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Startup QuanDx Looks to Parlay 'Yin-Yang' Nucleic Acid Probe Tech into MDx Products


Having recently secured funding from a private investor, moved to the San Francisco Bay Area, and obtained the rights to a key patent covering its core nucleic acid probe technology, molecular diagnostics startup QuanDx is now shifting its attention toward developing clinical assays and forging business partnerships.

Specifically, the company has begun a small-scale clinical trial in China for its first commercial product, called Q-Fusion, a multiplex, real-time PCR-based kit to simultaneously detect 30 fusion genes in leukemia patients, QuanDx CEO Matthew Lei said recently.

In addition, QuanDx has developed a one-tube assay to detect and quantify specific BCR-ABL fusion gene transcripts to monitor tyrosine kinase inhibitor treatment response in Philadelphia chromosome-positive acute myeloid leukemia patients, Lei said.

All of QuanDx's development work revolves around its proprietary Yin-Yang probe technology, which can specifically detect nucleic acids in a homogenous format for multiple applications.

During a recent visit to the GenomeWeb offices in New York, Lei told PCR Insider that these applications include qPCR, long non-coding RNA detection, next-generation sequencing target capture and enrichment, microarray analysis, and live cell imaging.

Lei said that the Yin-Yang probe technology was invented in the early 2000s by one of his colleagues, Qingge Li, a professor at China's Xiamen University. Through a relationship with Fred Kramer, a researcher at the New Jersey Medical School and Public Health Research Institute of the University of Medicine and Dentistry of New Jersey, Li applied for patents covering the technology in the US and other parts of the world outside of China.

Further detailing the backstory of the probes' development, Kramer told PCR Insider this week that his group forged this relationship with Li when he served a sabbatical in Kramer's lab at PHRI and UMDNJ.

"[Li] thought it was valuable and thought he should have it patented elsewhere in the world," Kramer said. "We talked it over at the institute … and offered to buy the patents from the inventors. We had an arrangement that was very similar to the patent policy that we have for inventors within PHRI."

It turned out, however, that there was little interest from potential partners in the Yin-Yang probe technology — that is, until Lei and QuanDx came along. Lei founded QuanDx in New York and originally inked a licensing agreement for the probe technology from PHRI in the US and Europe.

Recently, however, QuanDx identified a private institutional investor in the Bay Area — "the resources are much better there [than in NY]," Lei noted — spurring the company to move its headquarters to Menlo Park, Calif., and purchase worldwide exclusive rights to the Yin-Yang probe patents from PHRI.

The probes, also previously called "displacing probes" or "double-stranded probes," comprise two complementary oligonucleotides of different lengths, the longer of which is labeled with a fluorophore and the shorter of which — around 10 base pairs shorter — is labeled with a quencher or fluorescence acceptor.

In its natural state, the probe is non-fluorescent due to the close proximity of the fluorophore and quencher. However, in the presence of a target nucleic acid, the negative strand is displaced by the target and the fluorphore emits fluorescence.

"The probes have extremely high specificity because they are double-stranded, and high sensitivity because the background is so low," Lei said. A nucleic acid amplification assay using Yin-Yang probes, he added, "works similar to that of TaqMan except that you collect the signal at the annealing stage instead of the extension step. This allows you to collect the signal very quickly."

He added that such assays have a wider temperature range than TaqMan and can be run on any commercial qPCR instrument.

In addition, the assays can be formatted to simultaneously detect multiple targets, a feature that, like standard qPCR, is somewhat dependent on the number of fluorescence channels on a given instrument. The Yin-Yang probes actually allow a slightly higher degree of multiplexing — described by the formula 2n-1 where "n" is the number of fluorescent channels. "So, if you have four channels, it's 15-target multiplexing," Lei said.

Kramer, who in 2011 joined QuanDx's scientific advisory board, is intimately familiar with the Yin-Yang probe technology, and is also one of the inventors of molecular beacons — a nucleic acid probe technology with similar characteristics that PHRI has successfully outlicensed to dozens of companies worldwide.

"When we saw it, we thought it might be a significant competitor to molecular beacons, and that's why we ultimately bought up the technology," Kramer said. Molecular beacons are single-stranded probes tagged with fluorophores and quenchers, and their key feature is their specificity, which arises because they can assume one of two states — bound to a target, or free to form an internal hairpin structure — and the fluorescence difference between those states can be quantified.

"We can tune the design of the molecular beacons so it's just a bit more favorable to form the probe-target hybrid," Kramer said. "That way, if there is a mismatch or mutation present in the target, that weakens the probe-target hybrid, and the alternative stable state of not being on the target and not fluorescing is favored."

Yin-Yang probes, he noted, "have the same tunable property" in that their lengths can be adjusted to favor hybridization with each other or with a target nucleic acid.

"We saw it as doing something quite the same as molecular beacons," Kramer said. "From my point of view, Yin-Yang probes should work as well as molecular beacons or TaqMan probes. The success of [QuanDx] is really dependent on identifying clinical areas where assays are needed and doing the clinical and developmental work to really get good assays."

With its recent move and investment — the amount of which Lei declined to disclose — QuanDx has begun such development work in earnest.

The company is already selling its first commercial product, the Q-Fusion assay, which screens for 30 fusion genes for leukemia using a single PCR reaction across eight tubes, providing results in two to three hours. This product, which is for research use only, is currently being evaluated in a "small-scale trial in China," Lei said.

"Now we are coming out with AML and [acute lymphoblastic leukemia] products, and BCR-ABL is next," Lei said. The attractive feature of QuanDx's BCR-ABL monitoring assay, he added, is that it will be simultaneously qualitative and quantitative, whereas most current monitoring techniques involve endpoint PCR and capillary electrophoresis analysis followed by real-time PCR for quantification in a separate step.

Lei said that QuanDx is also seeking corporate partners to help develop the Yin-Yang probes for use in applied markets such as food safety, veterinary medicine, and environmental testing.

Alongside its internal cancer work, QuanDx is also looking at how the probes might be useful in molecular assays for infectious disease, he said.

The company is holding off on seeking additional investments in the near future, but might revisit that strategy late this year or early next year, Lei said. In the meantime, QuanDx is also applying for research grants to support various development projects and is hoping to bring in some revenues with its small product portfolio.

"We feel that we are a couple of steps ahead of other companies because we already have a product," Lei said.