SBIR-STTR Award

Direct to Phase II

Our goal is to commercialize R-2487 as a novel, orally administered therapy for long-term disease remission ofrheumatoid arthritis (RA). RA is a chronic, systemic inflammatory disorder affecting up to 1% of the USpopulation1, 2. While many organs are affected in RA, the synovial joints are primarily afflicted with debilitatinginflammation. 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 targetingcytokines and T-B interactions, no therapy can induce long-term disease remission34. TNF-α antagonists caneffectively diminish inflammation and attenuate destruction of cartilage and bone7-10. However, some patientseither fail to respond to, or relapse with, anti-TNF therapy. Prolonged treatment can make patients susceptibleto 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. Forthese 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 immuneresponse against the host's own tissues in an enduring manner and 2) maximally balance the relationshipsbetween effector cells of different lineages to prevent relapses of chronic inflammation. Such an approach willprovide 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) fromhuman 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 waseffective at preventing and treating multiple experimental models for arthritis16, 18, 33, 57, as well as models forSjogren's syndrome, diabetes, and multiple sclerosis17, 58, 59. To avoid challenges associated with producingsufficient quantities of recombinant CFA/I and to improve the mucosal PK/PD properties of CFA/I following oraladministration, we successfully developed a new L. lactis strain (referred to as R-2487) that expressesfunctional CFA/I from a genome-integrated expression operon. We also validated that R-2487 possesses theimportant 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 developmentstrategy, this Phase II SBIR application is intended to build upon our success and advance R-2487 towards theIND 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 oraldose and PK/PD for R-2487 in mice, 4) prepare a GMP master cell bank and manufacture R-2487 for GLPpharm/tox studies, and 5) perform GLP toxicology studies with R-2487 to enable IND filing.

Public Health Relevance Statement:
Project Narrative 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.

Project Terms:
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