Antibodies in Drug Discovery: Identifying Novel Biomarkers to Overcome Sjögren’s Syndrome
Article Aug 02, 2017 | by Dr. Petra Budde, Head of Medical Research, Protagen and Dr Peter Schulz-Knappe, Chief Scientific Officer, Protagen.
Sjögren’s syndrome hit the headlines recently as tennis star Venus Williams opened up about suffering from this incurable autoimmune condition. Although it affects millions of adults worldwide (of which 90% are women), Sjögren’s syndrome is a relatively unknown disease in which the immune system attacks moisture-producing (exocrine) glands, such as tear ducts and salivary glands. This causes a range of debilitating symptoms, such as dry eyes and mouth, fatigue, and joint pain, as well as an increased risk of developing life-threatening lymphoma and other cancers.
Sjögren’s syndrome has so far proven difficult to characterize and diagnose, and this has made the development of new treatments challenging. Yet, great strides have recently been made in understanding its pathogenesis, providing an exciting opportunity to identify biomarkers to improve diagnosis and the assessment of disease activity. We look at a recent collaborative project that has started to identify these biomarkers, and consider how one day they could be used to inform better diagnostic and treatment decisions to give Sjögren’s syndrome sufferers a new lease of life.
Barriers to effective diagnosis
Experts have been uncertain about the exact cause of primary Sjögren’s syndrome (pSS), which presents on its own rather than in tandem with other rheumatic conditions (as is the case in secondary Sjögren’s). The subsequent lack of effective therapeutic targets/pathways has made the development of new pSS treatments challenging.
In addition, diagnosing Sjögren’s syndrome can be difficult because its symptoms and physiological markers (e.g. autoantibodies expressed in patient blood, such as anti-nuclear antibodies, rheumatoid factor, SS-A and SS-B) tend to overlap with those of many other autoimmune conditions, such as rheumatoid arthritis and systemic lupus erythematosus. Furthermore, these biomarkers, while clinically significant, are not ubiquitously expressed in patients suffering from Sjögren’s syndrome.
As such, there is currently no single test that gives a definitive diagnosis (which can take as long as three years following the onset of symptoms) and no method of stratifying patients into disease-relevant subgroups based on the biomarkers they express to help drug development.
Homing in on a cure
Sjögren’s syndrome currently has no cure. Sufferers are typically advised to adopt self-help measures for symptomatic relief, such as using saliva substitutes for dry mouths, and eye drops for dry eyes. It is also recommended that sufferers get regular exercise and change their diet; for example, Venus Williams adopted a raw vegan diet to help fight her condition. Some medications are available to help alleviate symptoms, such as pilocarpine for dry mouth and eyes, and hydroxychloroquine for joint pain, although these medicines can cause severe side effects and can take several months to work.
Yet, the development of effective therapies is becoming increasingly realistic as new therapeutic targets are identified. This is due to recent research advancements elucidating the pathogenesis of pSS, and the discovery of biomarkers that could improve how the disease is diagnosed, characterized and subsequently treated.
One key breakthrough has revealed that the overexpression of B-cell activating factor (BAFF) is involved in the pathogenesis of pSS. Specifically, studies have found that elevated BAFF levels typically found in pSS patients (compared to healthy individuals) undermine B-cell self-tolerance by saving the auto-reactive B-cells from natural cell death via apoptosis. It also amplifies B-cell signaling to promote the irregular maturation and differentiation of B-cells into plasma cells that secrete autoantibodies (AABs) locally, which is a hallmark of the disease.
Consequently, profiling these AABs as novel biomarkers is being heralded as a way to improve diagnosis and disease characterization, and to enable the development of effective therapies.
A new diagnostic toolkit to enhance drug development
Recently, a new collaboration between Protagen and Novartis Pharmaceuticals has successfully profiled AABs in the serum of pSS patients, to reveal novel biomarkers associated with the disease and its activity.
The results were presented in a poster at the recent EULAR conference in Madrid, Spain. They demonstrated how Protagen’s autoantibody identification platform, SeroTag®, identified novel AABs whose expression correlated with measures of clinical outcomes and salivary BAFF levels in pSS patients. This means that these biomarkers could potentially be used as reliable, sensitive, and specific diagnostic and disease activity indicators for pSS.
Given these promising results, Protagen aims to use these novel biomarkers to improve the diagnosis and characterization of Sjögren’s syndrome, as well as to stratify patients into disease subgroups - based on their disease profile and likely response to treatment - via the development of a new Sjögren’s diagnostic tool.
This new diagnostic tool could therefore lead to improved therapeutic success and a better quality of life for the millions of patients suffering from Sjögren’s syndrome around the world.