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Mission Bio's New Single-Cell Research Platform Marries Sequencing, Cell Surface Protein Analysis


NEW YORK – With the launch this week of its new Tapestri platform, single-cell omics firm Mission Bio is looking to make further inroads into the clinical trial and drug development businesses.

The new system adds protein measurements to the company's traditional focus on single-cell DNA sequencing, allowing researchers to make DNA and protein measurements in a single experiment and in single cells.

The system uses BioLegend's TotalSeq antibodies, which are conjugated to oligonucleotides, allowing them to be read out via single-cell sequencing. The current version of the Tapestri platform is intended for analysis of cell surface proteins, which enables researchers to identify cell type and subtype, generating data analogous to that provided by flow cytometry.

"We're tagging the antibodies using oligo-barcodes and those are the same type of barcodes that are used to label the DNA, as well, said Charlie Silver, CEO and cofounder of Mission Bio. "You get an integrated and simultaneous read-out out from the same NGS."

In a study published last week in Nature Communications, researchers from the University of Texas MD Anderson Cancer Center who had early access to the new Tapestri platform, used the combined DNA-protein analysis to track changes at both the genetic and phenotypic level in a group of acute myeloid leukemia (AML) patients.

Another early-access user of the new platform is Stephen Chung, assistant professor of internal medicine at the University of Texas Southwestern Medical Center specializing in myelodysplastic syndromes and acute myeloid leukemia. He noted that in his research he has been interested in profiling both the cell surface proteins and the DNA of disease stem cells in myeloid malignancies but that existing methods for collecting this data were laborious and low throughput.

Traditionally, he said, when looking at markers of diseased versus non-diseased stem cells, researchers would sort the two populations using flow cytometry and then try to grow colonies of those cells that could be used for genetic analysis. The colony growing process, in particular, was often time-consuming and inefficient, Chung said.

"It was really a low-throughput method and limited by the efficiency of colony formation," he said.

Recently developed single-cell sequencing techniques by Mission Bio and others have streamlined the process of collecting nucleic acid data, Chung said. The ability to now combine that with single-cell data on cell surface protein markers is "a huge leap forward in enabling the type of studies that we would like to do," he said.

Companies like 10X Genomics, Proteona, and NanoString also offer the ability to analyze nucleic acids and proteins at the single-cell level, but these companies are focused on RNA-seq as opposed to DNA.

Compared to DNA sequencing data, RNA-seq provides more limited depth and coverage, Chung said.

"If you have, say, 10 to 20 commonly mutated genes that you are looking for in diseases like AML or MDS, taking samples from a patient and being able to tell from RNA-seq which mutations are present in these samples really isn't possible with current single-cell RNA-seq technology," he said. "Because of the [limited] depth and coverage of the sequencing, you too often miss the locus where your mutation is."

He noted that this was particularly a challenge for researchers like himself who are interested in relatively rare cell populations like diseased hematopoietic stem cells.

"From an average bone marrow biopsy, we might get a few thousand hematopoietic stem cells, so if you aren't able to get the genotype information on the vast majority of those, then it isn't a tractable problem," Chung said.

He said that his lab had begun using the previous Tapestri platform which provided just single-cell DNA-seq data about a year ago but with an eye towards the expansion of the system to cover surface proteins, as well.

Chung has been studying the dysregulation of cell surface markers in diseased hematopoietic stem cells since his postdoctoral work and has been using flow cytometry combined with sequencing to link the cell surface profile of such cells to their genotypes.

Mission's platform, he noted, has enabled his team to do this "at single-cell resolution and in a high-throughput [and] highly multiplexed manner where we can look at many more cell surface markers at one time than we can with flow cytometry," he said.

Conventional flow cytometry typically tops out around a dozen protein markers whereas the Tapestri platform can, in theory, multiplex dozens to hundreds of markers. Chung said that to date his lab has measured around 15 protein markers in its experiments with the system, five or six of them core markers that distinguish between different cell types and then another 10 or so markers that are candidate markers the researchers believe could help distinguish between normal and dysregulated stem cells.

Nigel Beard, chief technology officer and senior vice president of operations at Mission Bio, said that consulting with leading researchers in hematological cancers the company has arrived at a 45-plex of surface protein assays it is offering along with 500 DNA targets as part of its standard panel offering, but he noted that the platform could measure many hundreds of proteins were customers to require it.

Silver said that the company continues to build out new catalog content on both the protein and DNA side for additional disease areas and that it also offers customers the ability to design custom panels.

While the platform is confined for now to cell surface proteins, Beard said that down the road Mission Bio plans to add the capacity to measure intracellular proteins, which could allow researchers to, for instance, investigate connections between genetic mutations, changes in proteins signaling, and cell surface protein dysregulation.

"We do have a very clear product roadmap to use protein in other ways," he said. "You can imagine pharmaceutical companies are very interested in that [intracellular protein] mechanism, too."

Silver said Mission Bio is targeting the system primarily toward clinical trial and drug development work where it believes it can provide more rapid assessments of whether and how patients are responding to treatment and help researchers better understand the underlying reasons why patients do or don't respond or develop resistance to a therapy.

The company has focused primarily on blood cancers thus far but is developing applications and panels for solid tumors, as well, Silver said.