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For all types of tests: Signatope’s biomarker assays

Signatope is a new biotech company that has been offering innovative biomarker assays for application in drug discovery since August 2016. The company’s assays can be used in all phases of drug development to detect potential adverse drug effects on the kidneys, liver and other organs in any species whatsoever using minute amounts of sample.

Around 12 months before founding Signatope GmbH, Dr. Oliver Pötz’s team of researchers from the NMI Natural and Medical Sciences Institute in Reutlingen had already attracted attention with an innovative biomarker assay. In July 2015, the researchers achieved a respectable 6th place in the Science4Life business plan competition to which over 60 business plan proposals had been submitted. In August 2016, the seven researchers were ready to spin out Signatope GmbH from the NMI. Signatope is the 13th life sciences start-up company that has been spun out of the NMI in the 30 years that the institute has existed.

Signatope GmbH’s founding team (from left to right) Prof. Dr. Hugo Hämmerle, Dr. Oliver Pötz, Dr. Hannes Planatscher, Dr. Octavian Schatz and Dr. Thomas Joos. © Signatope GmbH

The NMI researchers’ success was not just a matter of chance. They worked hard for many years to lay the foundations for the new biomarker assay: “We were part of several major European projects in which our task was to validate our protein marker candidates in human urine samples characteristic of kidney damage. Such markers can be used in clinical Phase I studies to detect at an early stage adverse effects of the drugs under investigation,” says Pötz, Signatope GmbH’s CEO. However, the NMI team did not just want to develop a Phase I test method, but had a far more ambitious goal right from the outset, i.e. to develop a biomarker assay that could be used in all phases of the drug development process rather than just in clinical Phase I trials. The researchers also wanted the test to be suitable for application in a broad range of animal models used in preclinical studies. This is a mandatory step in the lengthy process of drug development and always precedes clinical testing in human patients.

Glossary

  • Antibodies are blood proteins (immunoglobulins) which are produced by the B lymphocytes in response to disease. They recognise foreign substances that have entered the body (e.g. bacteria) and help the body fight against a particular disease and develop an immunity to that disease.
  • Enzymes are catalysts in the living cells. They allow the execution of chemical transformations of the metabolism at body temperature.
  • A gene is a hereditary unit which has effects on the traits and thus on the phenotype of an organism. Part on the DNA which contains genetic information for the synthesis of a protein or functional RNA (e.g. tRNA).
  • Being lytic is the feature of a bacteriophage leading to the destruction (lysis) of the host cell upon infection.
  • Screening is a systematic test procedure that is used to identify certain characteristics within an array of samples or persons. In molecular biology screening is used to filter a designated clone out of a gen bank, for example.
  • Genetic sequences are successions of the bases adenine, thymine, guanine, and cytosine on the DNA (or uracil instead of thymine in the case of RNA).
  • Transformation is the natural ability of some species of bacteria to take up free DNA from their surroundings through their cell wall. In genetic engineering, transformation denotes a process which is often used to introduce recombinant plasmids in E. coli, for example. This is a modified version of natural transformation.
  • Bioinformatics is the science of managing and analyzing biological data using advanced computing techniques. Currently it is used mainly for the forecasting of the meaning of DNA sequences, the protein structure, the molecular working mechanism and the properties of active substances. (2. sentence: mwg-biotech)
  • Validation is the process of verifying a thesis or a method of resolution in relation to the problem that should be solved.
  • Expression means the biosynthesis of a gene product. Usually, DNA is transcribed into mRNA and subsequently translated into proteins.
  • Pathology is a section in medicine which deals with the reasons, the development and the consequences of pathological symptoms as well as of abnormalities.
  • The term metabolism includes the uptake, transport, biochemical conversion and excretion of substances within an organism. These processes are necessary to build up the body mass and to meet the energy demand of the body. The opposed processes of metabolism are called anabolism and catabolism. Effectiveness of several enzymes could be catabol and anabol. Within one biochemical pathway they cannot work in both directions at the same time.
  • An epitope is the part off an antigen that is recognized by an antibody. There are several different epitopes on the surface off an antigen. An antibody specifically binds a single epitope.
  • Biomolecules which can bind active agents are called targets. They can be receptors, enzymes or ion channels. If agent and target interact with each other the term agent-target-specific effect is used. The identification of targets is very important in biomedical and pharmaceutical research because a specific interaction can help to understand basic biomolecular processes. This is essential to identify new points of application.
  • Federal Ministry of Education and Research

