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RareCyte Targets Spatial Biology Market with New Orion Instrument

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NEW YORK – Life science firm RareCyte has taken a turn from the cell isolation and analysis tools that have thus far been its main focus, with the launch of a new system designed for high-resolution spatial analysis of tissue samples.

The firm's Orion instrument relies on high-resolution microscopy technology similar to what has been at the core of its tools for isolation, characterization, and biomarker analyses of rare cells in areas like cancer and prenatal testing.

In the context of spatial biology, the company has created a system that can image a pathology slide at both high speed and high resolution, while providing significantly more multiplexing capability than available alternatives, with 21 fluorescence channels.

As biochemical and molecular disease research has evolved, investigatiors are increasingly interested in examining not just the presence or absence of biomarkers but understanding how such signals are distributed across cell populations and how these spatial details might influence disease or other aspects of biology.

One area of increasing attention has been spatial genomic technologies — with new systems launched by NanoString Technologies and 10X Genomics in recent years that allow researchers to quantitatively analyze large panels of molecular targets while maintaining information about their spatial origin that can be used to map them back onto the topography of an original tissue section.

With Orion, RareCyte is addressing a different, potentially complementary need, said Tad George, RareCyte's SVP of Biology R&D.

"Technologies like NanoString's or 10X, these are really RNA-focused technologies that [are] deep in terms of the number of RNAs you can look at simultaneously, but very low resolution – typically less than 50 to 200 microns. So they're useful for kind of a broad transcriptional based profiling," George said.

"We don't do that. What we do is highresolution imaging. So we typically are imaging at the 0.3 to 0.5 micron resolution space, so sub-cellular resolution," he added.

According to George, available platforms for such higher-resolution applications have so far been limited to somewhere between three and seven channels multiplexing capability due to spectral overlap.

"When you are analyzing tissue, just to be blunt, seven targets is not enough," George said. "Health and disease really are dictated by the types of cells that are in the space and how they're interacting with one another. And their functions are dictated mostly by their protein expression, so you really want to probe and measure as many proteins [as possible] and also know where they are in relation to one another within a tissue to get a complete picture of what's going on with the disease or the treatment."

"You can imagine with all that heterogeneity and complexity, if you're forced to only use seven markers, there's lots of compromises ... you almost have to know what you're looking for … so there's a huge demand to look at many more proteins with sub-cellular resolution," he added.

Researchers have gotten around this via techniques and platforms that allow for cyclic, or repeated immunofluorescence, whereby you iteratively stain and strip and restain slides so that you can overlay greater numbers of targets.

This process can be lengthy, though, George argued, often taking more than a week just to do staining and imaging. The process also means a challenge to reproducibility and robustness for use in things like larger-scale trials where consistency of assays is crucial.

"The other technology that addresses this actually doesn't use fluorochromes, they use metal-conjugated antibodies. These are the imaging mass cytometer products that Fluidigm or IonPath produce," George added.

"The nice thing about those is you can stain the tissue with all your markers in one staining process that might take a few hours as opposed to weeks," he said. "[But] the challenge is they're extremely slow on the acquisition side, sometimes taking a week or two just to image a very small portion of the tissue, and certainly not used for whole-slide imaging."

With Orion, RareCyte was able to create an instrument that can image an entire pathology slide in 21 fluorescence channels. The process involves a single stain, without the need to cyclically process and strip slides. And the imaging is speedy enough that a whole slide can be completed within a day.

Although the imaging technology is proprietary, George said that it involves the fact that the fluorochromes involved are specifically matched to the instrument. "The instrument knows what to expect out of the fluorochrome profiles, so it is able to take those 21 fluorescent signatures and isolate them all into 21 individual channels," he explained.

Along with the Orion instrument itself, RareCyte will provide what it calls TissuePlex reagent kits that provide the ability to customize profiling panels for different applications.

"In terms of the future vision for this, we're still very early," George said. "We have shown a 21-marker panel on tonsil and lung, with a mixture of tissue architecture markers ... cell surface markers that are used to identify different cell types ... functional markers such as PDL-1... basically markers that are used to identify different cell types, probe their functional status, and also to look at … spatial arrangement … but we expect that people will be interested in making their own panels, so the TissuePlex reagent system is designed to be flexible."

According to George, RareCyte hasn't experimented itself with downstream quantitative processing. But he said that the system is designed to be open-ended. "We generate [image] files that are fully compatible with ... downstream software programs that have quantitative abilities … so there's really no reason why someone wouldn't be able to apply quantitative downstream image processing," he said.

The company also hopes and anticipates users will experiment with the system across diverse analytes. "We've been initially focused on antibodies to protein targets, but there's really no reason why you could not also probe for RNA, et cetera. We just haven't developed those reagents," George said.

"The Orion instrument itself doesn't really care how the signals are generated. So we are hopeful that people will apply it to other analytes beyond just proteins for sure," he added.

The company disclosed that its first early users for the system are Peter Sorger and Sandro Santagata at the Laboratory of Systems Pharmacology at Harvard Medical School and Brigham and Women's Hospital.

According to the lab's website, the LSP is a multi-disciplinary effort tasked with investigating drug action across biochemical and genetic networks.

George also said that the firm is in late-stage discussions with several other early adopters, and although Orion is a research-use tool, there could certainly be applications for clinical translation, where many researchers are interested in panels of 10 or more biomarkers. "They just haven't had a system that can do that," he said.

"With our circulating tumor cell technology, we've designed tests for multicenter trials ... so we know how to develop repeatable, reproducible, clinical-level assays. If there do become [Orion] panels that that multiple people want to run lots of samples with, RareCyte definitely has that depth and experience to do those kinds of things," he said.

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