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Liotta, Petricoin Launch New Firm, Tech Could Increase, Improve Biomarker Finds

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Lance Liotta and Emanuel Petricoin have launched a new company to capitalize on technology they developed to better capture low-abundance protein biomarkers and protect them from degradation.
 
The technology, dubbed Nanotrap, was originally created to detect early-stage diseases such as cancer. Its use and the company’s commercialization efforts, however, will be initially directed at the screening of human-growth hormone in urine.
 
The new company, called Ceres, has licensed Nanotrap exclusively from the university.
 
Liotta and Petricoin remain at Theranostics Health, a company they co-founded last year [See PM 03/29/07]. Liotta is the vice president of research and development while Petricoin is the chief scientific officer.
 
The creation of the company was announced this week and company officials said it plans to move into a 2,400-square-foot space in Prince William County, Va., in the early fall. The facility will house the company’s administrative and some research and development operations.
 
Exploiting technology developed by Liotta, Petricoin, and colleagues at George Mason University aimed at improving biomarker discovery work, Ceres anticipates launching a test based on Nanotrap in the fall.
 
While the proteomics field is saturated with biomarker-discovery work and bloated with biomarkers, the success rate of validating useful markers has been alarmingly low. According to its creators, the Nanotrap technology promises to improve that by addressing two obstacles: the capture of low-abundance proteins, and the degradation of proteins.
 
Described in a December 2007 article in the journal Nano Letters, Nanotrap is based on hydrogel technology and currently takes the form of a spherical, carbon-based nanoparticle that collects, concentrates, isolates, and preserves molecules found in body fluids.
 
The inability of current technology to capture low-abundance proteins is a well-documented problem in proteomics. And in blood, it is a particular issue because of the body fluid’s wide dynamic range — 10 orders of magnitude — and the heavy concentration of the most abundant proteins, such as IgG and albumin. The 10 most common proteins account for 90 percent of all proteins found in blood, but it is the remaining 10 percent that has fascinated and eluded biomarker researchers.
 
In the Nano Letters article, the authors said that conventional detection methods are limited in their ability to find such molecules. Two-dimensional gel electrophoresis lacks the sensitivity and resolution to detect and quantify low-abundance and low-molecular-weight proteins. And mass spectrometers, though highly sensitive, cover only three to four orders of magnitude, resulting in low-abundance proteins being hidden by high-abundance ones.
 
Another challenge to biomarker work is the instability of the potential biomarkers. Immediately after procurement, blood proteins become susceptible to degradation by endogenous proteases or exogenous environmental proteases such as those associated with blood clotting, bacterial contaminants, or enzymes shed from blood cells, the authors said.
 
“Many scientists have biomarkers that have literally [had to be discarded] because the biomarker could never survive the problem of stability to actually make it into a routine, reliable clinical test,” Liotta, co-director of the Center for Applied Proteomics and Molecular Medicine at GMU, told ProteoMonitor this week. “There are many promising biomarkers and promising biomarker careers that have foundered on that problem.”
 
For their technology, the GMU team chose a responsive hydrogel, poly(N-isopropylacrylamide), or NIPAm, an extensively studied temperature-sensitive hydrogel, which they said in Nano Letters is “appealing for their potential biotechnological applications because of their stability, uniformity, and versatility with regard to the ease of making physical-chemical modifications in the particles.”
 
In testing their technology, they found that it was able to rapidly capture both fluorescein isothiocyanate and isothiocyanate-labeled myoglobin, a finding they confirmed by SDS-PAGE analysis.
 

“The fact that we’re using nanotechnology to do this and it’s not limited to proteomics is a big benefit to us.”

The scientists also constructed a second class of gel particles containing NIPAm and acrylic acid, NIPm/AAc, to incorporate a charge-based affinity bait into the particles and showed that they were able to concentrate analytes from solution with “substantially greater efficiency relative to underivatized NIPAm particles,” according to the article.
 
Finally, they tested their technology for its ability to protect proteins from degradation. They incubated the NIPAm/AAc particles in a solution containing trypsin and lysozyme in conditions that would allow both to enter the particle. Analysis of the captured proteins by SDS-PAGE after incubation for one hour and overnight showed only two bands, one corresponding to trypsin, the other to full-length lysozyme, which they said indicates no degradation of the proteins had occurred.
 
