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NanoString Unveils New DNA-RNA-Protein Chemistry as It Takes Aim at Immuno-Oncology Market

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NEW YORK (GenomeWeb) – NanoString Technologies has taken a step toward addressing basic and clinical research needs in immunoncology with the launch of new chemistry that enables analysis of DNA, RNA, and protein analytes from the same sample, on the same cartridge, at the same time.

In addition to the launch, NanoString executives discussed the firm's plans to develop companion diagnostics with partners in the pharmaceutical industry.

"When we think about the last 10 or 15 years of cancer innovation, it's really been about targeted therapies," NanoString CEO Brad Gray told GenomeWeb on the sidelines of the firm's first-ever investor day, held Friday in New York. "You identify which mutation is driving the tumor's growth and then you have a molecule that inhibits that protein. That is a DNA sequence game."

"The next 10 years, I think, are more about immunotherapy, and the immune system status is not coded in DNA," he said. "In order to understand how the immune system might be harnessed to fight cancer, that's not a DNA sequencing problem, it's an RNA/protein problem."

Gray predicted that pairing targeted and immunotherapies would become a more common approach to treatment and would require simultaneous analysis of both tumor DNA changes and changes in the immune system. "Our technology is the only platform that can do both at the same time on the same system," he said.

NanoString's new barcoding chemistry for the nCounter platform is a triple play, offering researchers the ability to detect DNA, RNA, and proteins from the same sample and to harmonize the data analysis. Dubbed 3D Biology, the technology is the result of three years of development led by Joe Beechem, NanoString's senior VP of research and development.

With the launch of 3D Biology, NanoString has joined Fluidigm as a genomics company pivoting to also address proteomics.

"It's solving the 'lost in translation' problem," Beechem said. "All your data comes out in the same data space."

Currently, researchers must merge data sets from different experiments. "That's a real mess," Beechem said. Limited samples must be split and protein analysis data from, say, a flow cytometry core facility must be merged with RNA sequencing data.

Using assays developed with the new chemistry, a technician can perform a single experiment using one sample that can provide all the information.

"What you want to do is understand the biology. You don't have to ask, 'Did I normalize my data correctly?'" he said. "You can plot your data on exactly the same axis. You're not spending all your time trying to convince yourself what's real."

Integrating the data will allow better longitudinal studies of the immune response, Beechem said. "Unless you get that complete picture of what all the molecular analytes are doing, you're going to be missing big things." RNA and protein levels are often not correlated for particular cell types. He pointed to cases such as studies of CD4 cells, where mRNA levels remain high for days but are not translated, and thus the protein levels are lower than mRNA levels might otherwise suggest.

Beechem said it was a challenge to get NanoString's optical barcoding technology to work with proteins. The barcodes attach to the proteins with a photocleavable primary antibody covalently labeled with a single-stranded DNA 60-mer. Thus, the readout attaches to the analyte directly, without the use of secondary antibodies.

Using a photocleavable linker is an added touch that allows researchers to investigate complex scenarios. Some biological environments are too complicated to perform the hybridization necessary for detection, he said. In this case, shining a light in the experiment will separate the barcode from the antibody. "It allows you to back yourself out of a really messy situation and you can still measure proteins."

Beechem said he was surprised by how well the protein antibodies worked when designing the first product, an RNA and protein panel. Looking for 30 antibodies to include on the panel, Beechem started with 60, expecting many not to work. In reality, only two of them didn't work. "I spent less time debugging the raw antibody multiplexing than I thought I would," he said. That's important, because it will allow NanoString to develop panels with best-in-class antibodies to detect proteins, he said.

Gray hopes that 3D Biology will open the door to further collaborations with pharmaceutical companies. He said that NanoString is looking to build on its experience developing the Prosigna breast cancer panel to increase its menu of diagnostic tests.

"[Biopharma] companies are understanding now that the next era of companion diagnostics are not as simple as one marker at a time," Gray said. The new chemistry will help evaluate how DNA, RNA, and protein are related in immuno-oncology. Already, NanoString's business development team is evaluating "more opportunities than we can shake a stick at right now," he said.  

"We don't spend time within the company trying to discover new diagnostics," Gray explained. Instead, the firm relies on its partners' internal biomarker discovery using nCounter systems.

The firm's relationship with Merck, the largest owner of nCounter systems, exemplifies this strategy.

NanoString and Merck recently formed a partnership to develop a companion diagnostic for Merck's anti-PD-1 inhibitor, Keytruda, based on biomarkers discovered by the pharma giant. Gray suggested that there could be many more arrangements like this.

"There have been over 60 different diagnostic signatures [discovered using nCounter] that have been published in the peer-reviewed literature, any one of which could form the basis for a diagnostic. There are over 70 [nCounter] systems in 50 companies that have done biomarker work on our systems," he said.

This forms what Gray called NanoString's "dark pool of content," further noting that the firm has increased the size of its business development team to address the plethora of opportunities to develop new diagnostics. "If a biopharma company wants to build a diagnostic and is willing and able to put the economics into that, we can flex our capacity up to serve their needs."

The first product to feature the new protein barcoding technology is the nCounter RNA:Protein PanCancer panel, which NanoString launched last week. The panel includes 30 protein targets and 770 RNA targets selected for immuno-oncology research, interrogating genes related to the hallmarks of cancer and proteins involved in immune responses, such as checkpoint receptors.

The panel sells for $495 per sample, reflecting the price of $275 for the RNA components that were previously available. "There's enough hunger for doing protein and RNA to justify the price," Gray said.

As the firm launches more panels, customers will be able to mix and match RNA and protein sets to customize their targets to their research. "It's a combinatorial situation," Gray said. "From a menu of modular panels, we can offer a tremendous variety of plug and play tests."

NanoString is developing several tests for researchers, including a SNP detection assay that uses a new hybridization barcode that will be sensitive to single base changes.

By the end of 2016, NanoString expects to have at least three more protein packs on the market as well as the SNP mutation detection product. Other future panels based on 3D Biology chemistry will include those looking at immune cell profiling, DNA damage repair, and adaptive immunity. 

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