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IONPath Targeting Immuno-Oncology, Pathology With Multiplexed Protein Imaging System

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NEW YORK (GenomeWeb) – Pathology firm IONPath is planning a 2019 launch of its mass spec-based multiplexed protein imaging system.

Based on multiplexed ion beam imaging, the system will compete most directly with Fluidigm's Hyperion imaging mass cytometry platform and, according to IONPath CEO Harris Fienberg, could offer higher levels of speed, sensitivity, and resolution than the Fluidigm system.

Like Hyperion, the IONPath system uses metal-conjugated antibodies to tag proteins of interest. However, while Hyperion uses laser ablation to ionize samples for mass spec analysis, IONPath uses multiplexed ion beam imaging (MIBI). Additionally, the Hyperion uses Fluidigm's CyTOF technology for sample analysis, while the IONPath uses secondary-ion mass spec with a TOF analyzer.

According to Fienberg, the IONPath's resolution advantage stems from its use of an ion beam, as opposed to a laser. The Hyperion's laser focuses to a level of 1µm, whereas the ion beam used in the IONPath system goes down to around 100 nanometers. The narrower the beam used for ionization, the higher the system's potential resolution.

Fienberg claimed the IONPath has a speed advantage, as well, asserting that it could in 15 minutes analyze a tissue sample that would take the Hyperion over three hours.

He said that the company has also done comparisons of the two instruments indicating that the IONPath offers higher sensitivity, though that data has not yet been published.

Fluidigm declined to comment regarding comparisons of the Hyperion and IONPath instruments, noting that the IONPath system was not a commercial product yet. University of Zurich researcher Bernd Bodenmiller, whose lab played a significant role in developing the technology underlying the Hyperion, likewise declined to comment, noting that he did not have knowledge regarding the specs of the IONPath instrument.

Bodenmiller began considering use of the CyTOF technology for imaging while a post-doc in the lab of Stanford University professor Garry Nolan. Another of Nolan's post-docs, Mike Angelo, is an IONPath co-founder and did much of the development of the IONPath system while part of the Nolan lab. Angelo was first author on a 2014 Nature Medicine paper detailing the technology while Nolan was senior author on the study.

Nolan is an investor in IONPath and is listed by it as a co-founder, though he said he currently has no role in the company. He has also collaborated with Fluidigm and DVS Sciences, the original inventor of the CyTOF technology, on method and technology development for that system. He was previously an investor in Fluidigm but said he has since sold all his holdings in the firm and has not had a relationship with the company for several years.

Nolan is also a co-founder of Akoya Biosciences, which is commercializing another multiplexed tissue imaging technology developed in his lab, called CODEX. That system is a potential competitor to both the Hyperion and IONPath systems, though unlike those systems, it does not use mass spectrometry but rather uses oligonucleotide-linked antibodies to tag proteins for imaging with conventional fluorescence microscopes.

Nolan agreed with Fienberg's assessment that the IONPath system offers superior resolution, sensitivity, and speed compared to the Hyperion. He said his group has also been using the IONPath system to do three-dimensional analysis of tissue samples, generating 3D images of cells at a resolution of between 50 and 90 nanometers. He added that he is currently preparing two papers based on this work.

Nolan suggested that one advantage the Hyperion has over the IONPath is the fact that it is already on the market. Fluidigm launched the instrument in October of 2017 and according to the company, its recent user meeting was attended by 80-plus owners of the system.

While IONPath doesn't plan to launch its instrument until next year, Fienberg said it has several systems in the field at leading cancer research institutions and is also using the system for service work with pharmaceutical companies looking for markers of drug response and supporting trials of immuno-oncology therapies.

Launched in 2014, IONPath currently has around 30 employees and has raised more than $15 million in venture funding to date.

The company and collaborating researchers published a study this month in Cell in which they used the system to image 36 proteins at sub-cellular resolution in samples from 41 triple-negative breast cancer patients. The scientists profiled the 8002 μm of each sample at a resolution of 500 nm, looking at between 3,000 and 10,000 cells per patient and measuring the expression of proteins including tumor-related proteins like EGFR and p53, markers of proliferation and metabolic activity like Ki-67 and pS6, immune proteins like CD4 and FoxP3, and immunotherapy targets including PD-1, PD-L1, LAG3, and IDO.

Using a deep-learning based approach to analyze their data, the researchers identified differences between patients in terms of the types and quantities of immune cells present in the tumor microenvironment and also identified specific spatial compositions of immune cells that they were able to associate with overall patient survival.

Like Fluidigm with the Hyperion, IONPath plans to focus heavily on research into immunotherapy, Fienberg said.

"Immuno-oncology is definitely the area we are leading with," he said. "Folks in [immuno-oncology] are struggling to stratify their patient populations, and so much of the response to those drugs is based on the tumor microenvironment, which is incredibly complex. It involves dozens of cell types and so it's really the perfect place for our technology, which allows you to visualize 10, 20, 30, 40 proteins and look at a dozen or more cell types and expression levels in the tumor simultaneously."

He said neurology will also be an area of focus for the company.

Fienberg said IONPath aims ultimately to establish its technology as a clinical platform for use not just in pathology research but clinical pathology itself. This, he said, has informed the development of the system, with the company focused on making it easy to integrate with existing pathology workflows.

"That has been part of the vision from the beginning," he said. "If a technology like this does not fit into a clinical workflow, it's never going to be used, no matter how great the data is."

This effort has been informed by Angelo's background as a pathologist, Fienberg said, noting that the sample staining processes used by the platform are similar to those used in conventional pathology. Additionally, the system works with formalin-fixed paraffin-embedded tissue, which is among the most common formats for storing clinical samples.

"From the very beginning, this was designed with pathologists and pathology in mind," he said, adding that one of the company's first hires was a former medical director of the histology lab at the University of California, San Francisco, who heads its research services department and is involved in validating its reagents.

At around $1 million per platform, the IONPath system is significantly more expensive than conventional pathology equipment, but Feinberg said the company believes the system's ability to provide significantly richer data in an automated manner will make it worth the added investment.

"We think that instead of a pathologist looking at 100 samples a day, they could, as has happened with EKGs and radiology, have a computer-assisted approach where the multiplexing capability [of the system] will give them all the data they're used to but also all of these analytics on top of that data to allow them to make a more accurate diagnosis, a faster diagnosis, and perhaps have even a pathologist who maybe doesn't have as much training as, say, a very senior attending, have that same level of confidence in their diagnosis," he said.

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