Science Pool

In the ever-evolving landscape of biomedical research, proteomics has emerged as a crucial field for advancing drug discovery and development and biomarker discovery. Evotec stands at the forefront of this scientific frontier, offering cutting-edge mass spectrometry-based proteomics solutions. Here’s how Evotec’s innovative technologies and comprehensive services deliver exceptional value to customers, driving breakthroughs in clinical research, such as discovery of stratification biomarkers and diagnostic markers for the discovery of novel targets.

Revolutionizing Proteomics with Advanced Platforms

ScreenPep™ Platform: Evotec’s ScreenPep™ platform is a high-throughput, automated system designed for deep-coverage proteomics of cell lines, tissues or biofluids. When applied to plasma or serum it can identify up to 1,500 proteins , making it incredibly efficient and cost-effective. This platform is ideal for large-scale studies, in which sample quantity may be limited but extensive protein identification is required.

Proteograph™ Technology: As the only Center of Excellence in Europe offering Proteograph™ technology, Evotec provides an unparalleled capability to identify up to 5,000 proteins from human biofluids such as serum, plasma, and cerebrospinal fluid (CSF). This technology leverages nanoparticle-based methods to achieve deep proteome coverage, significantly enhancing the scope of biomarker discovery and translational research.

Integrated MultiOmics Solutions: Evotec excels in integrating proteomics data with genomics, transcriptomics, and metabolomics, offering a holistic approach to biomarker discovery. This integrated solution, facilitated by Evotec’s PanHunter platform, allows for comprehensive data analysis and interpretation, enabling researchers to uncover complex biological insights and accelerate drug development processes.

Customized and Scalable Services: Understanding that each research project has unique requirements, Evotec offers highly customized services tailored to meet specific client needs. From optimizing study designs to adapting sample preparation workflows for difficult and rare samples, Evotec ensures that every project receives the precise attention and expertise it demands.

Exceptional Expertise and Infrastructure: With over 20 years of experience and more than 50 mass spectrometers across its sites, Evotec is one of the largest providers of proteomics services worldwide. Their dedicated team of bioinformaticians and proteomics experts continuously develops and refines in-house pipelines, ensuring the highest standards in data quality and analysis.

High-End Mass Spectrometry: Utilizing cutting-edge mass spectrometry instruments, Evotec guarantees high-sensitivity and high-precision proteomics. These advanced technologies are crucial for detecting low-abundance proteins and analyzing post-translational modifications, providing deeper insights into protein functions and interactions.

Advantages of Mass Spectrometry-Based Proteomics

Unbiased Protein Measurement: Unlike antibody or aptamer-based techniques, mass spectrometry provides an unbiased measurement of all proteins containing tryptic peptides. This comprehensive approach allows for a more accurate and complete proteome analysis, essential for discovering new biomarkers and therapeutic targets. The quantification is also not impacted by any conformational changes.

Versatility Across Species: Evotec’s proteomics solutions are not limited to human samples; they are also applicable to various species, including animals used in health studies. This versatility broadens the research applications and facilitates translational research from preclinical models to clinical settings.

Detection of Protein Isoforms and Modifications: Mass spectrometry is uniquely capable of detecting protein isoforms and post-translational modifications, such as phosphorylation and ubiquitination. This capability is vital for understanding protein functions and regulatory mechanisms, paving the way for novel therapeutic strategies.

Cutting-Edge Technology and Continuous Innovation: Evotec’s commitment to innovation is exemplified by their continuous development of nanoparticle-based proteomics in collaboration with Seer Inc. This ongoing enhancement ensures that Evotec remains at the forefront of proteomics research, providing customers with the most advanced and reliable technologies available.

Conclusion

Evotec’s clinical proteomics capabilities offer a robust, scalable, and precise solution for drug development and biomarker discovery. By leveraging advanced technologies, integrated MultiOmics approaches, and customized services, Evotec empowers researchers to make significant scientific advancements. Partner with Evotec to unlock new possibilities in your research and drive the future of healthcare innovation.

For more information, please contact us at info@evotec.com or visit our website at PanOmics - Technology Platforms - Evotec Website (English)

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In the quest to revolutionize immunotherapy, the identification of naturally presented peptides bound to HLA class I and II molecules from cancerous cells holds paramount importance. These peptides, crucial for developing immunotherapy-based treatments, also offer promising avenues for combating infectious diseases. Evotec's pioneering immunopeptidomics platform stands at the forefront, enabling the unbiased discovery of novel immunotherapeutic targets.

This comprehensive approach extends beyond cancer research, facilitating the identification of diagnostic and monitoring biomarker signatures across normal and altered cells in cohort studies. It sheds light on the intricate interplay between T cells and MHC-presenting cells, deepening our understanding of immunobiology.

