Genomics and proteomics have exploded into biological discovery over the past two decades increasing the identification of biomarkers for disease patterns and processes. Making use of these biomarkers within diagnostic and disease profiling assays could allow earlier diagnosis and more personalised treatments, but in order for this to be successful biomarker research must happen in parallel with the drug discovery and development processes.
Early diagnosis offers an effective strategy to reduce the morbidity and mortality of many diseases, while good quality biomarkers can increase the accuracy of diagnosis and offer specific patient targeted therapies. This has been to shown to be very important in the field of immuno-oncology, helping to select the best patient subsets for effective treatment. Based on molecular profiling of the patient and tumour physiology, matching the correct drug to patients expressing specific biomarkers has yielded very promising results, particularly in the case of immune checkpoint blockade such as PD-L1 inhibitors.
The recent development of highly selective molecular targeted therapeutic agents, such as PD-L1 inhibitors, requires robust and well-validated disease biomarkers. However, a large gap remains between the initial reports of biomarkers often with diagnostic performance that cannot be reproduced in later studies and full clinical implementation and validation of the biomarkers. This is due to issues in study design, assay platforms and the availability of specimens for biomarker development. The disparity between biomarker identification and validation increases the cost and reduces the speed of drug development. More than 90% of oncological drugs currently entering clinical development fail to gain market approval as they are unable to demonstrate a therapeutic benefit during clinical trials.
Drug development costs may be reduced by clear biomarker validation and utilisation. This could contribute to minimising the risk of clinical trial failures, by enriching trial populations with specific molecular subtypes that may respond better to targeted therapies. In addition to guiding clinical decision making the accurate evaluation of disease biomarkers within the clinic can justify both treatment and interventional strategies. Well-validated biomarkers can be used within the drug development process and the clinic as tools for target discovery, within early target assessment, for evaluating a medicine’s mechanism of action, for dose determination, for prediction of a drug’s effects, for patient selection, for therapy monitoring and for prognostication. Of course the ultimate goal of the process is to establish accessible biomarker tests with clinical utility that can inform clinical decision-making to improve patient outcomes, but as the current success rate of clinical translation of biomarkers being just 0.1% shows current identification and validation strategies are often ineffective.
Most biomarkers are in the exploratory phase. Critical for the application of these biomarkers as diagnostic and prognostic factors is their validation as yielding reliable and meaningful information regarding a disease process. Early work focused on nucleic acid biomarkers (DNA, SNPs and mRNA profiles), but it is now being recognised that their utility as clinically applicable tools may be limited and that protein biomarkers offer a significantly greater level of differentiated information.
Immunoassays continue to be the most sensitive, specific and selective technology to interrogate protein biomarkers. Developing suitable protein-based assays remains a significant challenge, both with in terms of the technical aspects of affinity reagent and assay development and the validation of the targeted analyte. Despite the difficulties the development of accurate assays to probe potential biomarkers is important to correctly validate them and for use in subsequent drug development processes targeting a specific biomarker for clinical utility.
For novel candidate biomarkers immunoassays will often not exist and so affinity reagents to make up the assay will have to be developed. As the specificity and sensitivity of the affinity reagents is critical to the quality of the immunoassay it is important that this step is done correctly. What’s more different affinity reagents are often required for biomarker analysis in different immunoassays, from ELISA to IHC to mass spec, depending upon the different assay environment and antigen structure being examined. ELISA remains the most clinically relevant immunoassay for biomarker detection, with the sandwich assay being the most common format used. ELISA offers the ability to analyse numerous samples simultaneously with low variation. Sensitivity and specificity of the affinity reagents used in the ELISA are both critical elements that determine the quality of the resulting ELISA test.
Access to high quality antigen in the format in which it will be detected during the assay is important to obtaining functional affinity reagents for use in biomarker assays. This is often a limiting factor in the development of affinity reagents. However, the unique screening and isolation processes in Affimer® development mean that we only use very small amounts of antigen, which can help to overcome this limitation. Oftentimes antibodies developed are not appropriate for the intended immunoassay, as the conditions used to screen are different to the diagnostic assay or the antibody does not have the necessary specificity or affinity for the assay. These issues are compounded for sandwich assays where two complementary antibodies must be identified. Because of these factors biomarker discovery greatly outpaces the ability to develop affinity reagents for biomarker and proteomic research. Again Affimer technology can provide solutions to prevent this problem arising, by working with you to incorporate your intended end use conditions into our screening process to ensure functional affinity reagents are isolated from our processes.
To overcome the high clinical failure rate of drugs in development biomarker research and validation cannot be an afterthought to the drug development process, being carried out once a medicine enters clinical trials. The development of sensitive and specific affinity reagents and immunoassays to detect these proteins is clearly an important part of this process and should be explored early on to reduce timeframes and costs within drug discovery and development.