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Proteomics Research Innovation Progressed in 2022 Despite Challenging Business Conditions

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NEW YORK – Following the broader life science tools space, proteomics firms experienced something of a retrenchment in 2022 as the boom times of the previous two years gave way to layoffs, strategic realignments, and delays.

But while proteomic businesses faced challenges, proteomics research continued to move forward as the field pushed into emerging areas like single-cell, single-molecule, and spatial analyses.

Single-molecule protein analysis firm Quantum-Si is emblematic of the split in 2022 between proteomics' business fortunes and the progress made on the research and technology side. The company started the year with the resignation of its then-CEO, John Stark, leading Founder Jonathan Rothberg to step in as interim CEO. Meanwhile, the firm's stock price, which peaked at $20.49 in February 2021, slid from $7.87 at the end of 2021 to where it currently sits, trading at below $2 for the last week.

At the same time, the company this week launched its Platinum protein sequencing platform, a benchtop device that uses amino acid-specific probes readout via a semiconductor-based sensing device to analyze proteins at the single-molecule level. The instrument, which sells for $70,000 and will begin shipping in Q1 2023, isn't yet capable of full de novo protein sequencing, but its launch is notable as marking the first commercial release of an instrument intended for single-molecule protein sequencing — an area that has seen an influx of industry and academic attention and investment in recent years.

Indeed, this fall, the Netherlands' Delft University of Technology hosted a conference on single-molecule protein sequencing that provided a glimpse at how rapidly this space has grown. Dozens of researchers from commercial companies like Quantum-Si, Nautilus Biotechnology, Erisyon, and Oxford Nanopore presented on developments in the field.

This was the third edition of the conference, which Cees Dekker, a Delft professor and one of the organizers, noted had grown from 60 participants at the first event in 2017 to 160 participants this year.

Over that time, the field has moved from being focused largely on basic science and technology development to approaching actual applications, as demonstrated by the recent Quantum-Si launch.

"It's clear we have fantastic potential for applications," Dekker said, adding that he believes single-molecule approaches could prove particularly useful for things like analysis of very low-abundance proteins and measurement and localization of protein post-translational modifications where mass spectrometry has traditionally struggled.

In fact, most single-molecule companies are primarily focused on these types of targeted analyses because proteome-scale experiments will likely remain beyond their capabilities, at least in the near term.

Single-molecule firms like Quantum-Si and Seattle-based Nautilus Biotechnology took advantage of the 2021 boom in proteomics investment to go public. Both companies listed on the Nasdaq via business combination transactions with special purpose acquisition companies (SPACs), with Quantum-Si raising gross proceeds of roughly $425 million and Nautilus garnering $345 million.

The ongoing economic downturn has occasioned some belt-tightening, though.

"When you think about the general macroeconomic climate change, we saw it coming. We knew there was going to be a change, but we weren't sure when, and we weren't sure the magnitude of it," said Parag Mallick, Nautilus's cofounder and chief scientist. "As we look at it today, it's likely not going to abate in 2023, and so as a development-stage company we are trying to find that sweet spot between accelerating platform development … while also being very efficient and careful with our cash runway."

Nautilus this year pushed back the release of its single-molecule platform from 2023 to 2024 in part due to difficulties developing and sourcing the affinity reagents the system requires.

In keeping with Mallick's comments about the macroeconomic landscape, CEO Sujal Patel said during the company's Q3 earnings call that the company plans to aggressively control expenses as it works toward the planned platform launch.

Other proteomics tools companies also adjusted their strategies to the new business climate. In August, single molecule immunoassay firm Quanterix announced a restructuring effort in which it laid off around 130 employees, 25 percent of its workforce, as it refocused its commercial efforts as part of a program intended to improve the quality of its assays and ability to manufacture them at scale. Single-cell proteomics firm IsoPlexis also underwent restructuring, cutting around 20 percent of its workforce. The company was acquired this week by Berkeley Lights in an all-stock deal valued at $57.8 million.

Fluidigm, meanwhile, received a new name — Standard BioTools — a new management team, and a $250 million investment from Casdin Capital and Viking Global Investors. New CEO Michael Egholm, former chief technology officer of Danaher Life Sciences, aims to revamp the company's management processes and reorganize its strategy around its mass cytometry technology with the goal of bringing the struggling firm to profitability.

Even amidst the more challenging environment, a number of new proteomics companies appeared on the scene and a number of existing companies brought new platforms to market. One of the hottest areas was spatial proteomics, which saw several new entrants as well as fresh investments by traditional proteomics players.

Swiss immunohistochemistry firm Lunaphore moved into the high-plex protein imaging space with the launch of its Comet platform. Another Swiss company, Navignostics, launched this year with plans to use single-cell spatial proteomics data to support oncology drug development efforts and guide cancer treatments.

Also this year, Marlborough, Massachusetts-based Akoya Biosciences presented data from its PhenoCycler-Fusion system in which researchers used the platform to analyze a panel of 100 proteins at single-cell resolution across whole-slide samples, an increase over the system's previous multiplexing limit of around 40 proteins. Standard BioTools, meanwhile, released the latest version of its imaging CyTOF system, the Hyperion+, which the company said offers a 1.6-fold lower limit of detection than the previous system along with the ability to process 100-plus samples per week — double the throughput of the previous Hyperion system.