Evotec's meticulously crafted experimental strategy, coupled with its state-of-the-art capabilities in high-end quantitative mass spectrometry, achieves unparalleled sensitivity. This precision is essential for distinguishing disease-specific neoantigens from their normally presented counterparts. By integrating whole exome sequencing and transcriptomics data, the platform empowers the discovery of neoepitopes, while advanced statistics and bioinformatics tools enable comprehensive data analysis and interpretation, facilitating peptide prioritization.

The platform's capabilities are exemplified by its ability to identify up to a thousand peptides per sample, providing direct detection of presented peptides, surpassing computation-intensive in silico predictions. Moreover, validation and accurate quantification of individual peptides are ensured through targeted mass spectrometry (PRM-MS).

In essence, Evotec's immunopeptidomics platform represents a transformative leap in the field, offering unparalleled insights into immunobiology and neoantigen identification, with profound implications for the development of immunotherapy-based treatments and the fight against various diseases.

For further inquiries, contact Evotec's experts at info@evotec.com or learn more here 

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Evotec offers state-of-the-art mass spectrometry-based proteomics solutions to support drug development and biomarker discovery. Our ScreenPep™ platform enables high-throughput, automated plasma and serum proteomics with deep coverage, identifying up to 1,000 proteins from minimal sample volumes. As Europe's exclusive provider of Proteograph™ technology, we can identify up to 5,000 proteins from human biofluids, enhancing biomarker discovery. Integrated with genomics, transcriptomics, and metabolomics data, Evotec's proteomics services offer a holistic approach to translational research.

With over 20 years of experience and advanced technologies like timsTOF and Orbitrap, Evotec delivers precise, comprehensive, and scalable proteomics solutions tailored to customer needs.
read out factsheet to learn more about our clinical proteomics and how we can support your drug development

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Biomarkers are very useful tools for drug developers as well as for clinicians. In drug research and development, they add value as they improve the success rate of clinical trials. In the clinic, they validate the eligibility of patients as well as the efficacy of an approved treatment. In the recent Evotec webinar on aging, Elizabeth van der Kam, SVP, Translational Biomarkers and Human Sample Management, gave an overview on biomarkers in general and the role of biomarkers in aging.

In fact, the success rate of clinical studies can by doubled by introducing biomarkers early on, that can predict efficacy and potential safety issues. Biomarkers also may be important to reduce costs by running smarter trails in smaller groups of patients and if translated to companion diagnostics, biomarkers enhance the readiness of payers to reimburse a novel drug, but they also enable higher profits as the drug can be sold together with a diagnostic test. Therefore, Evotec´s strategy is to develop a biomarker as early as possible during the R&D process.

Types of biomarkers

There are several types of biomarkers. Useful for early studies are biomarkers that demonstrate target engagement, meaning they show that a drug candidate hits the target in the relevant organ and triggers a response. However, target engagement not necessarily means that this is relevant for the disease.

Another classification consists of surrogate biomarkers, which exhibit correlations with the disease or its progression and could hold relevance in the context of the disease More useful are efficacy markers which are not just correlated but causative for the disease. Another important class of biomarkers are safety biomarkers which, as an example, alert a clinical trial leader or a physician that the drug also hits another target and could potentially cause an issue. Then there are stratification markers indicating the likelihood of a patient to respond to treatment. This is important as non-responders should not be included in trials or prescribed an ineffective treatment. Last but not least, there are diagnostic and prognostic biomarkers that help to better understand the disease and its progression, to establish the right dosage, assess efficacy and predict disease progression and monitor the patients.

In any case, a biomarker needs to be translatable and relevant, and its measurement should be feasible, robust, reliable, and durable.

Biomarkers in aging

The situation is complex in aging. Chronological age is not the best inclusion criterium for clinical trials of medicines trying to improve the health span of elderly patients as chronological age can be very different from biological age.

But how to define biological age? What markers are out there? Of course, there are a lot of markers of biological age, e.g., body composition, body fat, physical appearance and function, muscle mass, grip strength, walking speed, balance, wrinkles, grey hair, but also blood-based changes in terms of hormone and vitamin levels and progressing diseases such as poor eyesight, osteoporosis, declining kidney function, and many more.

However, none of these markers is sufficient as a stand-alone data point. Some of the changes observed in elderly people can also be found in younger people or in patients with non-age-related diseases. The best biomarkers are the ones that can be established without subjective assessments.

The situation is further complicated by the fact that aging is not a disease, and that any intervention should be made early before the onset of typical signs of aging. Ideally, one would have biomarkers that can tell which category of older people will develop certain diseases. At present however, there are biomarkers indicating changes in many pathways and targets, but these often only indicate a certain chance of getting a disease.

