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Quantum-Si, Nautilus Tout Targeted Protein Analysis Capabilities of Respective Platforms


NEW YORK – While commercialization efforts at next-generation protein analysis outfits Quantum-Si and Nautilus Biotechnology have gone less smoothly than originally projected, recent developments indicate both companies' platforms are progressing.

In particular, the firms' work on targeted applications appears to be moving forward, with Quantum-Si, whose platform is specifically focused on targeted protein analyses, recently releasing an updated version of its protein sequencing kit, and Nautilus presenting data at the US Human Proteome Organization (HUPO) annual meeting this week on the use of its platform to measure a mixture of tau isoforms.

Quantum-Si's V2 Sequencing Kit, which the company launched in February, features a new amino acid recognizer that enables the company's Platinum protein sequencing platform to now directly identify 13 amino acids, said Brian Reed, the company's head of research.

Improvements to the efficiency of the company's chips also allow researchers to analyze more peptides per experiment, said Quantum-Si Chief Commercial Officer Grace Johnston, noting that this has driven down the per-amino-acid cost of analyses.

The company has also provided new functionality in the platform's user-facing software that improves its ability to identify unknown proteins, Reed said.

The Platinum sequencer uses amino acid-specific probe, or recognizer, readouts via a semiconductor-based sensing device that measures the timing of emissions following excitation of target molecules, enabling single-molecule sequencing of peptides, including post-translational modifications.

While Quantum-Si does not currently have probes to all 20 amino acids, Reed said that the instrument is able to collect data on all the amino acids in a peptide by observing how the probe's binding to a specific amino acid target is affected by the amino acids adjacent to that target.

"The recognizers are binding on and off to the N-terminal amino acid repeatedly, and each of those binding events has a typical duration, which reflects the affinity for that amino acid," Reed said. "If we change one of the downstream [amino acid] residues — say, the next residue gets changed from a [leucine] to a [serine] — that changes the affinity [of the recognizer to its target] slightly, and that ends up changing the kinetics."

That change in kinetics can be used to identify peptides not directly targeted by the company's current set of recognizers, Reed said. He cited as an example work Quantum-Si has done on the platform detecting the conversion of arginine to citrulline, a process known as citrullination that is involved in a variety of autoimmune diseases.

"We were able to show that if you change the arginine to citrulline and sequence that peptide, it changes the kinetic signature," he said. "We don't have to have a recognizer for [citrulline]. We detect its influence on the kinetics of the binding events."

Chris Mason, professor of genomics, physiology, and biophysics at Weill Cornell Medicine, installed a Platinum instrument at the end of 2023 and has been using it to analyze cytokines as part of his lab's work in oncology and on biological changes linked to spaceflight.

Mason said he hopes the system will help him and his colleagues get a better look at variant forms of the cytokines as well as post-translational modifications.

In his work with the platform thus far, Mason said he is seeing around 16 amino acids detected "pretty routinely" with somewhat noisier signal produced by the other four amino acids.

"We can see them all, but the 16 are of a much higher quality," he said. "There's some headroom for improving the models, for sure."

He added that his lab has also been able to detect several kinds of post-translational modification, including glycosylation and acetylation.

In keeping with Quantum-Si's positioning of Platinum for targeted applications, Mason said that he had found the instrument is best suited to analyses of samples containing around a dozen proteins or protein variants.

"We've only had it for a few months, so it's a bit early, but definitely that's the sweet spot," he said.

"In terms of a technology, this is not something where you are going to put [in] a crazy mixed sample with thousands of proteins and ram it through the machine," he added, noting that in conversations "with people in the market," he has come across some misconceptions regarding the instrument's intended use.

Nautilus Biotechnology, on the other hand, very much intends to market its Proteome Analysis Platform as a tool for large-scale proteomic discovery experiments. The company's progress in this regard has lagged well behind its projections, however.

Nautilus' platform uses chips functionalized with DNA origami structures that allow researchers to deposit single proteins in extremely dense arrays, enabling single-molecule analysis of as many as 10 billion individual proteins. The company analyzes the arrayed proteins by iteratively staining the sample with semi-specific affinity agents and then using machine learning to identify individual proteins based on the patterns of affinity agent binding observed. Because the platform uses single-molecule technology, proteins are quantified simply by counting them following identification.

At the US HUPO annual meeting this week, Nautilus presented developments in its work toward broad proteomic analyses but did not produce any data indicating the platform is currently capable of such work.

Nautilus did, however, share data from an analysis of tau proteoforms, providing an example of how its technology might prove useful for more targeted work.

Company researchers started with the 0N and 2N isoforms of tau, then phosphorylated a portion of both forms to produce an 0N isoform phosphorylated at threonine 181 and serine 396 and a 2N isoform phosphorylated at serine 214. They then mixed these four isoforms in a defined ratio and introduced the sample to the instrument.

By iteratively probing the sample with antibodies specific to these individual phosphorylation sites, they were able to quantify the levels of the different tau isoforms in the sample, with their measurements largely matching the expected ratios.

They were also able to detect tau forms where the phosphorylation reaction had not proceeded as expected, producing 0N tau that was phosphorylated at 181 but not 396 and vice versa, as well as an 0N tau form phosphorylated at all three sites.

"There is no other way to know that on a given molecule you had both the phospho-S396 and the phospho-T181," said Parag Mallick, Nautilus' cofounder and chief scientist.

The company has signed research agreements with Amgen, Genentech, and MD Anderson for use of its technology for similar targeted applications.

Commercial struggles

Two of the most prominent proteomics startups to go public amidst the booming life science markets of several years ago, Nautilus and Quantum-Si have struggled to find solid commercial footing.

In February, Nautilus delayed the projected launch of its platform to 2025, the most recent in a series of delays. The company initially said it aimed to measure 2,500 proteins per run by early 2022, to measure up to 10,000 proteins per run by late 2022, and to analyze full proteomes by the middle of 2023. In 2022, it pushed a planned 2023 launch to mid-2024. In August of last year, it announced that while it continued to target mid-2024 for its launch, it was scaling back the specifications for the initial version of the platform.

Quantum-Si, meanwhile, announced plans in August 2023 to revamp its software and sample prep plans for Platinum and to review its R&D process. Following that review, the company said it was shifting to what it called a "controlled commercial launch" mode, with a full commercial launch planned for early 2024.

During Quantum-Si's Q4 2023 earnings call in February, President and CEO Jeff Hawkins said it expects to move into full commercial launch in Q1 2024. He said the company, which posted $400,000 in Q4 revenue, anticipates growth on a quarter-over-quarter basis throughout 2024 and added that it has increased the list price of the Platinum instrument from an initial $70,000 to $85,000.

The company plans to launch a V3 kit for the Platinum system by the end of Q3 2024.