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Proteome Sciences Completes 1,000-Patient Validation Study of Alzheimer's Plasma Protein Markers


By Adam Bonislawski

Researchers from Proteome Sciences, the UK's National Institute for Health Research, and Millipore have completed a 1,000-sample validation study of blood-based protein biomarkers for Alzheimer's disease.

Preliminary results from the study identified three biomarker panels – each containing between 11 and 16 proteins – that can distinguish between controls, mild cognitive impairment, and Alzheimer's disease, Ian Pike, Proteome Sciences' chief operational officer, told ProteoMonitor.

The data were presented this week at the Research & Standardization in Alzheimer's Disease 2012 meeting in Melbourne, Australia, by Simon Lovestone, director of the NIHR's Biomedical Research Centre for Mental Health and of the Research King’s Health Partners Academic Health Sciences Centre, London.

According to Pike, Proteome Sciences and Kings College London jointly own intellectual property for the panels, and Proteome Sciences has an exclusive license to commercialization rights.

Proteome Sciences also has an exclusive licensing deal with Millipore for research use of the markers on that company's Milliplex MAP platform, which is based on Luminex's xMAP technology.

The validation study, Pike said, follows on discovery work done several years ago by Proteome Sciences and researchers, including Lovestone, at King's College London. Some of that discovery work was published in a 2006 Brain paper.

In that work the researchers "analyzed a cohort of Alzheimer's patients and a cohort of age- and sex-matched controls using a range of techniques including two-dimensional gels" and an earlier iteration of Proteome Sciences' Tandem Mass Tag isobaric tagging reagents, Pike said.

"That [research] identified an original panel of 30 or 35 [plasma] proteins," linked to Alzheimer's, which the company and its Kings College partners also jointly patented, Pike said.

In the recently completed study the team measured these markers and combinations thereof in 1,000 randomized, blinded samples comprising age- and sex-matched Alzheimer's cases, MCI cases, and controls, using both the Milliplex MAP platform and selected-reaction monitoring mass spectrometry.

The researchers then assimilated the mass spec data and the immunoassay data with about 250 clinical measures they had for each patient into a unified database, which they then submitted to univariate and multivariate analyses, Pike said. "And by doing that we identified between 11 and 16 proteins in each [of three panels] that differentiate between Alzheimer's and controls, Alzhiemer's and MCI, and MCI and controls," he said.

In addition to providing validation data on the markers, the study offered a good test of the robustness of Proteome Sciences SRM-MS platform, Pike said. He noted that at 2,000 measurements from 1,000 samples, it represented one of the larger multiplexed SRM-MS-based protein biomarkers studies to date.

"We had very robust measurements with good reproducibility across the sample cohort," he said. "The mass spec platform held up extremely well in terms of being able to handle that many samples."

Alzheimer's biomarkers have of late been a significant area of focus for Proteome Sciences, and, in fact, last year the company released a report it had commissioned that estimated that protein biomarkers for Alzheimer's disease would represent a cumulative $9 billion market over the next ten years (PM 6/3/2011). In addition to their promise for diagnosis and predicting progression of the Alzheimer's, early detection and progression biomarkers are seen as key to pharmaceutical research into drugs for the disease.

Proteome Sciences currently offers an SRM-MS assay for measuring nine plasma proteins linked to Alzheimer's disease as well as a mass spec-based assay for measuring phosphorylated tau in cell culture and tissue samples. It introduced the plasma protein panel in July of 2010 (PM 7/16/2010) and inked a contract with pharmaceutical company Eisai in February 2011 to use it in that company's drug-development work (PM 2/4/2011). The nine proteins in the panel were included as part of the validation study presented this week, Pike said.

Much Alzheimer's biomarker work has focused on proteins in cerebrospinal fluid. Sample collection for CSF studies and clinical applications, however, requires patients to undergo a lumbar puncture. Plasma proteins like those investigated in the Proteome Sciences-NIHR validation study, on the other hand, are desirable because they can be sampled via a blood draw, making them more useful for purposes like regular monitoring.

Alzheimer's markers have typically been more difficult to detect in plasma than CSF, however, and some high-profile Alzheimer's plasma biomarker research has shown poor reproducibility.

In particular, a team of Lund University researchers published a study in January in PLoS One in which they evaluated a panel of 18 plasma proteins previously identified as Alzheimer's biomarkers in a 2007 Nature Medicine study produced by a Stanford University team headed by Tony Wyss-Coray (PM 1/30/2012).

The Lund researchers were unable to reproduce the original study's results and found that, according to its new analysis, none of the 18 proteins could identify Alzheimer's patients with high diagnostic precision.

Based on the results of the Nature Medicine paper, Wyss-Coray founded the biotech firm Satoris, which aimed to commercialize the markers. However, in an interview with ProteoMonitor following the release of the Lund group's PLoS One paper, he said that he and his collaborators had been "probably a bit naïve and too enthusiastic" about the markers they identified.

Rules-Based Medicine – now Myriad RBM – acquired Satoris in May of last year. The proteins have made it into research panels now owned by Myriad RBM, but not into an US Food and Drug Administration-approved diagnostic, and, Wyss-Coray said, he believes work on the markers is "on the backburner."

"I think there are differences [in the plasma proteome of Alzheimer's patients], and actually we continue to see differences, but I think there are a lot of issues," he said, adding that that his lab has since moved away from blind biomarker discovery work and is focusing on identifying signaling pathways linked to Alzheimer's with the aim of better understanding mechanisms of the disease.

"Measuring plasma proteins is a huge challenge, and I think most people who have experience in the field recognize that," Wyss-Coray said. He added that many such efforts have been plagued by small sample sizes, noting that his team's original Alzheimer's work looked at roughly 100 patients and controls.

"Just measuring proteins in cases and controls and then thinking you have a biomarker for the disease isn't going to work unless you have the luxury of measuring 10,000 samples," he said.

Pike noted, however, that both the discovery and validation cohorts used in Proteome Sciences' Alzheimer's biomarker researcher were considerably larger than the sets used by either the Stanford or Lund teams. He added that a number of their markers – including proteins like clusterin, alpha-2-macroglobulin, and complement factor H – have been identified as Alzheimer's markers in independent studies.

Proteome Sciences has no plans to develop the markers as an in vitro diagnostic itself, Pike said, but, rather, it intends to license them out to interested diagnostic companies.

"We've been marketing [the markers] based on the preliminary data to a number of diagnostic companies, and I would anticipate that this data, when it is fully processed, will add to the weight behind these markers and generate a lot more interest," he said. The researchers, Pike added, are currently preparing their results for submission to a peer-reviewed publication.

The company is now focusing on analyzing the mild cognitive impairment data, "to better understand the drivers of cognitive dysfunction at early timepoints that best correlate with progression to Alzheimer's type dementia and other types of dementia," he said.

Proteome Sciences is also offering SRM-MS analysis of the proteins from the three panels out of its ISO 9001-accredited facility in Frankfurt, Germany. It might add certain of the proteins to its existing nine-protein SRM-MS Alzheimer's assay, as well.

"We already offer the nine-plex plasma assay, and we will certainly look at the various data going forward to see if it justified producing a new SRM multiplex [assay] covering more of these proteins," Pike said.

Have topics you'd like to see covered in ProteoMonitor? Contact the editor at abonislawski [at] genomeweb [.] com.