The challenge

At present, biomedicine does not have access to markers that can predict certain biological deteriorations, let alone predict potential success of a treatment. And how to define a subpopulation and forecast treatment success without waiting for years to see an effect?

Currently one of the best overall indicators of biological aging is inflammaging. It demonstrates changes in the immune system, inflammation, and an imbalance in the innate or the adaptive immune system, thereby predicting a high risk of unhealthy aging. However, inflammaging can also be caused by lifestyle and gender, so it is not an ideal biomarker. Recently, under review of the U.S. National Institute for Aging, the TAME BIO (Targeted Ageing with MEtformin) project tried to establish a basis for future biomarker discovery and validation and accelerate the pace of ageing-research. 

The project started out with more than 200 potential biomarker candidates that were screened for feasibility, dependency on gender, and environmental factors, etc., bringing down the list of candidates to less than 90. Then they were assessed for disease-relation, robustness, their association to multi-morbidity and the usefulness to clinical trials, leaving a final set of eight candidates. This was, however, a purely theoretical exercise and whether these candidates are useful in real life needs to be proven. At present, the jury is still out on useful biomarkers for trials and therapies to prolong health span and quality and duration of life.

Learn more in the webinar "A Spotlight on Ageing" by Elizabeth van der Kam, SVP, Translational Biomarkers and Human Sample Management at Evotec

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In the realm of drug discovery, unveiling the intricate interactions between bioactive compounds and cellular targets is paramount. Evotec leads the charge with its pioneering chemical proteomic applications, aimed at target deconvolution and selectivity profiling.

At the heart of Evotec's approach lies Cellular Target Profiling™, an unbiased and proteome-wide methodology that meticulously identifies and quantifies compound interactions with both on- and off-targets within the cellular milieu. Leveraging high-end quantitative mass spectrometry, this platform offers unparalleled insights into specific cellular targets, enabling precise target identification and determination of target-specific dissociation constants.

Central to this chemical proteomics approach is photoaffinity labelling coupled with mass spectrometry, allowing for the covalent capture of target proteins within live cells. This technique not only identifies target proteins but also visualizes compound-target interactions, shedding light on binding site locations within protein targets and complexes.

Evotec's chemical proteomic arsenal extends beyond target deconvolution to encompass diverse small molecule compounds. Activity-Based Protein Profiling (ABPP) offers a comprehensive view of enzyme classes, while KinAffinity® provides rapid target profiling of kinase inhibitors in cell and tissue samples. Unlike traditional biochemical kinase panel screenings, KinAffinity® evaluates inhibitors' target affinities across a spectrum of native kinases within their physiological cellular environment, facilitating hit-to-lead optimization with unprecedented precision.

With a track record of success in profiling various compounds, Evotec's expertise in quantitative proteomics stands as a beacon innovation in drug discovery. For those seeking advanced insights into target deconvolution, drug selectivity and activity profiling, Evotec's experts are posed to offer tailored solutions.

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In many diseases, genes are not altered, but their regulation is disturbed, and only recently have approaches emerged to target gene regulation as a therapeutic tool.

How are genes and their expression regulated? While the central dogma of the 1960s DNA->RNA->protein still holds true, recent advances in molecular biology have provided much insight into how cells regulate which genes are transcribed into mRNA and how translation of RNA into proteins is regulated. It is now known that mRNA can undergo many chemical modifications, induced by a variety of enzymes. These modifications affect mRNA maturation, stability, and lifespan, as well as the rate and duration of translation and mRNA degradation. Likewise, some small modifications can either prematurely terminate protein synthesis, reduce peptide yield, or alter the amino acid sequence of the translated protein.

While the existence of post-transcriptional RNA modifications has been known for more than 30 years, their mechanisms, functional consequences and connection with human diseases including cancers have only recently been elucidated, making RNA epitranscriptomics an unexplored and exciting field for drug discovery. Meanwhile, more than 150 RNA modifications have been reported and approximately 300 RNA-modifying enzymes have a potential as novel therapeutic targets.

Evotec's partner Storm Therapeutics is amongst the first companies to pursue RNA-modifying enzymes as drug targets. The company identified RNA methyltransferases, a class of approximately 75 enzymes, as the most promising target class. Some have been identified as important regulators of cancer development and progression and thus represent promising novel antitumoral targets. Storm focused on METTL3, an enzyme involved in the co-transcriptional methylation of internal adenosine residues in eukaryotic mRNAs. This enzyme regulates fundamental aspects of mRNA life cycle, such as splicing, transport to the cytoplasm, stability, and translation into protein. It was known that in AML cell lines, knocking out METTL3 leads to a pronounced antiproliferative effect associated with a reduction of the BCL2 (anti-apoptotic factor). In other models, a marked upregulation of genes associated with innate immunity, such as those in the interferon (IFN) signaling pathway was demonstrated following METTL3 depletion.

