A Novel Immune-modulating Probiotic for Treating Rheumatoid Arthritis 

About This Grant

Project Summary Our goal is to commercialize VTC-L35 as a novel, orally administered therapy for long-term disease remission of rheumatoid arthritis (RA). RA is a chronic, systemic inflammatory disorder affecting up to 1% of the US population1, 2. While many organs are affected, the main targets of RA are synovial joints. Approximately half of all RA patients become disabled as the disease progresses5. Treatment of RA remains a significant unmet medical need. Despite highly effective therapies targeting cytokines and T-B interactions, no therapy can induce long-term disease remission39. Thus, all treatments for RA, regardless of efficacy, result in patients consigned to a lifetime of costly biologic therapies that come with inherent risks of iatrogenic complications. For example, TNF-α antagonists can effectively diminish inflammation and attenuate destruction of cartilage and bone8-11. However, some patients either fail to respond to, or relapse with, anti-TNF therapy. Moreover, prolonged treatment with TNF-α antagonists can have harmful side effects, making patients more susceptible to opportunistic infections12-15. Instead, intervention strategies that focus on redirecting or reeducating immune responses to produce tolerance instead of inflammation have the potential as a superior treatment for RA. For these reasons, we are developing an oral immunotherapeutic that regulates auto-Ag-specific regulatory Tregs and Bregs to provide bystander tolerance. This approach has the potential to “switch off” the immune response against the host’s own tissues specific to RA in an enduring manner and maximally balance the relationships between effector cells of different lineages to prevent relapses of chronic inflammation. As such, our approach will provide patients long-term remission and increased safety without systemic immunosuppression. Given its potency to treat various autoimmune diseases, our project team recently engineered Lactococcus lactis to express IL-35 (VTC-L35) and queried the effectiveness of this recombinant strain to suppress collagen-induced arthritis (CIA)24. Oral administration of the IL-35-expressing probiotic effectively induced T regulatory cells and reduced the incidence and disease severity of inflammation in both prophylactic and treatment protocols in the mouse model of CIA24. Building from this initial work, we have engineered a clinical L. lactis strain (termed VTC-L35) that expresses human IL-35 from a genome-integrated operon. This application is designed to advance VTC-L35 towards the clinic by establishing its manufacturing, therapeutic activity, and animal safety. Successful commercialization of VTC-L35 will ultimately provide a profound front-line medical advancement in the treatment of RA, and potentially other autoimmune diseases as well.