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Immundiagnostik Deal Offers Thermo Fisher Chance to Highlight Immunoaffinity Mass Spec Workflows


Thermo Fisher Scientific last week announced a collaboration with German diagnostics firm Immundiagnostik for development of mass spec-based assays for protein and peptide quantitation.

The deal will focus on development and commercialization of new LC-MS/MS assays for the diagnosis of cardiovascular disease and bone metabolism disorders and offers Thermo Fisher a venue for refining and demonstrating its clinical mass spec workflows, in particular its Mass Spectrometric Immunoassay, or MSIA, technology.

Immundiagnostik's current protein tests are primarily ELISA-based, but the company "is very interested in incorporating mass spec into their workflows," Jeff Zonderman, Thermo Fisher's director of clinical and toxicology LC/MS, told ProteoMonitor. "They have methodologies they are looking at that they want to move to a mass-spec based platform… to take all the advantages of immunoaffinity and all the advantages and selectivity of mass spec and bring those together."

Mass spec vendors and researchers have long touted the technology's potential as an improvement over standard ELISAs for protein quantitation, citing advantages such as better specificity and multiplexing. However, while the technique has taken off as a basic research and biomarker-discovery tool, issues such as sensitivity, throughput, and variability have slowed its move into clinical applications.

Momentum, though, has been growing, with a number of biotech, pharma, and diagnostic firms pursuing or implementing mass spec-based protein assays (PM 9/21/2012). The Thermo Fisher-Immundiagnostik pact provides another example of this trend.

Much of the activity in mass spec-based clinical proteomics has centered around immunoaffinity mass spec, which, by using antibody capture of target proteins or peptides up front of mass spec analysis, increases the technology's sensitivity while reducing the chromatography time required for sample separation.

Mass spec firms including Agilent and Bruker have ongoing research collaborations exploring clinical proteomics workflows employing use of the SISCAPA immunoaffinity technique developed by SISCAPA Assay Technologies founder and CEO Leigh Anderson.

Thermo Fisher, on the other hand, has focused primarily on workflows using the MSIA immunoenrichment technology, which it acquired last year through its purchase of proteomics firm Intrinsic Bioprobes (PM 9/23/2011).

MSIA uses a patented pipette immunoenrichment technology that features a high-throughput, high-binding-capacity microcolumn activated with antibodies to isolate low-abundance proteins in complex samples. The isolated proteins are then passed on for mass spec analysis.

The platform is particularly useful for quantifying levels of different protein isoforms, which has become an area of growing interest in proteomics as evidence has grown that an understanding of such forms is key to basic biological and clinical research. For instance, in work on parathyroid hormone that Thermo Fisher and IBI collaborated on before the acquisition, the companies' researchers identified 17 variants of the molecule present in human plasma (PM 07/16/2010).

The notion is that by quantifying these different variants researchers can develop more accurate, specific tests than simply by measuring a patient's total PTH levels.

"The MSIA technology will allow Immundiagnostik to add further specificity to their ELISA-based approach," Mary Lopez, director of Thermo Fisher's Biomarkers Research Initiatives in Mass Spectrometry Center, told ProteoMonitor. "Basically, when immunoenrichment on the tips is coupled to [mass spec] detection, sequence specificity is possible. This results in the capability to make second-generation assays."

Beyond the ability to measure protein variants with increased specificity, the MSIA tips are a promising clinical technology due to their suitability to automated workflows, Zonderman said. Automation is key to the clinical implementation of mass spec-based proteomics as it enables higher throughput along with lower costs and improved analytical variation.

With MSIA, "you basically have a technology where you can put your antibody in a tip and automate [the workflow]," Zonderman said. "There are some other features of the technology that allow us to get very good recovery, great dynamic range, and really allow the mass spec workflow – which historically has been fairly difficult and not that reproducible – to now be closer to a standard bioanalytical assay."

Researchers and clinicians "are trying to put these protein, proteomic workflows together and move them into a more reproducible format where instead of running a few samples every day, you can run a few hundred, or thousands," he added. "And I think that's what Immundiagnostik and other collaborators we're working with are interested in."

The pact, Lopez noted, gives Thermo Fisher an opportunity to refine and demonstrate the MSIA workflow in a clinical research setting.

"The implementation of MSIA in the Immunodiagnostik environment confirms the potential value of the technology for clinical research," she said. "The partnership… is synergistic because they have the clinical expertise and access to samples, whereas Thermo [Fisher] can provide the cutting edge technology."

As Zonderman noted, sticking points still remain in clinical proteomics workflows, particularly with regard to the trypsin digestion step required for reducing the target proteins to peptides for mass spec analysis. However, he noted, the rise of suitable immunoaffinity techniques for the workflow are a significant and necessary advance.

"As you move forward there are certainly other things that proteins have to deal with that small molecules don't," he said. "But you nail these one at a time, and certainly the first big issue was just getting the proteins purified to a level where you could see them in the mass spectrometer – before you even get to the trypsin issues."

"Immunoenrichment mass spec is here to stay," he added.

In addition to the Thermo Fisher deal, Immundiagnostik also has collaborations with Waters and AB Sciex for work on LC-MS/MS assays.

Immundiagnostik did not respond by press time to requests for comment, but it noted these collaborations in its most recent 2012 newsletter, saying that they "will be continued in a joint development of mass spectrometry tests for the qualitative and quantitative analysis of diagnostic marker proteins for use in routine and research.