In autoimmune diseases, the immune system, which typically recognizes and eliminates threats, attacks its own healthy cells. In rheumatoid arthritis, the body targets the thin tissue that lines joints; in inflammatory bowel disease, it turns toward the cells of the gut; and in the case of lupus, the impact is often systemic, affecting multiple organs, such as the skin and kidneys.
Medicines currently available to manage the progression of these and other autoimmune diseases have dramatically improved many patient lives, but none have yet to offer efficacious, selective, and durable treatments for most patients. Flagship-founded Repertoire Immune Medicines is working to change that, collaborating with Bristol Myers Squibb to speed such therapies to patients.
We talked to Anthony Coyle, President and Head of Research and Development at Repertoire, to learn more about the company’s approach to developing medicines for this often-overlooked disease area.
Why is Repertoire focused on developing alternatives to current approaches for treating autoimmune diseases?
For decades, we've treated inflammatory and autoimmune diseases largely using immunosuppressive agents. Drugs like steroids exert an anti-inflammatory action by suppressing the entire immune system in a broad and nonspecific manner. This has tremendous implications for patients who require lifelong chronic treatment. In long-term use, these medications are often associated with significant side effects that include not only viral and bacterial infections, but also increased risk of cancer.
Over the last decade, we've seen the introduction of targeted biologics that have transformed the quality of life of numerous patients. But unfortunately, for many, these medicines do not adequately control their condition, as these medicines don't address the true underlying drivers of the disease. In addition, many patients don't have a durable response. Some patients respond initially, but subsequently, the efficacy of these therapeutics often wanes, requiring patients to cycle through various other anti-inflammatory drugs.
As a result, autoimmune diseases remain a challenge for physicians and patients to manage, and we are focused on filling this need by uncovering and targeting the drivers of disease to make new, more-effective therapies.
How does Repertoire both discover new medicines and support their clinical development?
Our immune system has billions of distinct T cells that comprise our T cell repertoire. The challenge has been to find and target the specific T cells that are at the heart of the dysregulated immune response. Current computational approaches are limited in terms of accuracy, but our DECODE platform offers superior precision in determining the presentable epitopes associated with various autoimmune diseases. Armed with this information, we can determine which T cells are responding to the presentable epitopes and driving the pathology of distinct autoimmune disorders. The platform also identifies the epitopes relevant to a disease that are common, shared, and most prevalent across patients.
We can also understand and monitor how the T cell repertoire changes in patients who, for example, may be having an acute flare of the disease and can provide insights into why a patient may not respond to a therapy. While we often highlight the platform’s discovery capabilities, DECODE also overcomes one of the huge limitations in understanding, tracking, and monitoring the T cell repertoire in the context of a clinical trial. After administration of a tolerizing vaccine, we can understand the magnitude and duration of the changes in the T cell repertoire, which will provide an early proof-of-mechanism to guide and potentially accelerate clinical development.
Repertoire is collaborating with Bristol Myers Squibb to develop tolerizing vaccines. What are tolerizing vaccines and how do they reset the immune system?
Our tolerizing vaccines are comprised of epitopes encoded by mRNA encapsulated in a lipid nanoparticle with an mRNA-encoded immune modulator. The vaccine triggers the body to expand a cadre of T regulatory cells that are specific to the antigen of interest. Those T cells then work to dampen the immune response and restore homeostasis, directly addressing the true driver of disease.
It is important to highlight that our DECODE platform allows us to target T cells specific to the antigen that is relevant to a disease and tissue. Other approaches to dampen inappropriate immune responses expand T regulatory cells but do so in a non-specific manner. T regulatory cells can also be generated through cell-based therapeutics, which is an exciting area of development, but the cost associated with these therapies are not insignificant. Our approach, on the other hand, allows us to create precise programmable medicines that can be adapted for different populations and diseases.
Tolerizing vaccines leverage a lot of the learnings gained in developing vaccines for infectious disease and cancer, providing long-term durable response with infrequent dosing. This will usher in a paradigm change for the management of autoimmune diseases. If we can administer a vaccine twice a year, for example, and generate a durable protective T regulatory cell response, patients can lead more productive lives without the need for constant disease management.
