Written by:
Executive Director and Head of Bioscience Immunology, AstraZenca
Vice President and Head of Translational Science and Experimental Medicine, Respiratory and Immunology, AstraZeneca
Building on decades of research, we are starting to unravel complex inflammatory cell signalling pathways and uncover key drivers that cause an imbalance in immune-mediated diseases.
With an estimated 5 million people worldwide living with lupus1 and 6.8 million with inflammatory bowel disease2, well-known immune-mediated diseases, there is a significant need for new innovative therapies to help improve outcomes for these patients.
Precisely targeting disease drivers in immune-mediated diseases
Moving away from the traditional stepwise treatment approach, the next-wave of therapeutic discovery is embracing the potential that precision medicine can offer - ensuring the right patient, gets the right medicine, at the right time. We are rapidly building our knowledge of disease biomarkers to help differentiate patient subgroups within a single disease, and develop diagnostic tests and precision medicines, which are targeted to the underlying causes of disease.
What is precision medicine in chronic diseases?
Inflammatory Bowel Disease
Our precision medicine approach in Inflammatory Bowel Disease (IBD) focuses on selecting distinct patient subpopulations through identifying biomarkers of disease. IBD is an umbrella term for conditions with chronic inflammation of the gastrointestinal tract and includes ulcerative colitis and Crohn’s disease. To date, our core research has focused on inflammatory cytokines called interleukins, known to be increased in these conditions, so we can identify patients who are failing to respond to treatment or become intolerant over time3.
The pro-inflammatory cytokine interleukin 23 (IL-23) is a known driver of inflammation and is mainly secreted by activated macrophages and dendritic cells located in tissues like skin, lung and the intestinal mucosa3. IL-23 potently enhances local inflammation by increasing T helper (Th) cells which are responsible for many of the autoimmune responses in IBD. Crohn’s Disease is driven by a Th1/Th17 interaction where IL-23 plays a key part and this is supported by genome-wide association studies that have strongly connected IL-23 to the pathogenesis of Crohn’s Disease.
The levels of IL-23 in the blood, even when elevated in disease, are hard to detect with easy-to-use technologies. An alternative biomarker is needed to clinically determine patients who have IL-23 driven disease. The effector cytokine IL-22 is a downstream product of IL-23 and has roles maintaining the integrity of the mucosal barrier and stimulating epithelial cell proliferation. It is also a direct indicator of IL-23 activity and therefore has potential as a disease biomarker3.
We believe that a significant reduction in IL-22 levels could be indicative of both disease activity and potential post-treatment disease modification. In collaboration with Roche Diagnostics, we are currently progressing the development of an accurate, non-invasive diagnostic test for IL-22 and exploring the interconnection between biomarker levels and clinical outcomes across a broad range of patients.
Systemic Lupus Erythematosus
Systemic Lupus Erythematosus (SLE) is a complex, chronic disease in which the body’s immune system attacks healthy tissue in any part of the body. It is estimated that at least five million people worldwide have a form of lupus1, which can manifest in a range of symptoms including skin rash, joint pain, swelling and fevers. Lupus remains poorly understood and the significant physical, emotional and socio-economic burden remains high for people living with the disease4.
SLE involves over activity of B-cells, T-cells and dendritic cells, as well as inflammatory cytokines such as type 1 interferons (IFN), IL-6 and B-cell activating factor. Cytokines regulate and coordinate the overall inflammatory response and in people with SLE over production results in a prolonged autoimmune response, leading to injury, inflammation and long-term organ damage5-10.
Research has shown an association between an elevated IFN gene signature and disease as well as a correlation between IFN protein levels and serological and clinical manifestations of SLE11. These data underscore our focus on IFN as a biomarker of SLE disease activity and is helping to guide our precision medicine approach. Research has shown that by measuring IFN mRNA levels instead of protein it was possible to detect an elevated IFN gene signature in over three quarters of adults in our patient cohort12. We’ve successfully deployed this blood-based biomarker test for IFN activity in clinical study programs to stratify patients with SLE and understand their underlying disease drivers12.
Moving forward, our scientists are also investigating other immune-mediated diseases where an IFN gene signature may enrich for patient populations likely to benefit from targeted treatments and improve their disease outcomes.
Bringing precision medicines to patients
There remains a huge unmet need for patients and healthcare systems in immune-mediated diseases. Providing access to routine diagnostics and precision medicines targeted to the underlying disease will be a powerful enabler of better patient outcomes and more sustainable care. Innovative financing, regulatory and clinical mechanisms will be necessary to support access and uptake. We are committed to working collaboratively with the immunology community to realise this potential and deliver precision medicine research to improve lives of those living with immune-mediated diseases.
