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European Biopharmaceutical Review

A Role for the Future

Ulf Landegren at Uppsala University explains how today’s biotech industry is finding that biomarker developments are a useful tool on the road to speedier drug discovery

There are endless possibilities in protein diagnostics and therapeutics, particularly when it comes to biomarkers. Identifying new biomarkers has proven challenging over recent years, but disappointments in speed and accuracy are becoming less frequent as the momentum behind discovery builds.

New applications of existing technology and broader experiences mean the life sciences industry is on the cusp of greater biomarker discoveries in the next 10 years. This article will explore the new technologies that researchers are using and the potential for biomarkers to save billions of dollars in health bills around the world.

THE ROLE OF BIOMARKERS IN MODERN MEDICINE

No two patients are the same and we know that two tumours in the same organs of two patients often react differently to the same treatment. Biomarkers will give the medical profession the ability to better predict which patients will benefit from specific treatments, facilitating personalised medicine. In particular, the expense of new protein-based therapeutics (biologics) has necessitated the development of better diagnostics, and measuring proteins may allow the medical profession to find which tumour patients will benefit from which therapy. For example, in breast cancer it is common to treat women with antibodies directed against HER2 proteins. However, cancers express the HER2 protein to variable extents and accurate measurement of this is crucial in selecting the best treatment. Another example of a successful biomarker is the presence of antibodies of IgE class in predicting an allergy. If the patient has elevated levels of IgE directed against birch pollen this indicates an allergy.

There is also hope that we will be able to monitor the effects of treatments to detect any relapse of the disease early by studying the appropriate set of protein markers.

Besides the obvious hope for more successful treatment, there is also a strong economic rationale here. New generation drugs and biologics, such as antibody therapies, are very expensive. Healthcare professionals are understandably reluctant to use them on patients if they have limited or no chance of benefiting from them, or if the potential result is unclear. For the industry it offers greater efficiency and economic benefits to identify which candidates are likely to be effective, by using this diagnostic tool early on in the drug development process. Increasingly, this stratification of patients into responders and non-responders will also be an important element of routine drug prescription beyond the research phase.

LEGACY ISSUES

While biomarkers sound like the key to more successful drug development, there are some legacy issues around the challenges of successfully identifying appropriate markers which leave some sceptical of their viability.

Older generation biomarkers have weaknesses. For example, the Prostate Specific Antigen (PSA) is known as unreliable for diagnosing prostate cancer, but remains one of the few available to diagnose any disease. In addition, biomarkers such as CEA and CA125 also have limited reliability in cancer diagnostics, and they fail to reveal the nature of a malignancy. The expectation is that future protein diagnostics will depend on measurements of panels of markers to ensure efficient detection, and to identify the nature of the disease.

KEY STEPS TO SUCCESS

There are three key steps to successful biomarker discovery:

  • Firstly, access to well-characterised patient samples in biobanks. These allow efficient validation of promising new biomarker candidates without having to go through the inconvenience of prospective sample collection.
  • Secondly, access to affinity reagents, including antibodies that can specifically bind to the proteins of interest. For example, the Human Proteome Resource, a joint project between the cities of Stockholm and Uppsala, is an excellent example of the creation of a basic resource to map the expression of proteins in healthy tissues and in diseases such as malignancies. This can provide an important basis to identify promising protein biomarkers for diagnostic use.
  • Thirdly, the molecular approaches used to study proteins. For example, the world of DNA analysis was revolutionised by the polymerase chain reaction (PCR) that came during the mid 1980s and largely solved problems of specificity and sensitivity of DNA analyses. In protein science we have seen slower development of new, highly specific detection techniques despite the obvious need. Emerging techniques offering improved performance and throughput could greatly improve opportunities for protein diagnostics.

ON THE CUSP OF DISCOVERY

We are now starting to see better approaches and more sophisticated uses of technology to identify and test biomarkers, with the development of innovative approaches taking advantage of the strength of DNA analysis techniques and their application to the understanding of proteins.

Scientists are looking at the creation of ‘go-between molecules’, such as antibodies that can bind to particular proteins, but that also bring with them attached DNA strands so that binding can be reported via the presence of specific DNA sequences. Using these types of reagents has aided the development of so-called ‘proximity ligation assays’. The assays are constructed so that when two antibodies with attached DNA strands bind with the target molecule being looked for, it brings the attached DNA strands into proximity. This allows one to join pairs of DNA strands by what is called DNA ligation, creating new DNA strands composed of the two parts that were attached to separate antibodies. These joined DNA strands then become reporter molecules, allowing one to detect the presence of the proteins so we can use DNA tools, such as PCR, to amplify the signal and detect even very minute amounts of proteins.

These proximity ligation protein assays take the best of both worlds: the ability to recognise proteins using high-affinity antibodies and the ability of DNA to store information about the detected proteins as strings of nucleotides, amplifying this information for sensitive detection.

The use of DNA reporter molecules now allows us to multiplex reactions in order to detect many proteins at the same time in very small sample aliquots, and then to decode which DNA molecules have been formed as a measure of which proteins were present in the sample and in what amounts. Scientists are using the proximity ligation assays both for measuring plasma proteins and also for visualising the location of proteins or interacting or modified proteins in tissue sections.

Recently, researchers looked for a class of structures that are being secreted from the prostate epithelium, so called prostasomes, which are composed of many protein molecules. In a small study they were able to demonstrate elevated levels of prostasomes in blood plasma from prostate cancer patients compared to normal controls. This suggested that these structures may have a greater diagnostic value compared to the established PSA test and will scale the study up in future to demonstrate in greater detail how it performs.

Key to the assay design was the ability to demonstrate the presence of several proteins in the prostasomes by using a total of five antibodies that all have to simultaneously bind these complexes before we can detect them. These complexes have not been possible to demonstrate in the blood of either healthy or diseased patients. Some assays, involving both antibodies and DNA strands, will now allow for the measurement of these complexes in the blood. The assay appears to tell cancer patients and healthy individuals apart.

There is a long way to go before this test becomes routine, but this new class of markers – previously inaccessible to analysis – may allow screening in men for prostate cancer, obtaining better information as to whether they really have a serious cancer or not, compared to the PSA test.

CONCLUSION

Biomarker discovery looks set to increase dramatically over the next 10 years. Not only will this aid the appropriate application of protein therapeutic reagents – improving patient care and helping to limit expenses – but it will also start to form part of an integrated and personalised healthcare programme for unconventional and standard drugs, as we start to see much more complex treatment schedules in the future.


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Ulf Landegren is Professor of Molecular Medicine at Uppsala University. Commercialised techniques originated by his group include the oligonucleotide ligation assay, padlock probes and proximity ligation technology for analysis of nucleic acids and proteins in research and for biomarker diagnostics. He is a member of EMBO, the Royal Swedish Academy of Sciences. He sits on scientific advisory boards for several biotech companies, and co-chairs a subproject on techniques and reagents for molecular analysis in the EU infrastructure on biobanks (BBMRI). His inventions have been licensed to leading biotech companies and to five spin-outs.
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