Technology Advances

click to enlarge   These data from a Thermo Fisher Scientific mass spectrometer show targeted peptide confirmation and quantitation using highly-selective reaction monitoring. (Source: Thermo Fisher Scientific)

Technologies from genomics and proteomics can already improve clinical trials. As Mary Lopez, PhD, director of Thermo Fisher Scientific’s Biomarker Research Initiatives in Mass Spectrometry (BRIMS) Center (Cambridge, Mass.), says, “Quantitative proteomics—using mass spectrometry to accurately quantify the amount of a particular biomarker—can provide a reading on whether a disease is present or likely to be present.” Such tests can be used in clinical trials to diagnose the progression or remission of disease in a patient. As Lopez says, “Mass spectrometry-based assays add specificity to clinical trials.”

Thermo Fisher’s TSQ Quantum Access—a triple quadrupole LC/MS—can be applied to clinical trial samples. “The Thermo Fisher umbrella of companies also gives us access to various sample-preparation tools to use with that MS,” says Lopez. Thermo Fisher software even predicts the most accurate targeted assay for a particular molecule to be monitored on the Quantum. “At BRIMS,” says Lopez, “we work with collaborators, such as the Mayo Clinic, to develop specific assays for putative biomarkers that could be used in a clinical trial to monitor drug efficacy or as a diagnostic.”

Using MS for such assays provides high throughput and multiplexing. As Lopez says, “The TSQ Quantum Ultra is the only triple quadrupole mass spectrometer that can employ high resolution—0.2 [full width at half maximum]—for precursor ion selection, allowing for highly-selective reaction monitoring, or H-SRM.” She adds, “This dramatically reduces the chemical interferences from the background while maintaining high transmission efficiency. In addition, this instrument can monitor over 300 H-SRM transitions per segment of LC run and trigger Quantitation-Enhanced Data-Dependent MS/MS (QED-MS/MS) for peptide-sequence confirmation.” So researchers could potentially accurately quantify numerous molecules simultaneously.

Some companies also improve existing assays. Singulex, Hayward, Calif., for example, developed a technique for single-molecule detection that “extends the dynamic range of immunoassays by one to two orders of magnitude,” says Philippe Goix, PhD, chief executive officer. “If you have an immunoassay, we can quickly integrate it into our platform without drastically changing it.” Singulex is already developing ways to use this technology in clinical trials. For one thing, its high sensitivity could measure normal levels of hard-to-measure proteins, and then look for changes after administering a drug during a clinical trial.

Eventually, genomics and proteomics will improve many clinical trial measurements.

Tomorrow's Trials     click to enlarge This light-producing mouse shows in vivo expression of the insulin promoter.(Source: Caliper Life Sciences) "We’ve seen our pharma partners using genomic technologies to find optical-based endpoints, such as biomarkers for clinical trials," says Mark Roskey, PhD, vice president, reagents and applied biology at Caliper Life Sciences, Hopkinton, Mass. Roskey also sees today’s technology moving even farther into tomorrow’s clinical trials. For example, Caliper developed a light-producing, mouse model of diabetes. In this organism, luciferase is inserted in the mouse DNA after the insulin promoter. "When the insulin promoter turns on," says Roskey, "those cells glow, and that can be viewed with our IVIS Imaging Systems." He adds, "This technology could be used to develop biomarkers to take into the clinic." Roskey also envisions some of Caliper’s proteomic technologies and products in future clinical trials. For example, the development of fluorescent probes that detect plaque could be used in studies of therapeutics designed to reduce or prevent plaque. "In vivo optical fluorescent imaging approaches can be used to detect enzymatic activity that is plaque-specific," says Roskey. Right now, this technique is limited to Caliper’s IVIS platform applied to mice, but Roskey sees human applications ahead. "This approach is amenable to human clinical trials," he says, "and in vivo optical imaging is just beginning to be used as a tool that would allow that."

About the Author
May is a publishing consultant for science and technology based in Minnesota.

This article was published in Drug Discovery & Development magazine: Vol. 11, No. 2, February, 2008, pp. 14-15.