Exploring a New World of Protein Biomarkers with the Power of Mass Spectrometry

There’s much more to understanding and treating disease than measuring the abundance of specific proteins – so in the search for biomarkers, we need to look further. Unbiased mass spectrometry proteomics offers the opportunity for deep biological insights and true discovery in biomarker research.

Biomarkers are growing in importance as an integrated part of the drug development pipeline. Clinical trials increasingly include biomarker discovery, patient stratification, and companion diagnostics to develop highly targeted therapies with greater chances of success.

State-of-the-art protein biomarker research has focused on the presence, absence or relative abundance of specific proteins, which are often linked to disease mechanisms. However, the functional state of any given protein is determined by many additional factors, including post-translational modifications, folding mechanisms and interactions.

Detecting the presence of proteoforms (different forms of the same protein) therefore provides a better read-out of what’s going on inside the body in terms of health and disease. Thanks to recent developments in mass spectrometry biomarker discovery, we can now dive into these multi-dimensional aspects of the proteome in the search for new, more informative biomarkers.

Mass spectrometry proteomics provides unbiased, proteome-wide discovery and a wealth of in-depth biological information, uncovering novel insights about protein structure and function, as well as post-translational modifications. [1]

Proteoform Changes are Central to Disease Pathophysiology

Many disease pathways involve changes to proteins and proteoforms, such as post-translational modifications, aggregation, misfolding, truncations, degradation, or changes in interactions, complex formation and binding partners – all of which can be detected through our proprietary mass spectrometry proteomics workflows.

For example, in Alzheimer’s disease, post-translational phosphorylation of the neuronal tau protein triggers the formation of neurofibrillary tangles and neuropil threads, which are defining pathological features of the disease. Researchers have exploited this biological phenotype and, as a result, phosphorylated tau is now a recognized diagnostic biomarker. [2]

Our phospho profiling service enables the identification and quantification of thousands of phospho-proteins with single-site resolution, which can provide novel insights into protein activation and potential phosphoprotein biomarkers.

Other diseases are associated with protein aggregation, truncation, and misfolding. For example, Parkinson’s disease is related to the presence of aggregated α-synuclein. Protein truncations have been linked to protection from liver disease, while prion diseases such as CJD are associated with misfolded prion proteins. Aggregated and misfolded proteins could prove to be useful biomarkers for many diseases, but their discovery and quantification requires conformation-specific detection, which can only be achieved through mass spectrometry approaches such as our proprietary LiP-MS and Hyper Reaction Monitoring proteomics workflows. [3], [4], [5]

Beyond their involvement in disease pathophysiology and potential as diagnostic biomarkers, protein alterations can also influence how patients respond to therapies. For example, mutations in cancer cells can cause post-translational modifications that affect the stability of PD-L1 receptors, which are commonly targeted by immune checkpoint inhibitor therapies.

These variations could influence how well an individual responds to PD-L1 inhibitors. A deeper understanding of the role these conformation-specific isoforms play in therapeutic responses could enable more tailored and effective treatments targeting the PD1/PD-L1 axis. [6]

Unlike affinity-based proteomics approaches, which require antibodies or aptamers raised against specific protein domains, mass spectrometry can detect all proteoforms and post-translational modifications resulting from underlying genetic mutations, providing new insights to inform the development of more effective immunotherapies.

Going Beyond Abundance

Proteins are organized into complexes, which dynamically change and reorganize. If we want to understand disease phenotypes fully, we also need to monitor dynamic protein interactions.

Our collaborator, Professor Paola Picotti at ETH Zurich, is already proving the power of this approach in her work mapping dynamic changes in the metabolic proteins of yeast and bacteria, uncovering novel functions and pathways. [7]

We are also expanding our technology to search for structural biomarkers, allowing you to explore the whole proteome and detect structural changes in proteins as they’re activated or form different complexes.

The Future of Proteomics is Here

At Biognosys, we are leading inventors and innovators of mass spectrometry-based proteomics solutions. Highly optimized workflows provide the deepest and most accurate view of the proteome available to date.

We gather >30,000 data points from a single plasma sample, including information about protein isoforms, mutations, structural changes, post-translational modifications, and modes of action. Our user-friendly analysis software then translates all this data into usable biological insights with the help of artificial intelligence and machine learning.

Our technology can be applied across a wide range of sample types and species, including blood plasma, cerebrospinal fluid (CSF) and tissue biopsy samples, supporting translation through every stage of the pipeline from drug discovery through to clinical research and the development of companion diagnostics.

Today’s mass spectrometry technology is taking us into a new era where we can go beyond protein abundance and gather multi-dimensional information from across the whole proteome, including insights into protein structure, dynamics, modifications and function. [8], [9]

We can reveal complex biology, truly address the molecular basis of health and disease, and translate all this information into meaningful biomarkers that bring forward life-changing health innovations.

Get in touch to find out how we can help you unlock the power of proteomics in your biomarker research.

References

 

1. Aebersold R, Mann M. Mass-spectrometric exploration of proteome structure and function. Nature. 2016;537(7620):347-55. doi: 10.1038/nature19949.
2. Molinuevo JL, Ayton S, Batrla R, et al. Current state of Alzheimer’s fluid biomarkers. Acta Neuropathol. 2018;136(6):821-853. doi:10.1007/s00401-018-1932-x.
3. Bartels T. Conformation-Specific Detection of α-Synuclein: The Search for a Biomarker in Parkinson Disease. JAMA Neurol. 2017;74(2):146-147. doi: 10.1001/jamaneurol.2016.4813.
4. Vejux A, Namsi A, Nury T, et al. Biomarkers of Amyotrophic Lateral Sclerosis: Current Status and Interest of Oxysterols and Phytosterols. Front. Mol. Neurosci. 2018;11:12. doi: 10.3389/fnmol.2018.00012.
5. Abul-Husn NS, Cheng X, Li AH, et al. A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease. N Engl J Med. 2018;378(12):1096-1106. doi: 10.1056/NEJMoa1712191.
6. Hsu JM, Li CW, Lai YJ, Hung, MC. Posttranslational Modifications of PD-L1 and Their Applications in Cancer Therapy. Cancer Res. 2018;78(22):6349-6353. doi: 10.1158/0008-5472.CAN-18-1892.
7. Cappelletti V, Hauser T, Piazza I, et al. Dynamic 3D proteomes reveal protein functional alterations at high resolution in situ. Cell. 2021;184(2):545-559.e22. doi: 10.1016/j.cell.2020.12.021.
8. Larance, M., Lamond, A. Multidimensional proteomics for cell biology. Nat Rev Mol Cell Biol. 2015;16, 269-280. doi: 10.1038/nrm3970
9. Boersema PJ, Kahraman A, Picotti P. Proteomics beyond large-scale protein expression analysis. Curr Opin Biotechnol. 2015;34:162-70. doi: 10.1016/j.copbio.2015.01.005.