However, tackling new classes of enzymes such as RNA methyltransferases requires breaking new ground in assay development, screening, and downstream hits to guide progression. To address these challenges, Storm and Evotec began collaborating in 2016, which later evolved into an integrated drug discovery and development alliance focused on novel small molecule RNA epigenetic drugs for oncology and other diseases. Using Evotec's fully integrated small molecule drug discovery and development platform, including biomarker support (development of a m6A-mRNA level evaluation technic), STC-15 was identified. STC-15 is a potent, selective small molecule inhibitor of the mRNA modifying enzyme, METTL3. STC-15 was developed from high throughput screening to candidate nomination in less than three years.

In preclinical cancer models, treatment with STC-15 significantly inhibits tumor growth. In addition, a profound cell-intrinsic interferon response was observed, following an accumulation of double-stranded RNA. In mouse models, the induction of innate immunity mechanisms, such as the interferon pathway, enhanced T-cell mediated cancer cells killing. This work has been recently published in Cancer Discovery, a leading cancer journal (Guirguis, Ofir-Rosenfeld et al., 2023). Notably, it activated innate immune pathways and inhibited tumor growth as effectively as anti-PD1 therapy in some models. In addition, the data showed that the combination of the two agents resulted in significantly greater activity, leading to tumor regression and durable anti-cancer immunity. Detailed investigation of the mechanism of action of the two treatments revealed that they act independently, providing a strong rationale for their combination. This added significantly to previous studies where STC-15 demonstrated efficacy in leukemia models through mechanisms such as inhibition of leukemia stem cell function (Yankova et al., Nature, 2021). Furthermore, additional combination studies revealed a high degree of synergy between STC-15 and Venetoclax, a BLC2 inhibitor and standard of care therapy for acute myeloid leukemia (AML) patients.

This data provided the rationale for the development of STC-15 both as a monotherapy and as a combination partner for immune checkpoint inhibitors or with BCL2 inhibitors for the treatment of solid tumors and leukemias, respectively. Following the selection of STC-15 as a first-in-class development candidate in 2020, the seamless integration from project initiation to IND using Evotec's INDiGO platform led to the entry of STC-15 into Phase I clinical trials in 2022. The orally bioavailable, highly selective METTL3 inhibitor is being developed for the treatment of solid tumors and may also have potential in AML.

A phase 1, multi-center, open-label, first-in-human study is evaluating multiple ascending daily oral doses of STC-15 in a 3+3 cohort design. The study is designed to systematically evaluate the safety and tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of STC-15 in adult patients with advanced malignancies. Dose levels for further evaluation in expansion cohorts will be selected based on all available PK, PD, target engagement (including m6A-mRNA level evaluation), efficacy, safety, and tolerability data, including long-term safety data beyond dose-limiting toxicities (DLTs).

Patient enrolment started in November 2022, and the company anticipates top-line results in 2024.

The development demonstrates the benefits of Evotec's integrated, accelerated IND-enabling platform to support the exploration of novel and exciting biology to maximize innovation, to execute efficiently with rapid and seamless integration from target to IND.

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This review explores patient-centric omics mining strategies for target identification in disease mechanism-centric medicine. Using chronic kidney disease (CKD) as an illustrative example, the paper proposes a data-driven and unbiased patient stratification approach to support traditional classification based on observable clinical symptoms and diagnoses. Advocating for state-of-the-art systems biology, the paper suggests integrating transcriptomic, clinical, and morphological data to construct verifiable models of diseases like CKD. These models can provide a framework for mechanistic analysis and for the identification of potential therapeutic targets in the context of precision medicine.

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This factsheet looks at deciphering the immunopeptidome for neoantigen identification. 

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Our target deconvolution factsheet looks at the following areas:  

• Pioneered chemical proteomic applications
• Target selectivity profiling
• Evotec Cellular Target Profiling™
• Photoaffinity labelling coupled to MS
  
  
  

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Target identification is a fundamental first step in drug discovery, involving the discovery and validation of disease-associated molecular mechanism that can be modulated by a drug. In this whitepaper we introduce Evotec's PanOmics TargetID Framework developed by the Bioinformatics and Computational Biology teams. It is a modular system that uses computational tools coupled with expert assessments to identify and rank potential drug targets. Our framework delivers a comprehensive report with a list of disease-relevant targets, their scores, annotations, rankings, and detailed information on their druggability, biology, safety, competition, and efficacy..

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