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Nuclea Inks Collaboration with Thermo Fisher to Develop Mass Spec Assays for Type 2 Diabetes

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NEW YORK (GenomeWeb News) – Thermo Fisher Scientific and Nuclea Biotechnologies said this week they are collaborating on mass spec-based assays for quantification of native insulin and its therapeutic analogs.

According to Nuclea President and CEO Patrick Muraca, the two parties aim to clinically validate the assays using samples obtained by Nuclea with the eventual goal of bringing them to market for purposes including early detection and monitoring of type 2 diabetes.

Muraca told ProteoMonitor that, in addition to work on the insulin assays, the collaboration will take on discovery and validation of protein biomarkers linked to obesity, cardiovascular disease, renal disease, and overall metabolism. The two companies will share any intellectual property that emerges from the work, he said.

The native insulin and therapeutic analogs assay that is the initial focus of the collaboration is potentially useful for predicting response to therapy in type 2 diabetics, Muraca said. The assay is based on previous work done by Thermo Fisher researchers at the company's Biomarker Research Initiatives in Mass Spectrometry (BRIMS) Center.

At the 2014 Mass Spectrometry: Applications to the Clinical Lab annual meeting, the company presented a study led by BRIMS Center head Mary Lopez using its Q Exactive mass spec and MSIA immunoenrichment technology to quantify endogenous insulin and therapeutic analogs in patient plasma. In that work, they were able to quantify six different insulin variants at levels as low as 43 pg/mL in .5 mL of plasma.

In March, a group of company researchers, again led by Lopez, published a paper in Proteomics detailing the assay.

The Q Exactive work used high-resolution accurate mass (HRAM) mass spectrometry for quantitation, as opposed to the triple quadrupole-based approaches typically used for targeted protein quantitation.

Such HRAM-based quantitation, commonly termed parallel-reaction monitoring, has potential advantages compared to triple quad assays. Specifically, because high-resolution analyzers are able to collect data on a wide range of ions, the machines have the potential for easier assay development and better specificity.

In a triple quad-based SRM assay, the first quadrupole isolates a target precursor ion, which is then fragmented in the second quadrupole, after which a set of preselected product ions are detected in the third quadrupole. By contrast, HRAM uses the upfront quadrupole of a Q-TOF or Q Exactive machine to isolate a target precursor ion, but then monitors not just a few, but all of the resulting product ions.

Because of this, researchers don't have to determine upfront what the best transitions to monitor will be, significantly reducing assay development time. The larger number of product ions monitored via PRM should also improve the specificity of the analysis, since more transitions will be available to confirm a peptide ID. This might also reduce the effects of co-isolating background peptides.

However, while this initial assay development used the Q Exactive, the Nuclea collaboration will use triple quadrupole instruments – specifically Thermo Fisher's TSQ Vantage or Quantiva platforms – the companies noted.

The assay will also make use of Thermo Fisher's MSIA technology, which uses antibodies to pull down proteins of interest prior to mass spec analysis. The method improves the sensitivity of analysis as well as assay throughput by providing a highly enriched sample for introduction into the mass spec.

The Thermo Fisher collaboration, Muraca said, stems from previous work Nuclea did with the company in looking to put its fatty acid synthase assay, which it is developing as a marker for various cancers, onto a mass spec platform. He added that Nuclea plans to begin clinical validation of a mass spec-based FAS assay in the next several months.

Prior to its relationship with Thermo Fisher, Nuclea entered the mass spec space through its partnership with Clark University, under which the two established in 2011 a Proteomic and Metabolomic Center on the university's Worcester, Mass., campus. However, according to Muraca, the company is currently moving its mass spec holdings from Clark to a new facility in Cambridge.

Muraca also has a foot in mass spec-based biomarker research through Molecular Metabolism, a firm he founded in 2013 with the aim of developing clinical diagnostics in areas including diabetes and neurodegenerative disease. The company last year purchased the assets of defunct protein biomarker firm NextGen Sciences, which included mass spec assays for a number of potential protein biomarkers as well as mass spec instrumentation and research samples.

Molecular Metabolism has no role in Nuclea's Thermo Fisher collaboration, however, Muraca said.

Since launching in 2005, Nuclea has raised more than $25 million in funding and established collaborations with institutions including the Dana-Farber Cancer Institute and Boston Medical Center.

Commercial tests, however, have been slow in coming. According to Muraca, the company currently has two clinical assays on the market – ELISAs for the breast cancer marker HER-2/neu and renal cell carcinoma marker CAIX – both of which it acquired through its 2013 purchase of Wilex subsidiary Oncogene Science.

This week, Muraca sounded a note of hope that the Thermo Fisher deal could help his firm push additional products into the clinic. "Everything we are developing with Thermo Fisher will be a clinical tool," he said.

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