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Can Ciphergen s New ProteinChip SELDI System Fulfill All Its Promises?


Ciphergen Biosystems released a new ProteinChip SELDI mass spectrometry system last week, which it hopes will create new momentum for sales into the growing biomarker market and give its ailing stock a boost.

The company believes it has created a multi-purpose instrument, and is planning to sell it both for biomarker research and as a platform to run pattern-based assays in high throughput. “The whole system is built around being able to discover biomarkers and then turn them into assays, so you can use them on a routine basis,” said Martin Verhoef, president of Ciphergen’s biosystems division.

However, the company will likely have to convince its customers that its platform is this versatile, as at least one NIH researcher has told ProteoMonitor that he doubts the improved instrument can perform all these tasks.

The instrument, called ProteinChip System Series 4,000, boasts a number of improved features over the old system. However, no one outside of the company has beta-tested it so far, according to Verhoef.

The system is optimized for sensitivity, which is “roughly a factor of 10 better than the old instrument,” he said, with the limit of detection for intact IgG typically reaching 300 attomoles. However, Ciphergen did not provide any such number for a biological sample typically used in a biomarker discovery study.

The instrument can also cover a wide range of peptides and proteins in one experiment, ranging from 1,000 daltons to 300,000-400,000 daltons, Verhoef said. Also, its linear dynamic range is now on the order of 104, whereas “on the old instrument, we couldn’t even define it.”

In addition, Ciphergen says it has improved the reproducibility of the results obtained from its machine, compared to the previous model. The mass spec’s laser now scans an entire spot that carries a sample, rather than just part of it, so more data are acquired.

On the chip side, consistency will be improved, according to Verhoef, once Ciphergen automates production of its ProteinChip arrays in October, when it opens a new $1.5 million chip manufacturing facility. Previously, these chips were made “almost manually, with very little robotics help” in batches of 100-200, he said.

When it comes to resolution, the company does not want to be compared directly with competitors’ mass spectrometers, indicating this might still be a weak point. “We don’t define it in [mass spec] terms because that’s not very useful,” Verhoef said.

What is more important than mass spec resolution, he claimed, is how many proteins the instrument can distinguish in, for example, a serum sample — up to 5,000 in Ciphergen’s case, depending on how the sample is treated or fractionated prior to the experiment. “Mass spec resolution is really important if you do protein sequencing … ,” he said. “However, … what you are really interested in is discovering biomarkers out of as many proteins as you can make visible.”

To increase this number, Ciphergen plans to release two sample pre-treatment kits: A five-column prefractionation kit called MultiSelect will be commercially available within the next nine months. An affinity ligand-based technology called Protein Equilizer beads is currently available to early access partners and will be commercialized within one or two years.

Improving resolution by altering the flight tube, he said, would have compromised sensitivity.

The Series 4,000 comes in two flavors: The “personal edition” is operated manually and has a US list price of $125,000. It can be upgraded to an “enterprise edition,” an automated version that can run up to 168 chips unattended, which is listed in the US between $180,000 and $310,000. The first instruments will be shipped in mid-August, Verhoef said, and first orders are in.

Ciphergen plans to market the instrument for biomarker discovery and pattern-based assay development, propagating its own pattern-based approach. Ciphergen starts by analyzing a small number of samples to find a diagnostic pattern. The next step is to validate these patterns statistically in a larger sample set. Only then, a small panel of markers is chosen for identification, which involves purifying the peptides or proteins from the biological sample and sequencing them, which requires a higher-end mass spectrometer. Ciphergen uses an ABI QStar in house and sells an interface for its arrays for this instrument. After the peaks have been identified, Ciphergen says the pattern can be used as an assay on its SELDI platform in high throughput, using either chromatographic chips or chips carrying antibodies.

Purifying the markers from biological samples is “very difficult,” Verhoef conceded, but “gets much, much easier” with SELDI, which allows researchers to follow the peaks throughout the purification process.

However, Timothy Veenstra of the NCI thinks Ciphergen’s instrument is not necessarily suited for the discovery and identification part of the entire process.

According to Veenstra, who heads the biomedical proteomics program at the National Cancer Institute at Frederick, high resolution is crucial, because most of the diagnostic information is typically found below 12,000 daltons. “That’s a crowded region of the spectra, and to be able to distinguish components that may be close together is important,” he said. Veenstra and his colleagues published an article in the June issue of Endocrine-Related Cancer in which they compared diagnostic patterns obtained with a QStar and an older Ciphergen system, and concluded that “the use of high resolution MS yields superior classification patterns as compared with those obtained with lower resolution instrumentation.”

Veenstra also claimed that nobody has purified a low-abundance protein that came from a SELDI pattern yet. “Biomarkers that are specific for a specific disease state, we anticipate them to be of low abundance, and their technology is not well suited to [identify them],” he said.

Most proteins identified following the Ciphergen approach to date, he said, have turned out to be high-abundance inflammatory response proteins. Even in combination, these proteins may not be specific for a certain disease state. “You are just distinguishing cancer from normal, not ovarian cancer from normal [as well as other cancers],” he said.

Ciphergen, however, says it has successfully used its approach to identify three proteins which, in combination, are specific for ovarian cancer — a peptide fragment of a common protein, a modified protein, and a modified full-length protein, according to Verhoef. A study validating these markers in several hundred samples, including samples from other cancer types, in collaboration with several academic institutes, has been accepted for publication by Cancer Research, he said.

Rather than in discovery research, Veenstra thinks Ciphergen’s system has potential as a diagnostic tool. “This has potentially huge impact in diagnostic medicine,” he said. “But the power is not so much in identifying what these peaks are … The power is just in the pattern that you see,” which could distinguish disease states specifically.

However, pattern-based assays that don’t involve identification of the proteins — described in Liotta’s and Petricoin’s Lancet paper in 2002 — are precisely what Ciphergen no longer wants to be associated with. “We do not talk about a pattern of datapoints,” Verhoef said.

Meanwhile, Gordon Whiteley, director of the serum proteomics patterns clinical reference laboratory at NCI-Frederick, has been evaluating the pattern-based ovarian cancer test described in the Lancet article, including Ciphergen’s technology, in order to see if it can be used in an FDA-approved diagnostic test someday. Whiteley, with Ciphergen’s help, has been analyzing and optimizing every step in the process, from serum collection to robotic pipetting to acquiring mass spectra. “We did get it to be reproducible, and now we are about to proceed to the next step, which is the formal development of the methodology” under the FDA’s medical device regulations, he said. This will include a prospective clinical trial. “Our mandate is to say, ‘This is a legitimate method’ and give companies a gold standard or a reference point [and] confidence that they can invest money in this technology and develop their own tests and commercialize them,” he said.

— JK