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ASU Biodesign Scientists Hope to Apply Direct-to-Consumer Model to Proteomics Testing

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By Adam Bonislawski

Since 2007 companies like 23andMe, Decode Genetics, and Navigenics have offered direct-to-consumer genomic testing, but now researchers at Arizona State University's Biodesign Institute are looking to apply the DTC model to proteomics data, as well.

According to Stephen Johnston, director of the institute's Center for Innovations in Medicine, immunosignaturing – a technique for broadly profiling antibody expression levels using random-sequence peptide arrays – could potentially allow for the ongoing monitoring of individuals via serum samples that people "could just send in" — a service he described as "like 23andMe but in real time."

"Our big idea is that this is what healthy people will be sending in on a regular basis for diagnostic purposes," he told ProteoMonitor. "The idea is that people could send a drop of blood through the mail and we could do the [immunosignature] on that."

Developed over the last six years by Johnston and several colleagues at the Biodesign Institute, immunosignaturing uses random-sequence peptide microarrays to capture antibodies in patient blood samples. Based on the levels of antibody binding, researchers build antibody expression profiles that can then be correlated with various disease states.

In a study in the June 2010 issue of Vaccine, a team led by Johnston and Biodesign researcher Bart Legutki provided one of the first published demonstrations of the platform, using arrays imprinted with 10,000 random sequence peptides to distinguish the immunosignatures for mice and humans that had been vaccinated for seasonal influenza from those that had not.

In addition to seasonal flu, the researchers have used the platform to look at indications including infectious diseases like coccidioidomycosis, or Valley fever; breast, brain, and pancreatic cancers; diabetes; and Alzheimer's disease, Johnston said.

"We've done about 25 different diseases and looked at whether this basic platform can be used to distinguish different diseases from each other, and it looks to be fairly robust," he said.

In January 2010, Johnston, along with his Biodesign colleagues Neal Woodbury and John Rajasekaran, launched the company Healthtell to commercialize diagnostics based on the immunosignaturing technique. Currently, Healthtell's primary focus is on developing tests for breast cancer and Valley fever, Johnston said. He declined to offer a timeline for when the company might bring a product to market, noting that it was "difficult to predict."

"It depends on the indication," he said. "For something like monitoring people for the recurrence of cancer, which we think this could work pretty well for, that might be a shorter timeline."

The technique has also shown levels of sensitivity and specificity that suggest it might be useful as a general screening tool for various indications, Johnston said.

"That's an area to be explored, and it's probably going to be a moving target in that you'll be doing well in some areas and not as well in others as the technology develops. But we can certainly pick up pre-symptomatic disease," he said.

That, Johnston noted, is the ultimate goal – using the technology as a regular screening test for the early detection of a range of diseases. Such ongoing monitoring of a subject's immunosignature would allow for changes in antibody profile to be compared against an individual baseline, as opposed to conventional protein biomarker approaches that typically compare a patient's results against some population-wide cutoff.

"What we'd really like to see is this being used to monitor healthy people on a regular basis," Johnston said — "to be able to immunosignature their health status and make presymptomatic diagnoses."

Platforms for detecting patient immune responses have typically used arrays of native proteins to read antibody binding patterns – an approach that traditionally has been both expensive and time consuming. Recently, technologies like the nucleic acid programmable protein arrays developed by Johnston's fellow Biodesign researcher Joshua LaBaer have made the development of such arrays more feasible (PM 12/24/2010). The random-sequence peptide arrays used in immunosignaturing remain significantly less expensive to produce than native protein arrays, however, making it a more practical format for the regular screening Johnston envisions.

Another advantage of the format, he noted, is the stability of antibodies in serum, which allows for the sort of easy sample collection necessary for DTC-type testing.

"If you purify an antibody, it's very labile just like any protein, but antibodies in sera are very stable. We can leave sera out on a filter paper for a week at 37 degrees and we see little or no diminishing of the signature," Johnston said, adding that his group has a paper forthcoming that demonstrates this stability.

To expand the amount of available immunosignature data and further establish the platform's potential as a monitoring technology, the Biodesign researchers have launched a program aimed at enrolling roughly 125 healthy volunteers. These subjects will maintain health diaries and submit blood — via a bloodspot obtained with a fingerprick — for analysis up to twice a week for eight weeks. The researchers will try to correlate the immunosignature in the blood to their reported health status as well as use it in studies of normal immune response to various diseases.

"We think immunosignaturing is one of the best new diagnostic platforms out there," Johnston said. "It's so simple to do, and it seems to be pretty robust, so that's why we're pushing it."

How the technology will fare in clinical trials remains to be seen. Thus far, Johnston said, the bulk of the research on the platform has been done with historical samples. Even if it delivers on its early promise, though, commercializing immunosignaturing as a DTC product will likely be a tricky process – at least if the history of DTC genetic testing is any guide.

After launching their first tests three years ago, DTC genomics firms maintained for several years an uneasy relationship with the US Food and Drug Administration, marketing their services largely as laboratory-developed tests over which the agency has traditionally exercised "enforcement discretion." In May 2010, however, in response to Pathway Genomics' plans to sell genomic sample-collection kits at retail stores Walgreens and CVS/Caremark, FDA sent letters to four major genomic testing companies instructing them to submit their products for review and clearance by the agency (PGx Reporter 06/16/2010).

Just over a month later, the Government Accountability Office issued the results of its own year-long investigation of DTC genomics testing, concluding that the companies' test results were "misleading and of little or no practical use to consumers" (PGx Reporter 07/28/2010). Since then, several firms, including Pathway and Navigenics, have changed their business models to require physician involvement in the testing process.

In addition to developing immunosignaturing for diagnostic purposes, Johnston and his colleagues are also investigating use of the technique for epitope mapping – identifying the binding regions of the captured antibodies in hopes of learning what proteins initiated the immune response, information that could aid in applications like therapeutic antibody development and vaccine design.

In a paper published in the November 2010 edition of Molecular and Cellular Proteomics the researchers detailed a bioinformatic approach to identifying antibody epitopes based on their binding to random-sequence peptide microarrays that Johnston said showed some limited potential.

"The question always comes up, 'Can't you read back from all the antibodies being bound [during immunosignaturing] to what was really in the proteome that caused that antibody response?'" he said. "So we approached that and asked, 'If we take an antibody and we put it on [the array] and we know what it binds [to], can we read back from what it bound to the real [epitope] sequence?'"

"The answer was, 'Sometimes, but only if you have a limited protein search area.' You can't go back to the whole proteome from a random sequence," he added. "You need to have a few candidate [proteins]. And we do use it that way. We can map where on a protein is the epitope that probably drove an antibody response."


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

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