Traditional mass spec vendors also made investments in spatial proteomics technology with Bruker presenting a new protein imaging platform developed in collaboration with AmberGen that uses MALDI mass spectrometry to measure peptide-linked antibodies in tissue samples. Additionally, the company's Canopy subsidiary recently launched a next-generation version of its ChipCytometry technology, a fluorescence microscopy-based spatial proteomic system that uses rounds of antibody staining to measure dozens of proteins in tissue samples.

At the American Society for Mass Spectrometry annual meeting in June, Thermo Fisher Scientific announced an agreement with Germany's TransMIT Center for Mass Spectrometric Developments at Justus Liebig University Giessen to promote a mass spectrometry imaging platform that combines its Orbitrap instruments with TransMIT's scanning microprobe matrix-assisted laser desorption/ionization (SMALDI) and 3D-surface technology. The system will allow researchers to perform spatial analyses of various analytes including metabolites, peptides, and enzymatically digested proteins.

On the research side, scientists at the University of Copenhagen and the Max Planck Institute of Biochemistry published a method combining laser microdissection and mass spectrometry to characterize thousands of proteins in small numbers of cells while retaining spatial information.

Northwestern University researcher Neil Kelleher, combined nano-desorption electrospray ionization (nano-DESI) with new direct mass technology released this year on Thermo Fisher's Q Exactive UHMR instrument to image intact proteoforms of up to 70 kDa at a spatial resolution of better than 80 µm. In a spatial top-down proteomic analysis of kidney tissue, the researchers identified 169 proteoforms using the technique.

As a pioneer of top-down proteomics, Kelleher has long argued for the importance of better proteoform-level information. He said he sees trends like the influx of investment into single-molecule technologies and their focus on characterizing proteoforms as helping to move the field in this direction.

In 2021, Kelleher and colleagues launched what they are calling the Human Proteoform Project, an effort that ultimately aims to characterize the proteoforms in 5,000 cell types at a depth of 1 million proteoforms per cell, making for a total measurement of roughly 5 billion proteoforms, with an estimated 50 million of those being unique. This year, project researchers produced the first paper to emerge from the effort, a study published in Science that detailed the proteoforms present in human hematopoietic cells.

2022 also saw continued improvement in the throughput of proteomics experiments. While boosting throughput has long been a preoccupation within the field, two factors — the growing adoption of single-cell proteomics and renewed interest in plasma biomarker work — have made the issue perhaps more salient than ever, suggested Jennifer Van Eyk, professor of medicine and biomedical sciences at Cedars-Sinai Medical Center.

"We're seeing more and more automation and high-throughput at the discovery level in more and more labs," she said. "People are automating sample prep. Industry is offering us better automation systems. You are seeing labs using shorter [separation] gradients, but they are equally robust. I think the big move is into higher throughput, bigger [sample] numbers, and more reproducible [experiments]."

On the single-cell side, advances included the integration of the widely used DIA-NN analysis software into single-cell workflows, as well as Bruker's coupling of its timsTOF SCP instrument with Scienion's CellenOne F1.4 instrument for dispensing single cells and its proteoChip platform for automated single-cell proteomics sample preparation, providing a commercially available end-to-end system for single-cell proteomics.

On the plasma biomarker front, one of the year's notable developments was Exact Sciences' $15 million purchase of German plasma proteomics firm OmicEra Diagnostics. Exact CSO Jorge Garces said the Madison, Wisconsin-based company plans to use OmicEra's mass spectrometry-based proteomics technologies for cancer biomarker discovery, noting that recent advances in mass spec-based plasma proteomics "have allowed us to feel more comfortable using this technology for biomarker discovery," indicating proteomics' potential in the fast-growing multi-cancer early detection space.

Proteogenomics was another major area of emphasis for the field, as the National Cancer Institute launched the fourth edition of its Clinical Proteomic Tumor Analysis Consortium (CPTAC), which aims to use proteogenomic analyses to study questions including drug response and resistance in cancers including melanoma, multiple myeloma, acute myeloid leukemia, and non-small cell lung cancer. The initiative provided $11.3 million in funding in 2022, with funding anticipated to continue at a similar level over a total of five years.

Another major proteogenomic effort, the UK Biobank Pharma Proteomics Project (UKB-PPP), released findings this year in which researchers used Olink's Explore 1536 platform to measure 1,463 unique proteins per person in the plasma of 54,306 individuals and integrated that protein-level data with genomic information from the same subjects.

The study generated one of the most expansive datasets to date linking protein expression back to its genetic influences and provides a wealth of information for researchers in drug development and the life sciences more generally.

Olink and its competitor in the high-plex plasma proteomics space, SomaLogic, have both seen growing uptake of their systems for this sort of proteogenomic work. Olink plans to expand its assay menu from roughly 3,000 to 4,500 protein targets by the end of the year, while SomaLogic's SomaScan platform can measure roughly 7,000 proteins.

Proteomics firm Seer also moved into the proteogenomics market this year with the launch of a new software suite the company said will streamline the integration of genomic and proteomic data.

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