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Integrated Diagnostics Taking Aim at In Vivo Imaging, Therapeutics Markets with New PCC Reagents

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By Adam Bonislawski

Integrated Diagnostics this week introduced its new Protein-Catalyzed Capture Agents, or PCCs, a new click chemistry-based class of protein affinity reagents.

The reagents, which were described in a paper published in the September edition of the Journal of the American Chemistry Society, offer a smaller, cheaper, and easier-to-produce alternative to conventional monoclonal antibodies, said CEO Albert Luderer, and are the key elements of the company's push beyond its traditional focus on mass spec-based biomarker work and into in vivo imaging and therapeutics.

The PCC technology uses click chemistry combined with pairs of random peptide libraries – one containing acetylene functionalities and the other containing azide groups – to create affinity reagents to given proteins. Target proteins are screened against these libraries to find peptides that bind them. When these peptides bind, the protein epitope acts as a catalytic point for the acetylene-containing peptides and azide-containing peptides, which then link together via click chemistry, forming multi-peptide, protein-binding constructs that can then be pulled down and identified.

In the JACS paper, the researchers, led by California Institute of Technology professor Jim Heath – an Integrated co-founder and board member – used the technology to develop a capture agent for the protein Akt1. According to Luderer, the company has developed reagents to a number of other proteins, as well, and is approaching performance levels comparable to that of high-quality monoclonal antibodies.

With its use of large combinatorial peptide libraries to identify protein capture agents, the PCC technology resembles somewhat the DNA synbody work being done by John Chaput at Arizona State University's Biodesign Institute (see story this issue). However, while Chaput intends his reagents as alternatives to conventional antibodies, Integrated, Luderer told ProteoMonitor, is more interested in trying "to exploit those areas where monoclonals are weak."

In particular, he said, the company plans to pursue two main areas – the use of PCCs for in vivo imaging and therapeutics.

Integrated -- and proteomics research more generally -- has traditionally focused on in vitro diagnostics. However, in vivo imaging, including techniques like position emission tomography, is "another important area of diagnostics and one [in] which molecular diagnostics has never really been able to be efficaciously demonstrated," Luderer said.

PCCs, he said, could prove useful as indicator molecules for techniques like PET. Currently, he noted, "PET imaging really has only one or two indicator molecules – it's mostly glucose that is used. So you look at areas of metabolism and hotspots of metabolism" that may indicate cancer activity.

"But what we lack is, for example, an ability to test for surface motifs that would tell you, for instance, if you have a cancer, whether a cancer has metastasized," Luderer said. "While there are [protein] targets that you could look for [in vivo], you don't have a vehicle that can be used to expose the target."

Monoclonal antibodies are poorly suited to this purpose due to their large size and the fact that they can take several days "to hone in and focus" on an in vivo target, he said. On the other hand, "PCCs, being essentially small molecules, are going to be very fast identifiers of targets and have small molecule-like speed and penetrability for imaging," Luderer said.

Integrated isn't alone in exploring the potential of in vivo protein biomarkers. This month a team of researchers led by Stanford oncologist Dean Felsher published a paper in Science Translational Medicine on an algorithm they devised to predict response to cancer therapies based on cellular signaling protein dynamics and changes in tumor size.

In an interview following the release of the paper, Felsher told ProteoMonitor that he and his Stanford colleague David Paik are investigating techniques for measuring protein signaling in vivo using PET imaging. In an e-mail to ProteoMonitor this week, Felsher said that Integrated's PCCs could "be very useful" to this line of work.

In March, the US Food & Drug Administration moved medical imaging into its own drug center division due in part to anticipation of an increased demand for this technology in personalized medicine, Janet Woodcock, FDA drug division head, said at a conference hosted this week in Bethesda, Md., by the FDA and the Drug Information Association.

"The heart of a tailored therapeutic is a diagnostic, and it may be an in vitro test – that's what people think of," Woodcock said. "But it could be a medical imaging test. We think there will be a lot of business now [in this area.] We think [in vivo] imaging, being so dynamic and so forth, may be better in some ways than [in vitro] tests."

Beyond imaging, Integrated also hopes to develop the PCCs as therapeutics, Luderer said. "If you can target something in vivo, it doesn't take a great leap to realize that you might also have your therapy," he said, and, in fact, in the JACS paper the researchers demonstrated that in addition to acting as an affinity reagent, the PCC to Akt1 could be used as an inhibitor of the protein.

Luderer said the company has built PCCs to several other human therapeutic targets and has done pharmacokinetic and tolerability studies in rodents, "so this is something that might be elevated to human quickly."

"Over the next few months we'll be rolling out animal performance data, but we're quite far advanced in these studies, both in therapeutic mechanisms as well as in vivo molecular imaging," he said. While both programs are being pursued simultaneously, the in vivo imaging arm will likely be the first to market, he added.

The company's commercialization strategy for these programs remains to be decided, Luderer said, noting that while it might make sense to break the two efforts apart, the company's diagnostics work could prove useful to its therapeutics ambitions.

"Our read of the therapeutics industry today is that there's much more consideration of personalized medicine approaches to identify which patients benefit the most [from therapies]," he said. "This extends beyond in vitro tests potentially to imaging. So, breaking these [programs] up is possible, but right now we're holding everything together."

Integrated has also continued its mass-spec based in vitro biomarker work, with clinical trials underway for lung cancer and Alzheimer's diagnostics (PM 8/6/2010). In lung cancer, it is moving into a large verification trial that it plans to detail publicly in the late second quarter of 2012, Luderer said. "By that time we will have tested [more than] 500 highly pedigreed patients within the inclusion criteria of our product claim."

In Alzheimer's the company is engaged in what Luderer said is the "first diagnostic blood research test ever performed in patients that have full molecular characterization on cerebrospinal fluid markers."

Integrated has grown from eight to 25 employees over the last year and has opened two new facilities – its diagnostics headquarters in Seattle and another office in Los Angeles focused on the PCC program.

To secure rights to the click chemistry process used in making PCCs, the company has signed a worldwide licensing agreement with the Scripps Research Institute, home of Barry Sharpless, developer of the technology. It also appointed Sharpless as an advisor.


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

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