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Identifying Risk Factors for Long COVID With Single-Cell Proteomics

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Single-cell proteomics provides insights into the molecular mechanisms of cell function and can be applied to both healthy and diseased cells. IsoPlexis technologies for single-cell proteomics are used globally by researchers to understand the complex roles of immune cells, specifically multi-functional cells. In a recent paper published in Cell, the company’s platform was employed by researchers aiming to unravel the risk factors behind long COVID.

We caught up with Sean Mackay, CEO and co-founder of IsoPlexis, to find out more about the platform and how single-cell functional proteomics is contributing to our understanding of health and disease.

Katie Brighton (KB): How are single-cell proteomics approaches advancing the understanding of complex diseases?

Sean Mackay (SM): With the advancement of precision medicine, treatments are becoming more tailored to each specific patient’s individual needs. These personalized medicines rely on more advanced technologies that provide a higher resolution and deeper access to in vivo biology to create durable, curative impacts on health.

With genomic and surface marker analysis alone, researchers are missing critical functional information at a protein level. Traditional bulk methods average across all cells, losing critical cellular attributes key to understanding response in patients.

Single-cell functional proteomics reveals the functional cellular attributes that are important for driving immune responses, allowing researchers to gain deeper insights into the cells that are orchestrating responses in our bodies. Essentially, a better understanding of immune cell function can benefit the understanding and treatment of a wide variety of disorders.

Anna MacDonald (AM): What separates IsoPlexis’ approach from other single-cell technologies?

SM: Our platform, including the IsoLight and the IsoSpark, identifies “superhero cells” that would normally be missed by flow cytometry and single-cell genomics. We are probing the immune system to reveal unique immune biomarkers in small subsets of highly polyfunctional cells, which we call “superhero cells”. These superhero cells are essentially highly functional immune cells that orchestrate how an individual responds to treatment. Polyfunctionality has been found to correlate highly with key immune insights, such as potency, persistence and long-term response in patients as published in various studies.

Now, for the first time with IsoPlexis technology, we can identify and predict how these superhero cells orchestrate the immune response much earlier in the clinical process, by way of functional proteins (e.g., cytokines, chemokines, growth factors, etc.). In this manner, we can “tune” immunotherapies and targeted therapies at the cellular behavior level so that they are more precise and personalized.


AM: Can you tell us more about the Functional Cell Library and how it was created? What are “superhero” and “supervillain” cells, and how are they identified?

SM: The Functional Cell Library is an industry-first mapping of highly functional, proteomically driven cells, uniquely identified by IsoPlexis’ platform, that determine how the human body responds to complex diseases and therapies.

These cells can be either “superhero cells” (highly polyfunctional cells predictive of potency, patient response, survival, etc.), or “supervillain cells” (highly polyfunctional cells predictive of inflammation, toxicity, disease progression, etc.)

By identifying a comprehensive range of rare and important polyfunctional cells, the library categorizes how these cells have been used to predict cell product functional attributes and vaccine efficacy, predict and monitor patient response to therapies in a wide range of high impact journals.

In complementing the genomic data used in mapping the Human Cell Atlas, the Functional Cell Library adds a unique layer of proteomic data on the wide range of superpowered immune and tumor cell types uniquely identified by IsoPlexis' single-cell functional proteomics. The Functional Cell Library provides the bridge to leverage unique functional phenotyping data to patient responses in vivo for preclinical, translational and clinical applications.

It is a valuable resource across oncology, immunology, neurology, autoimmune disorders and infectious disease as well as cell and gene therapies, targeted therapies and more. It is available now as an industry-wide, literature-referenced, and consistently updated resource to leverage unique functional phenotyping data across a variety of cell types for product manufacturing and quality control as well as preclinical, translational and clinical applications.

KB: Can you give us an overview of the study published in Cell? What were the key findings?

SM: In the paper, titled "Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae", researchers correlated patient symptoms with in-depth profiling of blood-based biomarkers throughout COVID-19 infection to identify factors associated with the development of post-acute sequelae of COVID-19 (PASC). PASC is the technical term for long COVID, i.e., a range of new, returning or ongoing health problems people can experience four or more weeks following infection.

Authors followed 309 patients from initial clinical diagnosis to early-stage recovery from acute disease, spanning up to 2–3 months post-diagnosis to identify the early factors that contribute to long COVID, such as increased frequency of supervillain immune cell subsets.

KB: Can you tell us about how the IsoPlexis single-cell functional proteomics platform helped to identify the presence of different immune cell types and inflammation in long COVID?

SM: IsoPlexis’ single-cell proteomics provided a unique assessment to dissect the functional impacts of different cell types across multiple timepoints and the interplay between innate and adaptive immune responses that contributed to effector functions or inflammation in long COVID.

IsoPlexis proteomics revealed a correlation between the increased frequency of “supervillain” T cell subsets with type 1, type 2 and intermediate polarized endotypes of PASC and disease severity at convalescence. The single-cell functional data also demonstrates the “supervillain” monocytes in convalescent patients compared to healthy subjects that correlated with all four identifiable endotypes of PASC, indicating the impact of monocytes on a sustained inflammation at convalescence. 


KB: Now the study has identified four endotypes of post-acute sequelae of COVID-19, how could this information be used to shape treatment strategies?

SM: Through understanding the supervillain cells driving inflammation in diseases like COVID-19, we can apply these learnings to a wider array of critical challenges for inflammatory diseases, such as insights into disease progression, or the identification of potential targets for treatment. Our platform has previously been used for advancing vaccine development as well as understanding the mechanisms of transplant rejection, cytokine release syndrome and toxicity, and autoimmune inflammation.

KB: Aside from COVID-19, what other disease and application areas can single-cell functional proteomics benefit?

SM: Our single-cell functional proteomics is critical for applications in immune monitoring and immune health. The functional single-cell analysis from our platform has been published in several studies where our readout was uniquely predictive of patient attributes in research areas like cancer immunology, cell therapy, autoimmune inflammation and others.

Two recent Nature Medicine papers demonstrate the unique utility of IsoPlexis' single-cell proteomic platform for predicting the potency of novel cell therapies, including chimeric antigen receptor (CAR) T-cells in blood cancer and tumor-infiltrating lymphocytes (TILs) against solid tumors. One of the greatest challenges in improving cell therapies is understanding exactly how these living immune drugs work, as early as possible. Through these two high-impact publications, the researchers leveraged our unique single-cell proteomic analysis to gain a better understanding of how CAR-Ts and TILs function, which then leads to improved assessments of quality, potency and durability.

Additionally, our platform identified a blood-based biomarker that correlated with patient response and progression-free survival in a Phase 2 clinical trial for combination checkpoint and novel IL-2 agonist therapy, published in The Journal of Clinical Oncology.


KB: Anything else you’d like to mention?

SM: We have recently introduced Duomic, which uniquely provides researchers with the ability to identify gene expression profiles of these highly functional superhero and supervillain cells. For the first time, researchers can capture both functional proteomics and gene expression from the same single cell. This empowers researchers to drill down into the genetic drivers of those “super” cells, with applications in:

  • Revealing the genetic drivers of CAR T cells to create more potent and durable next-generation therapeutics
  • Profiling the TCR repertoire, accelerating the understanding of the immune system and ability to develop new therapeutics
  • Recoding gene and gene pathways driving therapeutic resistance and tumor progression


Sean Mackay was speaking to Katie Brighton, Scientific Copywriter and Anna McDonald, Science Writer for Technology Networks.