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PerkinElmer and Liotta, Petricoin Pen Partnership To Develop Immuno-Mass Spec Biomarker Platform


PerkinElmer has begun collaborating with Lance Liotta and Emanuel Petricoin of George Mason University to develop a new immuno-mass spectrometry-based platform for biomarker discovery.

The five-year alliance, announced last week, will focus specifically on using immuno-mass spectrometry to find biomarkers for ovarian, breast, and Stage I lung cancer, and to develop commercial diagnostics for those cancers.

The approach is called immuno-mass spectrometry because it uses an antibody-based immunoassay to first capture candidate disease-associated proteins and peptides, and then uses mass spectrometry to further hone in on the exact sizes of the peptides that have diagnostic potential. The technology builds upon Liotta and Petricoin's previous work using mass spectra profiles to distinguish between diseased and non-diseased samples.

"It's not just about capturing the right protein, it's about looking at a specific size isoform," Petricoin explained. "The new concept is that it's not just about whether the protein is there or not. We think, in fact, that most biomarkers discovered are going to be fragments or post-translational modifications of existing proteins. The slight size variation is going to make all the difference in whether or not it has diagnostic potential, and we're going to use mass spec to distinguish the fragments from the parental proteins."

"It's not just about capturing the right protein, it's about looking at a specific size isoform."

Mary Lopez, the collaboration's leader in the Molecular Medicine department at PerkinElmer, said that Liotta and Petricoin's work and concepts fit well into her company's BioExpression platform for biomarker discovery, which involves using technology made by Vivascience to elute peptides off of high-concentration carrier proteins, and then using PerkinElmer's prOTOF2000 MALDI mass spectrometers and mass spectra processing software, developed in conjunction with Nonlinear Dynamics, to find potential biomarkers.

"Our interest in working together had started in applying Liotta's concept of carrier protein capture to biomarker discovery," said Lopez. "Going back a few years, they had developed this hypothesis, and we were interested in working with them to try to develop some products to take advantage of that strategy."

In 2002, Liotta and Petricoin published a paper in Lancet that showed that differences in mass spec ion profiles could potentially be used for diagnosing disease (see ProteoMonitor 2/18/2002).

"We started to look at what are these peaks that are changing? What's their sequence? What's their identification? How are they produced? How did they get there?" Petricoin told ProteoMonitor.

After analyzing many peaks that were different between non-diseased and diseased samples, Liotta and Petricoin came to the conclusion that almost all of the peaks represented low-molecular weight peptides.

"We recognized that almost all of them are in this low-molecular-weight bucket â€" below 20,000 daltons, or even below 10,000 daltons," said Petricoin.

After further analysis, the pair found that the low-molecular weight peptides avoided being filtered out by the kidney by sticking to high-molecular weight proteins, such as albumin. They published this research in the October 2005 issue of Clinical Chemistry.

"We found that albumin was actually mopping [these peptides] up, and saving them from kidney filtration," said Petricoin. "For example, we found fragments of BRCA2 in the blood of ovarian cancer patients, but not in healthy controls. Well, BRCA2 is a very large protein â€" 400,000 daltons. It doesn't exist itself in the blood, but fragments of it do."

"This is a completely new and exciting path," said Petricoin. "It's not just about discovering new biomarkers. It's about building an entire new platform. In some ways we think it's exploring an entirely new concept in biomarker discovery and measurement."

Based on this research, Liotta and Petricoin developed a two-dimensional approach for finding biomarkers. First, the researchers use differences in mass spectra profiles to find a protein or peptide that shows different ion intensities between healthy and diseased samples. They then develop an antibody towards that protein or peptide.

Beyond that, the researchers use MALDI mass spec to look for fragments of captured proteins and peptides that differ between diseased and non-diseased samples.

"It's all about having an affinity immunocapture knowing the ID of the protein, then in the second dimension finding out what's the exact size of that molecule," said Petricoin. "If you didn't have the exact size, you wouldn't have the diagnostic potential."

Lopez said that she had worked informally with Liotta and Petricoin for a number of years before the current collaboration was formed.

When Liotta and Petricoin called Lopez to suggest a more formal collaboration with PerkinElmer, "it made sense for us to work together to move this concept of biomarker discovery one step further by going the immuno-mass spec route," said Lopez.

While researchers at George Mason University will be discovering what biomarker candidates to develop antibodies to, and using MALDI mass spec to identify the exact size of potential diagnostic markers, PerkinElmer will provide research support, postdocs, reagents, machines, and corporate know-how, Petricoin said.

Lopez said that to her knowledge, PerkinElmer is the only company that is pursuing an immuno-mass spectrometry approach to developing diagnostics.

"This is a completely new and exciting path," said Petricoin. "It's not just about discovering new biomarkers. It's about building an entire new platform. In some ways we think it's exploring an entirely new concept in biomarker discovery and measurement."

Petricoin said that he hopes to see a commercial diagnostic come out by the end of the five-year collaboration.

"The end product is not just some nice papers," he said. "The end product is to develop, optimize, and validate immuno-mass spectrometry with specific biomarkers for lung, breast, and ovarian cancer."

Both Lopez and Petricoin declined to comment on financial arrangements of the collaboration.

Petricoin added that he no longer has any ties to Correlogic Systems, the Bethesda, Md.-based company that developed the OvaCheck proteomic pattern-based ovarian cancer test.

"We had a CRADA [Cooperative Research and Development Agreement] with them when we were at the NIH, but that ended in March 2004, and we've had no involvement with them since then," said Petricoin. "They're developing and commercializing their own thing, which is great. We're not involved in their commercialization and their ongoing development."

â€" Tien Shun Lee ([email protected])

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