Disease Biomarkers for In Vitro Diagnostic (IVD) Development

In-Vitro Diagnostics (IVD) refers to the removal of blood, body fluids, tissues and other samples from the human body. The samples are tested and verified using in vitro detection reagents, kits, calibrators, and quality control materials. The process of prevention, diagnosis, treatment testing, post-observation, health evaluation, and genetic disease prediction.

Finding and discovering reliable biomarkers is critical for many common and major diseases. In recent years, with the development of immunology, molecular biology and genomics technology, scientists have achieved many important results. Relevant departments in various countries and regions have also introduced corresponding support policies, such as the Critical Path Initiative (CPI) issued by the US Food and Drug Administration (FDA) in 2004 and the European Medicines Agency Road Map to 2015 and the Organization for Economic Co-operation and Development (OECD) biomarkers in health applications and development policies clearly mention the key to biomarkers in new drug development and clinical treatment effect.

The development of basic and applied research on disease biomarkers, coupled with significant clinical needs and policy promotion, has also led to in vitro diagnostic(ivd) development, providing a powerful means for clinical testing.

  1. Progress in research oncancer biomarkers

1.1. Cancer biomarkers: researchers from the University of Würzburg, Germany, have used cancer molecules to diagnose cancer, and the study was published in the international journal ChemBioChem. Researcher Jurgen Seibel said that galectin-1 molecules help tumor cells hide. From the immune system attack, recent studies have suggested that when the function of galectin-1 is blocked, the immune cells will recognize the tumor and launch T cells to attack the tumor. Researcher Seibel and colleagues studied the specific part of the protein, the carbohydrate recognition domain, in which they designed a complex sugar molecule that would be well suited to the domain. They immobilized sugar molecules on a “parking site” and attached fluorescent dyes or drug molecules. In addition, the researchers described how the sugar molecule binds to galectin-1 with a high-resolution X-ray structure.

1.2. In a study published in the international journal Nature Medicine, researchers from Fudan University and Mayo Clinic in China identified a new mechanism of prostate cancer resistance to therapy through joint research. The development of new prostate cancer therapies provide ideas and hopes. In the article, the researchers explained that the mutations in the SPOP gene play a key role in the drug resistance of prostate cancer. The SPOP gene mutation is the most frequent genetic mutation in primary prostate cancer. These mutations are in the cancer pair. BET inhibitor drugs play an important role in the development of tolerance.

  1. Progress in research on cardiovascular biomarkers

Cardiovascular biomarkers: researchers from Michigan State University analyzed 240 patients in the emergency department to find out the relationship between cholesterol crystals and heart disease in patients. The study’s lead author, George Abela, chief cardiovascular specialist from MSU, analyzed the material composition of the heart arteries in patients with heart disease and found that 89% of them had excess cholesterol crystal deposits in the area.

  1. Progress in research on diabetes biomarkers

3.1. Special lymphocytes or new biomarkers that can be used as a form of type 1 diabetes. Researchers from the Necker Children’s Disease Hospital and the Cochin Institute have found that the onset of type 1 diabetes may be guided by the modification of MAIT lymphocytes, which recognize the components of the body’s microbial population. Thus as a novel biomarker for early diagnosis and prevention of diseases

3.2. The 3U Diabetes Alliance from Dublin City University, Eric West University and the Royal College of Surgeons of Ireland has a groundbreaking study that found biomarkers that might predict the development of type 1 diabetes. The researchers found that a substance called 12-HETE in the blood can be used to diagnose patients with type 1 diabetes. If the patient is not ill, the substance cannot be detected in the blood.

  1. Progress in research on biomarkers of nervous system diseases

4.1. Researchers from the Sanford Burnham Prebys Medical Discovery Institute identified a key peptide or helped early diagnosis of Alzheimer’s disease (AD), the results of which were published in the international journal Nature Communications. It can help researchers develop new ways to introduce drugs into the brain of patients to treat a variety of diseases, such as Alzheimer’s disease, Parkinson’s disease, stroke and glioblastoma.

4.2. In a study from Ohio State University, researchers seem to have found a diagnostic method that accurately predicts patients with Alzheimer’s disease. According to the author of the article, Mingjun Zhang, a professor of biomedical engineering at Ohio State University, first discovered biomarkers that could be accurately diagnosed: proteins that changed in the patient’s spinal fluid and blood. Specifically, as the disease of Alzheimer’s disease becomes severe, these proteins become longer, harder, and more susceptible to agglomeration.

Advantage

In vitro diagnostics provide significant clinical and economic benefits by providing targeted drug biomarkers to improve treatment efficiency while reducing complications. This approach can be based on the biomarker-based test results for drug development by correlating the efficacy of the drug with measurable biomarkers. In addition, this approach may increase the chances of success in key trials by centralizing the inclusion of patients with curative effects in clinical trials.