Analysis also indicated the presence of low-molecular-weight peptide fragments. The lysozyme had been proteolyzed by the trypsin in the absences of the NIPAm/AAc particles, according to the researchers.
 
“These results clearly indicate that sequestration of small proteins by affinity-bait particles can effectively shield bound proteins from proteases, including those … capable of entering the particle interior,” the researchers said.
 
Since the publication of the article, the GMU team has further refined the technology, building up the core shell of the particle by adding more layers and a molecular sieving shell, developing additional bait chemistry to put inside the particle, and adapting it for use with urine.
 
Because their follow-up work is not yet published, Liotta and Petricoin declined to disclose their findings but said that the new bait chemistry is designed to capture different kinds of molecules including glycoproteins, phosphoproteins, and positively and negatively charged proteins.
 
Nanotrapping HGH
 
Ceres’ initial technology commercialization efforts are directed at screening for human-growth hormone, “a market without competition at this point, at least for urine testing,” Thomas Dunlap, a co-founder and CEO of Ceres, told ProteoMonitor.
 
Sports-governing organizations will allow athletes to be tested for HGH via urine but not blood, but “currently it’s impossible to measure human growth hormone in urine because it’s at such extraordinarily low concentrations,” said Petricoin, chair of the department of molecular and microbiology at GMU. Liotta said that in urine HGH is 1,000 times less concentrated than in blood, below the sensitivity of immunoassays.
 
To Ceres, that represented an opportunity to apply the technology toward something no other technology addressed. The Nanotrap technology, its creators said, raises the level of HGH in urine so that it can be detected with existing immunoassays.
 
“We don’t have to invent new types of immunoassays,” Petricoin said. “All that was required was a technology to come in, do a rapid concentration, so we were able to engineer the chemical bait that binds human growth hormone.”
 
Company officials have been in talks with the World Anti-Doping Agency about a possible collaboration, which would involve further validation of the technology, Dunlap said, and if the agency is satisfied with the results, use of the technology. Manufacturing of a lab-based test for HGH is anticipated to begin in October.
 
According to Dunlap, the company made a conscious decision to apply the technology beyond proteomics. The short history of proteomics is one of companies investing their entire futures into the field, only to fail because technology development proved unexpectedly difficult or because the market wasn’t accepting of their products.
 
“I think one of the major pitfalls is tunnel vision with respect to the application of proteomics or products,” he said. “The fact that we’re using nanotechnology to do this and it’s not limited to proteomics is a big benefit to us.”
 
Still, its developers see obvious proteomics targets for the Nanotrap. The GMU researchers use the technology as the front-end fractionation part of all biomarker discovery work they are doing with body fluids, Liotta and Petricoin said, and are working on a kit based on the technology to be used as a general laboratory reagent for fractionating samples.
 
They also are collaborating with the Instituto Superiore di Sanita in Rome — the chief scientific arm of the Italian National Health Service — to hunt for biomarkers for a number of cancers, including breast, prostate, ovarian, and lung, as well as infectious diseases, Liotta and Petricoin said. They may also extend their work into neurodegenerative diseases. Ceres would have the rights to develop Nanotrap for any biomarkers discovered as part of that collaboration, Dunlap said.
 
Most of the proteomics applications will be left to the GMU team to develop, he said, because proteomics-based diagnostics take longer to develop, “so our smaller lab and start-up function is probably going to be to focus on things that we can commercialize more quickly.” That includes applications for nanoforensics, toxin purification, anti-pathogenic blood-borne viruses, and defense.
 
The company has raised $700,000 in private investments so far, and a private capital offering will be made in August with a goal of raising $5 million. In addition, Prince William County, located outside Washington, DC, has pledged $100,000 to develop Ceres’ headquarters.
 
The company expects to start generating revenues by the beginning of its second year of operation and reach profitability by its third year. The plan is for Ceres to go public or to be sold within four to six years, said Dunlap, a lawyer by training who has gone back to school in order to bone up on his scientific knowledge. He continues to practice law at his Virginia law firm.
 
Initially, the company will operate as an R&D and product-commercialization firm, but eventually would like to provide services to large pharma companies.
 
“Eventually, we’d like to be a full-service company,” Dunlap said, citing Invitrogen as a model for Ceres.

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