Our goal is to commercialize R-2487 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 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 T-B interactions, no therapy can induce long-term disease remission34. TNF-? 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 immunotherapeutic 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 in an enduring manner and 2) maximally balance the relationships between effector cells of different lineages to prevent relapses of chronic inflammation. Such an approach will provide patients long-term remission and increased safety without systemic immunosuppression. Originally conceived as a human diarrheal vaccine, we found that colonization factor antigen I (CFA/I) from human enterotoxigenic E. coli (ETEC) is effective at inducing auto-Ag-specific T regulatory cells18, 22, 54, 55, 56. CFA/I administered orally as purified protein or delivered via an L. lactis or Salmonella bacterial vector was effective at preventing and treating multiple experimental models for arthritis16, 18, 33, 57, as well as models for Sjogren?s syndrome, diabetes, and multiple sclerosis17, 58, 59. To avoid challenges associated with producing sufficient quantities of recombinant CFA/I and to improve the mucosal PK/PD properties of CFA/I following oral administration, we successfully developed a new L. lactis strain (referred to as R-2487) that expresses functional CFA/I from a genome-integrated expression operon. We also validated that R-2487 possesses the important key design features for a viable biotherapeutic candidate including functionality on human cells. Now that we have met with the FDA in the context of a pre-IND meeting to finalize our product development strategy, this Phase II SBIR application is intended to build upon our success and advance R-2487 towards the IND filing stage. The objectives are: 1) produce sufficient quantities of R-2487 to support in vivo development, 2) develop PK assays to measure R-2487 and CFA/I protein intestinal exposure, 3) determine the optimal oral dose and PK/PD for R-2487 in mice, 4) prepare a GMP master cell bank and manufacture R-2487 for GLP pharm/tox studies, and 5) perform GLP toxicology studies with R-2487 to enable IND filing.
Rheumatoid arthritis (RA) is a progressive autoimmune disease characterized by inflammation and pain of the joints. RA is a chronic, systemic inflammatory disorder affecting up to as much as 1% of the U.S. population1, 2. This project aims to develop a novel Lactococcus (L.) lactis line, R-2487, expressing colonization factor antigen I (CFA/I) for the treatment of RA. As an oral treatment that can induce T regulatory cells and control inflammatory responses, R-2487 is differentiated from other RA medications. Successful commercialization would ultimately provide a profound front-line medical advancement in the treatment of RA.
