers, plasma proteins currently in use as biomarkers for disease are generally limited to cardiac proteins as indicators of myocardial infarction, liver enzymes as indicators of drug toxicity, coagulation factors for management of clotting disorders, and insulin.

In all, only approximately 150 proteins in plasma are utilized in a laboratory setting for diagnosing diseases. In addition, the rate in which new protein diagnostic markers have been approved by the U.S. FDA has drastically declined over the past decade to less than one new marker per year. The vast complexity of the plasma proteome acts as the greatest restraint to protein biomarker discovery. The dynamic range of proteins within plasma is known to exceed over 10 orders of magnitude in concentration and could span up to 12 orders of magnitude. Current mass spectrometry analyses only provide a dynamic range up to four orders of magnitude in a single spectrum and between four and six when combined with on-line separations technologies.

Recent iterations of mass spectrometers with increased detection sensitivity, combined with novel separations technologies, are allowing researchers to delve deeper into the plasma proteome, but these researchers are still hindered by high- and medium-abundance proteins that mask or obscure the low-abundance proteins that are candidate biomarkers.

High- and medium-abundance proteins, which comprise over 99% of the plasma proteome, limit the discovery of low-abundance plasma proteins that offer the potential as biomarkers. Because high- and medium-abundance proteins in plasma impede discovery, many researchers have shied away from investigating plasma and instead directed their proteomics analyses at tissues and cell lines with much more even distributions of protein abundances.

Innovative solutions for proteomics sample preparation present researchers with the needed tools to simplify the plasma proteome prior to downstream mass spectrometry analysis. Kits for the affinity capture of high-abundance proteins selectively remove or partition proteins in plasma samples that bury valuable biomarker candidates. These kits allow researchers to enrich the low-abundance proteins that make up less than 5% of the protein mass in plasma. The enriched low-abundance proteins can then be further fractionated and effectively analyzed. Researchers who have traditionally shied away from investigating the plasma proteome due to its vast complexity are rapidly transitioning to plasma proteomics in search of potential protein biomarkers.

Adoption of kits for the affinity capture of high-abundance proteins is a substantial component to the healthy market growth of the total proteomics sample-preparation market. As researchers become further enabled by innovative solutions for proteomics sample preparation, it is expected that these researchers will identify new protein biomarkers that will revolutionize the early detection, prognosis, and therapeutic response in disease management.

The U.S. affinity capture kits market segment accounted for 10.9% of the total U.S. proteomics sample-preparation market revenue in 2005. The increasingly realized importance of affinity capture of high-abundance proteins in plasma, combined with established consensus for when and how to deplete, is expected to provide the market sector with a high compound annual growth rate of 22.4% from 2005–2010.

Jonathan Witonsky is an industry analyst in the drug discovery technologies and clinical diagnostics group of Frost & Sullivan. Web: www.frost.com. E-mail: [email protected].

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