People living with autoimmune diseases just want to feel better. While most of us can trust our immune systems to identify and attack only the unwelcome invaders—like bacteria or viruses—for reasons we don’t yet fully understand, some patients’ immune systems attack healthy tissue, causing inflammation, pain and damage in various parts of the body. Over time, the effects of these attacks can be devastating.
For the researchers trying to find new treatments to help these patients, immune-mediated diseases—diseases like rheumatoid arthritis (RA), Crohn’s disease, lupus, psoriasis and many others—present many challenges, not the least of which are their complexity and their heterogeneity. While many of these seemingly disparate diseases are, in fact, mechanistically linked to each other, the underlying cause of autoimmunity and/or chronic inflammatory diseases is unknown.
Advances in patient care
This is not to say we haven’t made great strides in patient treatment. To understand how far we’ve come, we need only look back about 30 years, when patients diagnosed with rheumatoid arthritis, for example, were treated with anti-cancer drugs. The hypothesis was that by inhibiting immune cell replication and therefore expansion of aberrant immune cells, the disease would be managed. This was a valid approach and these drugs did show efficacy in treating disease, but they also were quite toxic for patients.
One of the biggest advancements over the past 20 years has been the realization and demonstration that inhibiting single pathways (single cytokines) can have profound effects on immune-mediated diseases. One example is anti-TNF and the introduction of biologic therapies that block the function of this protein and reduce inflammation in several immune-mediated diseases. Recently, a second great example has emerged, with the promising efficacy observed in psoriasis due to inhibition of the IL-17/IL-23 pathway.
For many patients, these therapies have been life-changing. There are many patients, however, for whom current treatment options have not been effective enough, making it critical that we continue advancing our research efforts. While there are a variety of ways we might go about this, two ideas stand out. First, we need to build a better fundamental understanding of the underlying disease pathologies, and second, we need to explore combination approaches to treatment to give us the best shot at providing paradigm-changing therapies to patients.
Getting to the root cause
Since we know that not everyone responds to existing therapies that target a single cytokine, it tells us that something else is driving their disease, and this is where disease pathology comes into play. AbbVie, in partnership with the National Institutes of Health, the U.S. Food and Drug Administration and many industry and non-profit partners is part of the Accelerating Medicines Partnership (AMP), whose goal is to increase the number of new diagnostics and treatments for patients and reduce both the time and cost to develop them.
AbbVie is involved with AMP in two areas of focus, Alzheimer’s disease and Immunology, specifically RA and lupus. In RA and lupus by applying sophisticated genetic/genomic and cellular technologies, we are able to not only identify the cells that are dysfunctional but also to look at the gene expression of single cells to determine what role it plays. Do we need to target an entire group of cells to have a profound impact on disease? Or are there ’trouble-makers’ within the group we could target more specifically? We now have tools and technologies that will allow us to ask and answer these questions.
We hope that by using tissue and blood sample analysis from patients with these diseases, we might be able to find differences between those who respond to certain medicines and those who don’t. This would help us to better match patients with the treatments most likely to work for them. We also are looking to develop a greater systems-level understanding of these diseases so that we might identify new targets for therapies.
Delivering a one-two punch
Another area of focus for us is looking at combination approaches to treatment to drive greater efficacy for patients. To understand the value in combining mechanisms, we need only look to our colleagues in oncology research.
Years ago, following the first mapping of the human genome, oncology scientists started analyzing tumor cells at the molecular level to figure out why they behaved differently. Asking this basic question and analyzing tumor versus normal tissue is where important discoveries were made, such as the roles of the HER2/neu and BRCA proteins in certain breast cancers. Now there are targeted therapeutics aimed at these proteins, providing more personalized treatment for patients who are also more likely to respond.
Indeed, for many years now, treating cancer has involved combining different mechanisms to disable the cancer, and much of the current research also is focused here. Having amassed significant knowledge about the mechanisms that tumor cells use to escape treatment, approaches targeting several of those pathways are being combined with success. Researchers also are combining treatments aimed at activating the immune system to recognize and fight the tumor cells with existing treatments.
In immunology, we are just at the beginning of realizing the dream of being more precise in our immunomodulation. We have been developing delivery platforms such as antibody-drug conjugates (highly specific antibodies linked to potent inhibitors that go right to the diseased cells and limit impact to healthy tissue), as well as methods of delivering therapeutics directly to the gastrointestinal tract. These are exciting technologies aimed at improving efficacy and tolerability for patients, and they are showing promise. Given what we know about immune-mediated diseases, we believe that getting patients into true remission will require a combination of these and other approaches to deliver a one-two punch to the disease.
Lisa Olson, Ph.D., is vice president of immunology research and head of the AbbVie Bioresearch Center based in Worcester, Mass., U.S.A.