Dogs, cats, humans – a biomarker assay for all species

However, the crux of the matter is that although many metabolic pathways and proteins are basically the same in all species, there are nevertheless some molecular features that vary from species to species. The devil is in the detail, as the saying goes. In addition, healthy and diseased metabolisms differ from each other, and consequently so do the quantities of biomarker molecules produced. Signatope GmbH’s solution to these problems is using antibodies that Pötz and colleagues have been studying for a long time. These antibodies have rather short (four amino acids) recognition sequences (signatures) that match the epitopes of relevant marker molecules. These small epitopes are identical in all species. The team based the development of its XIM (cross-species immunoassays) tests for use in the pharmaceutical industry on these findings. The company name Signatope reflects the researchers’ scientific idea and is derived from the words signature and epitope.

Using a mass spectrometer enabled the team to accelerate its test method. The photo shows a Signatope team member operating the device. © Signatope GmbH

“The prerequisite for our approach is, of course, that the epitopes are identical in all animal species used in preclinical trials,” says Dr. Hannes Planatscher, a founding member of the company and bioinformatician who ran the time-consuming database screens required for identifying suitable epitopes. Planatscher is also studying business administration, which is useful for his role as the start-up’s CFO (chief financial officer). Bioinformatics also helped the team develop a method to analyse the specificity of an antibody under investigation and identify the molecule to which it binds.

The problem associated with such small recognition sequences is their relative abundance. A method to accurately determine protein concentration in blood or urine samples was therefore required. The team chose mass spectrometry, which sorts all peptides that have bound to an antibody according to their mass to charge ratio. Signatope’s technology combines XIM and mass spectrometry. Pötz explains how Signatope’s unique method works using names as an example: "Let us assume that we want to identify the name Christoph and that we have an antibody that targets the fragment ‘Chr’. It goes without saying that the antibody also targets names such as Christopher, Christiane and others that start with Chr. In a second step, a mass spectrometer will therefore have to be used to identify the name we are looking for, i.e. Christoph, based on its specific mass."

Rapid results for very little material thanks to antibodies and mass spectrometers

The technology is fast and versatile. The practical application concept convinced the jury of the BMBF’s GO-Bio competition back in 2012. The German Federal Ministry of Research and Education granted the researchers financial support for a period of four years. Funding will end in 2017, but will have enabled the start-up company to optimise the technology for further applications whilst it is already active on the market. Signatope targets mainly big research-based pharmaceutical companies, but also small biotech companies and research groups. In short, the company targets all companies and institutions involved in the drug development process. For the time being, Signatope is mainly focused on biomarker proteins involved in the metabolism of drug candidates in the liver and kidneys.

Enzymes of the cytochrome P450 complex, which are responsible for the biotransformation of drugs, and liver transport proteins are excellent examples of proteins whose expression is up- or downregulated when certain compounds are degraded. The analysis of these proteins is key to discovering interactions with new drug candidates. Our method enables these proteins to be rapidly quantified based on a relatively small amount of sample,” says Pötz summarising the advantages of the method for potential clients. In the long term, Pötz and his colleagues also plan to offer biomarker assays that specifically detect potential damage to blood vessels and other organs.

The demand for non-invasive biomarker assays is huge and will continue to increase in the future, as Planatscher explains. “In the drug discovery area, traditional histopathological investigations will increasingly be replaced with biomarker assays. The fact that regulatory authorities are increasingly tending to recommend biomarkers for testing new drugs supports this assumption. It can also be assumed that such assays will become mandatory for drug discovery. Generally speaking, we believe that such assays have great future potential.” The reduction of the number of histopathological tests will also contribute to reducing the number of animal experiments or help improve the data collected, which is another factor that favours biomarker assays in general and innovative Signatope assays in particular.

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