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Tohoku U Spinoff Targeting Pharma Industry with SRM-MS Assays for ADMET Research

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By Adam Bonislawski

Having recently inked deals with two contract research organizations, Japanese proteomics firm Proteomedix Frontiers is looking to apply its targeted mass spectrometry platform to drug discovery and development.

In particular, the company, which was spun out of the lab of Tohoku University researcher Tetsuya Terasaki in March 2010, is targeting drug absorption, distribution, metabolism, elimination, and toxicity – or ADMET – research, as a well as drug efficacy testing and diagnostic biomarker development.

According to Terasaki – who is a director of the company – his lab has developed SRM assays for more than 400 proteins that could be important to drug development efforts, including more than 200 membrane transport proteins plus a number of cytochrome P450 enzymes and UDP-glucuronosyltransferases.

Because these transporters and enzymes "play a very important role in determining how long drugs stay in the body and where they go in the body," reliably quantitating them "is very important to predicting drug [activity]," Terasaki told ProteoMonitor.

"If we can have information about the transporter protein or enzyme protein expression in the normal and disease states, we can theoretically predict a drug's distribution in humans," he said.

Proteomedix Frontiers plans to offer its targeted mass spec services to pharma primarily through CROs, Terasaki said. Thus far, the company has signed two agreements – one with Japanese CRO Sekusiu Medical and another with French CRO Bertin Pharma. It hopes to sign a third with a North American firm within the next several months, he added.

The company also plans by the end of the year to launch several kits for researchers interested in running its SRM-MS assays in their own labs. Kits will contain reagents for sample preparation, as well as stable isotope-labeled internal reference peptides and wildtype peptides for building calibration curves.

The first kit, Terasaki said, will cover seven human transport proteins identified in a March 2010 publication by the US Food & Drug Administration as being particularly important for monitoring drug-drug interactions. Also in the works is a kit covering assays for four liver transport proteins as well as four cytochrome P450 enzymes.

Protein quantification – and quantification of membrane transport proteins in particular – has become easier in recent years due to improvements in mass spec technology, Terasaki said.

"In the past three years the ability of the machines has changed dramatically, so assay sensitivity has increased significantly," he said, citing a study his team published in 2008 wherein they quantified a series of membrane transporter proteins using SRM-MS on an AB Sciex API 5000 instrument.

At that time, Terasaki said, the researchers were only able to measure transporter proteins in extracted plasma membrane, where the proteins are located. The greater sensitivity of newer instruments – particularly AB Sciex's TripleTOF 5600, which Terasaki's team has been using for much of their recent work – allows them to work with tissue homogenate, which simplifies sample preparation.

"The advantage of the 5600 is that the [signal-to-noise] ratio is reduced significantly," he said. "So that means that you can use, [for example,] liver homogenate for the quantification, which before was not possible."

He noted also that in addition to quantification, the 5600 is well-suited to "biomarker discovery studies to identify new transporters or new receptors in the target tissue, so that is also one of the reasons that we are using this machine."

The core intellectual property underlying Proteomedix Frontiers' targeted mass spec platform is an algorithm developed in Terasaki's lab and patented by Tohuku University for selecting in silico proteotypic peptides for SRM-MS. The company has an exclusive license to this IP from the university.

Asked how SRM-MS assays measuring proteins using the peptides selected via the firm's in silico method compare to assays for the same proteins using peptides identified in publicly available resources like the SRMAtlas being developed by Swiss Federal Institute of Technology Zurich and Seattle's Institute for Systems Biology, Terasaki said that "frankly, we are not too satisfied with those databases."

"We've compared results [using peptides] selected by our algorithm and [peptides] from the [SRMAtlas] and our experience is that we prefer to use our own selection criteria."

Proteomedix Frontiers is not alone in applying SRM-MS to pharmaceutical research, with firms including Proteome Sciences (PM 11/19/2010) and SISCAPA Assay Technologies (PM 06/17/2011) striking deals with drug companies in recent months. Typically, however, these deals have focused on diagnostic biomarkers or markers for measuring drug efficacy, making Proteomedix Frontiers' interest in ADMET research somewhat unique.

Terasaki said the company has received inquiries from a number of US and European pharma companies. In April, his lab published in collaboration with scientists at Boehringer Ingelheim a study in the Journal of Pharmaceutical Sciences on the use of SRM-MS for the simultaneous quantification of drug transporters, cytochrome P450 enzymes, and UDP-glucuronosyltransferases in human liver tissue in which they measured the levels of 21 proteins that could be useful in developing pharmacokinetic and safety profiles for new drugs.

Other pharma firms have recognized the potential usefulness of protein biomarkers for investigating drug safety and efficacy, as well. At the 2011 Association for Mass Spectrometry's Applications to the Clinical Lab meeting in February, Pfizer associate research fellow Hendrik Neubert highlighted some of that company's mass spec-based biomarker work, noting that his team has found mass-spec-based protein biomarker approaches useful for gaining insight into target pathways and molecules, as well as good pharmacokinetic and pharmacodynamic models (PM 02/18/2011).

Terasaki noted that while Proteomedix Frontiers is focused mainly on assays to support drug development, his team is also interested in identifying protein biomarkers – particularly receptor proteins – for companion diagnostic use. In a paper currently in press at Neuropathology and Applied Neurobiology, his lab, along with collaborators at Kanazawa University, used SRM-MS to show that platelet-derived growth factor receptor is highly expressed in anaplastic meningiomas, suggesting that this form of brain tumor might be receptive to treatment by the kidney cancer drug sunitinib – sold by Pfizer as Sutent – which targets PDGFRβ.

"The strategy is, the doctor sends the brain cancer tissue to us and we simultaneously quantify the target receptor proteins in this tumor tissue," he said. "In this way we can know which drug target proteins are in this cancer tissue and how much they are expressed."


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

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