SBIR/STTR Award attributes
Project Summary Our goal is to develop a novel, immunological-directed L. lactis probiotic-based therapeutic for the treatment 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 in RA, the synovial joints are primarily afflicted with debilitating inflammation. Approximately half of all RA patients become disabled as the disease progresses. Treatment of RA remains a significant unmet medical need. Despite highly effective therapies targeting cytokines and immune cells, no therapy can induce long-term disease remission38. TNF-α antagonists can effectively diminish inflammation and attenuate destruction of cartilage and bone7-10. However, some patients either fail to respond to, or relapse with, anti-TNF therapy. Prolonged treatment can make patients susceptible to cancer and opportunistic infections11-14. Moreover, many current treatments for RA, no matter how effective, consign patients to a lifetime of costly biologic therapies with attendant risks for iatrogenic complications. For these reasons, we are developing an oral immunotherapy that regulates auto-Ag-specific regulatory T cells (Tregs) to provide bystander tolerance. The two main goals of this approach are: 1) to “switch off” the immune response against the host’s own tissues and 2) balance the effector cell relationships to prevent relapses of chronic inflammation. Originally conceived as a human diarrheal vaccine, we discovered that colonization factor antigen I (CFA/I) from human enterotoxigenic E. coli is effective at inducing auto-Ag-specific Tregs when administered orally22, 56-58. To avoid challenges associated with producing large quantities of CFA/I protein and improve the mucosal pharmacokinetic (PK) and pharmacodynamic (PD) properties of CFA/I following oral administration, we developed an L. lactis-CFA/I expressing product (referred to as R-2487) and validated its efficacy in multiple autoimmune models. R-2487 was effective at reducing arthritis symptoms in animal model studies, along with experimental models of Sjögren’s syndrome, diabetes, and multiple sclerosis17, 30, 59, 60. Prior SBIR and Seed investment funding and an FDA pre-IND meeting has enabled us to position R-2487 ready for clinical testing. This Fast Track application is focused on obtaining human validation for R-2487 by completing a first-in-human Phase 1 RA proof-of-concept clinical trial. The Specific Aims are: 1) finalize R-2487 clinical supply packaging, 2) prepare and file an IND with the FDA, 3) complete a Phase 1 proof-of-concept clinical trial, 4) analyze patient samples before/after dosing to evaluate pharmacodynamic changes and biomarkers, 5) perform Phase 2 clinical manufacturing scale up development to ready R-2487 for larger confirmatory trial. Successful commercialization of R-2487 will provide a profound medical advancement for treating RA.