In recent years, the development of biomarker targeted therapies has been the focus of biomedical research. In 2016, 6 of the 22 new molecular entities (NMEs) and biologics approved by the FDA were targeted therapies, accounting for 27% of the total. Compared with the 14% in 2011 and the 5% in 2005, it can be seen that the approval rate of targeted therapeutics has increased significantly. Although the number of approved therapeutic drugs in the total number of approved NMEs continues to increase, it has been mainly concentrated in the field of cancer, and targeted therapy in other disease areas is very limited. There are many reasons for this phenomenon: first, even if there is some progress in the field of cancer treatment recently, there are still many unmet clinical needs in this field, especially the clinical efficacy is relatively poor, and the non-targeted treatment program is serious. Adverse events, etc. Second, our current scientific understanding of cancer and its genomic etiology is deeper than any other non-communicable disease. Therefore, many of the cellular mechanisms triggered by tumor-induced gene mutations can be targeted using appropriate drugs. Finally, the choice of patients with cancer treatment targets has a huge economic impact: cancer treatment is usually expensive and can significantly increase expenditure, but the economic benefits of targeted therapy for patients who may be effective are also obvious.

In general, biomarkers can be incorporated into clinical development programs in two ways. The first method is to use a genome-wide association study to determine the biomarker signature corresponding to a significant drug. Because this method is indirect (i.e., independent of any information related to known drug characteristics and mechanisms of action), it may be affected by a variety of factors (including biomarker distribution, population and geographic differences), so this method is less likely to bring value to the payer or the pharmaceutical company. The second method is more ideal, and the biomarkers are directly related to the method of action of the drug. This is a typical targeted tumor drug in which the biomarker itself may be a drug target. For example, epidermal growth factor receptor (EGFR) inhibitors (such as erlotinib) and human epidermal growth factor receptor 2 (HER2) inhibitors (such as pertuzumab). In other cases, biomarkers can identify another protein in the drug’s pathway of action, which can cause the drug to lose its effectiveness on the tumor (eg, RAS mutations can block the action of the HER2-targeted drug panitumumab). In any case, the correlation between biomarker detection and drug activity is first determined in a non-clinical (in vitro) study and then initially assessed in an early clinical study.

Any biomarker reagent for patient selection and enrollment in a stratified oncology trial will appear in the indication of the drug, so the reagent must be marketed as a companion diagnostic test available for sale. Companion diagnostics (CDx): means the use of in vitro testing equipment to provide certain disease information to help improve the safety and effectiveness of the corresponding drug during use. Concomitant diagnosis features: one is to screen patients who are suitable for treatment with specific drugs, and the other is to screen patients who are not suitable for specific drug treatment, that is, patients who may have serious side effects or have weak reactions to drugs, and thirdly, monitor the treatment effect of patients and guide the development of the most suitable treatment plan, and this is also the role of biomarkers. It helps to identify the population of patients most likely to respond to treatments, promotes the use of drugs in relatively limited markets, improves the effectiveness and safety of drugs, and reduces the waste of value due to weak patient response to drugs.

Biomarkers have become a key element in the current precise treatment or development of drugs. With the deeper understanding of the molecular mechanisms of disease, all disease treatment methods will eventually be able to develop biomarkers.

Reference

[1] Blackhall F, Peters S, Kerr K M, et al. Biomarkers[J]. Annals of Oncology, 2012, 23:ix73-ix94.

[2] Zhang Z, Jr B R, Yu Y, et al. Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer[J]. Cancer Research, 2004, 64(16):5882.

[3] Li J, Zhang Z, Rosenzweig J, et al. Proteomics and bioinformatics approaches for identification of serum biomarkers to detect breast cancer.[J]. Clinical Chemistry, 2002, 48(8):1296.

[4] Zhang Z, Chan D W. The road from discovery to clinical diagnostics: lessons learned from the first FDA-cleared in vitro diagnostic multivariate index assay of proteomic biomarkers.[J]. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2010, 19(12):2995.

[5] Azzazy H M, Mansour M M. In vitro diagnostic prospects of nanoparticles[J]. Clinica Chimica Acta, 2009, 403(1):1-8.

[6] Lewandrowski K, Tamerius J, Menegus M, et al. Detection of Influenza A and B Viruses With the Sofia AnalyzerA Novel, Rapid Immunofluorescence-Based In Vitro Diagnostic Device[J]. American Journal of Clinical Pathology, 2013, 139(5):684-689.

[7] Listed N. Medical devices containing materials derived from animal sources (except for in vitro diagnostic devices), guidance for FDA reviewers and industry; availability–FDA. Notice[J]. Fed Regist, 1998, 63(215):60009-60010.