Erisyon: Improving Immuno-Oncology Treatments with Single Molecule Protein Sequencing

Erisyon is proud to announce that we’ve recently been awarded a $2.2M grant from the Cancer Prevention and Research Institute of Texas to develop a diagnostic for the selection of immuno-oncology treatment using our proprietary Fluorosequencing technology. The project is a collaboration with MD Anderson targeting a Non Small Cell Lung Cancer (NSCLC) biomarker developed at the Weizmann Institute and has the potential to address a major unmet need in the field of checkpoint inhibitors.

Fluoroseqencing - High Throughput, Massively Parallel, Single Molecule Proteomics

Erisyon was founded in 2018, emerging from the labs of Profs Eric Anslyn and Edward Marcotte of UT Austin and shortly before a landmark Nature Biotechnology paper was published that introduced and detailed Fluorosequencing. This technology brings the benefits of next generation DNA sequencing to proteins including the ultimate sensitive of a single molecule, massively parallel experimentation with billions of reads, and absolute quantification of proteins in a sample with digital counts of molecules.?

The Fluorosequencing technique works by capturing high fidelity partial sequences of the peptides produced after digesting proteins. These partial sequences, called fluorosequences, are usually a subset of amino acids but they can also be de novo identification of post translational modifications like phosphorylation. The fluorosequences are then matched against a reference database of proteins that have been generated from the genome and the transcriptome.

As a result, the ideal set of applications for Fluorosequence to tackle include those that require high sensitivity, unbiased detection, and digital quantification.

The Dysregulation of the Immunoproteasome - A Biomarker for Immune Checkpoint Inhibitor Therapy

Immune Checkpoint Inhibitor (ICI) therapies have revolutionized the treatment of cancer. By resuscitating the body’s natural strategy for clearing diseased cells, ICI has saved millions of lives while also creating multi-billion dollar market opportunity.

The radical success of immune checkpoint inhibitors has also led to a variety of successful diagnostics to support their application. According to DeciBio, the market for immuno-oncology diagnostics was $6.7B in 2023 and expected to nearly double by 2028. Within this market the largest segment is testing for NSCLC which accounts for over one third of this spend.

Even with rapid adoption, however, there still does not exist a reliable diagnostic for selection of treatment. Immuno Histo Chemical (IHC) tests are the front line diagnostic for determining treatment potential but the assay is qualitative. Tumor Mutational Burden (TMB) and Micro Satellite Instability (MSI) are effective genetic tests that provide insights into the potential diversity of the immuno-peptidome but do not reveal whether those signals will be displayed by the cell. Unfortunately, without greater insight into dysregulation of the cell’s proteomic machinery we’re left guessing as to which ICI therapy will be most effective given a patient’s condition.

In May of 2023, Prof Yifat Merbl’s lab at the Weizmann Institute published a promising biomarker that may allow clinicians to make these choices with greater precision. In a Nature Cancer paper, Javitt, et al. demonstrated that when PSME4, an immunoproteasome regulatory element, is over-expressed in Non Small Cell Lung Cancer (NSCLC) it acts as a cap that attenuates the processing of proteins into HLA peptides. As a result, these tumor cells demonstrate one of the hallmarks of tumor evading cancer where the cell reduces or eliminates its HLA peptides.

Prof Merbl and her team furthermore showed, both in model systems and in retrospective studies, that determining whether a patient’s cells had overexpression of PSME4 was an effective and accurate biomarker for response to ICI therapies. Capturing this information early enough can give a clinician enough time for the appropriate intervention.

Fluorosequencing and the PSME4 Biomarker

Unfortunately, bringing this biomarker to the clinic by conventional proteomic techniques is unlikely. While mass spectrometry is making great strides in sensitivity, the sample concentration present in tumor biopsies remains challenging as a routine diagnostic. RNA sequencing and quantification is not well correlated with protein expression and certainly does not provide information on protein complex assemblies. Finally, ratiometric affinity assays are not quantitative enough for this biomarker.

Erisyon’s Fluorosequencing technology, on the other hand, addresses all of these shortcomings: Fluorosequencing’s single molecule sensitivity makes tumor biopsies accessible; Fluorosequencing’s massively parallel architecture produces billions of reads, enough to deal with the dynamic range of protein enrichment; and its unbiased detection provides digital quantification to produce a direct stoichiometry of PSME4 to the immunoproteasome complex.

Erisyon's CPRIT Grant

Erisyon is excited to be awarded a $2.2M grant from CPRIT, working with Prof Jianjun Zhang, Chair of the MD Anderson Moon Shot GEMINI program, over the next two years to develop and apply Fluorosequencing to identify and quantitate PSME4 levels in patient samples. We thank the CPRIT for its generosity and look forward to soon making positive contributions to the lives of patients.

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