With the use of single-cell proteomics, identifying risk factors for long COVID

With the use of single-cell proteomics, identifying risk factors for long COVID ...

Proteine with single-cell interactions provides insight into cell function and can be applied to both healthy and diseased cells. In a recent paper, researchers identified the key factors behind the long-term COVID.

Sean Mackay, the CEO and co-founder of IsoPlexis, was interviewed to learn more about the platform and how single-cell functional proteomics is assisting us in understanding health and disease.

Katie Brighton (KB): What are single-cell proteomics techniques capable of advancing understanding of complex diseases?

Sean Mackay (SM): With the advancement of precision medicine, treatments are becoming more tailored to each specific patient''s particular needs. These personalized medicines rely on advanced technology that improve patient resolution and enhanced access to in-vivo biology to have lasting, curative outcomes.

Researchers are missing critical functional information at a protein level without using genomic and surface marker analysis alone. Traditional bulk therapies average across all cells, losing critical cellular attributes.

Proteomics with a single-cell functional structure reveals the important cellular properties for regulating immune responses, allowing researchers to gain deeper insights into the cells that are responsible for our responses. Essentially, a better understanding of immune cell function can benefit the understanding and treatment of a wide variety of illnesses.

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

SM: As a result of our flow cytometry and individual cell genomics, we are investigating the immune system to discover unique immune biomarkers in small subsets of highly polyfunctional cells, which we call superhero cells. Polyfunctionality has been discovered to be well-functioning immune responses, including potency, persistence, and long-term response in patients.

For the first time, with the IsoPlexis technology, we can identify and predict how these superhero cells orchestrate the immune response much earlier in the clinical process, using functional proteins (e.g., cytokines, chemokines, growth factors, etc.). In this way, we can tailor 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 the superhero and supervillain cells, and how are they identified?

The Functional Cell Library is a world-first representation of highly functional, proteomically driven cells, which is uniquely identified by the IsoPlexis platform, that determines how the human body responds to complex diseases and therapies.

These cells can be either superhero cells (highly polyfunctional cells capable of potentiality, patient response, survival, etc.) or supervillain cells (highly polyfunctional cells capable of inflammation, toxicity, disease progression, etc.)

In a wide range of high-impact journals, the library categorizes how these cells have been used to measure cell product functionalities and vaccine efficacy, predict and monitor patient response to therapies.

The Functional Cell Library, based on the human cell Atlas'' genomic data, has provided a unique layer of proteomic data on the wide spectrum of superpowered immune and tumor cell types that was uniquely identified by IsoPlexis'' single-cell functional proteomics. The Functional Cell Library is used as a reference to patient responses in vivo for preclinical, translational, and clinical applications.

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

Could you give us a brief overview of the Cell study? What were the key findings?

SM: In the paper titled "Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae," researchers investigated patient symptoms using in-depth analysis of blood-based biomarkers throughout COVID-19 infection to identify obstacles 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 may experience four or more

309 patients were followed from initial clinical diagnosis to early-stage recovery from acute illness, spanning up to 23 months post-diagnosis to determine the early implications of long-term COVID, such as the increased frequency of supervillain immune cells subsets.

Can you tell us more about the IsoPlexis single-cell functional proteomics platform that aided in identifying the presence of different immune cell types and inflammation in long-term COVID?

SM: A unique approach for IsoPlexis single-cell proteomics was provided to investigate the functionalities 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-term COVID.

Prolonged to IsoPlexis, which demonstrated the increase in supervillain T cell subsets with type 1, type 2 and intermediate polarized PASC endotypes, and disease severity at convalescence. The combined functional analysis also demonstrated the supervillain monocytes in convalescent patients, compared to healthy individuals who correlated with all four specific PASC endotypes, indicating the effect of monocytes on a sustained inflammation at convalescence.

COVID-19 has been identified as four endotypes of post-acute sequelae, and how should this information be utilized in treatment strategies?

Through discovering the supervillain cells that drive inflammation in COVID-19, we can apply these lessons to a wide variety of critical challenges for inflammatory diseases, such as insights into disease progression or the identification of suitable therapeutic targets. Our platform has previously been used to develop vaccines, as well as understanding the mechanisms of transplant rejection, cytokine release syndrome, and toxicity, and autoimmune inflammation.

What other diseases and applications might benefit from single-cell functional proteomics, outside of COVID-19?

SM: Our single-cell functional proteomics is vital for immune monitoring and immune health. In several studies, our functional single-cell analysis was designed to save patient attributes in research areas, such as cancer immunology, cell therapy, and autoimmune inflammation.

IsoPlexis'' unique-cell proteomic platform for predicting the potential of novel cell therapies, including chimeric antigen receptors (CAR) T-cells in blood cancer and tumor-infiltrating lymphocytes (TILs) for strong tissue. One of the most important challenges in improving cell therapies is acquiring the ability to understand exactly how CAR-Ts and TILs function, which leads to improved evaluations of quality, potential potentiality and longevity.

In a Phase 2 clinical trial for combination checkpoint and novel IL-2 agonist therapy, our platform developed a blood-based biomarker that correlated with patient response and progression-free survival.

Is there anything else you want to mention in this article?

Duomic, a platform that allows researchers to identify both functional proteomics and gene expression from a single cell, according to SM. This allows researchers to dive deeper 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 spoke with Katie Brighton, a scientific copywriter, and Anna McDonald, a science writer for technology networks.

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