Cooperative Agreement UH3DE034134

A NOVEL IMMUNOLOGICAL-DIRECTED PROBIOTIC FOR THE TREATMENT OF SJOGREN'S SYNDROME - PROJECT SUMMARY OUR GOAL IS TO DEVELOP A NOVEL, IMMUNOLOGICAL-DIRECTED L. LACTIS PROBIOTIC-BASED THERAPEUTIC FOR THE TREATMENT OF SJOGREN'S SYNDROME (SS). SS IS A PROGRESSIVE, CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY INFLAMMATORY CELL INFILTRATION OF THE SALIVARY AND LACRIMAL GLANDS, RESULTING IN ACINAR EPITHELIAL CELL ATROPHY, CELL DEATH, AND LOSS OF EXOCRINE FUNCTION1-6. AT LEAST HALF OF SS PATIENTS DEVELOP EXTRAGLANDULAR INFLAMMATORY DISEASE AND HAVE A WIDE RANGE OF SYSTEMIC CLINICAL MANIFESTATIONS THAT CAN AFFECT ANY ORGAN SYSTEM, INCLUDING CONNECTIVE TISSUE, AND 5- 10% OF PATIENTS DEVELOP LIFE-THREATENING LYMPHOMA7, 8. SS IS A DEBILITATING DISEASE AFFECTING AS MANY AS 3.1 MILLION INDIVIDUALS IN THE U.S.9, 10, WITH WOMEN BEING AT LEAST NINE TIMES MORE LIKELY TO BE AFFLICTED WITH SS THAN MEN5, 10, 11. TREATMENT OF SS REMAINS A SIGNIFICANT UNMET MEDICAL NEED. CURRENT TREATMENT RELIES ON REPLACEMENT THERAPIES SUCH AS ARTIFICIAL SALIVA AND EYE LUBRICANTS OR IMMUNOSUPPRESSIVE AGENTS12, 13. WHILE WE UNDERSTAND THAT TREGS ARE IMPORTANT IN CONTROLLING SS 14-16, MULTIPLE ANTIGENS INVOLVED IN THIS DISEASE PROCESS (I.E., A-FODRIN17-20, RIBONUCLEAR PROTEIN RO/SSA17, 21, 22, LA/SSB17, 21, 22, AND M3R22-24) MAKE ORAL TOLERANCE APPROACHES PROBLEMATIC. THUS, THE CAPACITY TO STIMULATE REGULATORY CELLS INDEPENDENT OF KNOWING THE ANTIGEN SPECIFICITY FOR THE DISEASE POSES AS AN ATTRACTIVE THERAPEUTIC APPROACH. 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 CELLS WHEN ADMINISTERED ORALLY VIA A L. LACTIS BACTERIAL DELIVERY SYSTEM25-27, 28. 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. INDEED, R-2487 WAS EFFECTIVE AT REDUCING CLINICAL SYMPTOMS IN A SS ANIMAL MODEL29, 30, ALONG WITH EXPERIMENTAL MODELS OF RA, DIABETES, AND MS31-36. PRIOR SBIR AND SEED INVESTMENT FUNDING HAS ENABLED US TO EFFECTIVELY ADVANCE R-2487 TO BE POISED FOR CLINICAL TESTING. AS PART OF THESE EFFORTS, WE HELD AN FDA PRE-IND MEETING TO FINALIZE OUR IND-ENABLING PLANS AND ALIGN OUR CMC/MANUFACTURING STRATEGY WITH FDA PERSPECTIVES. THIS UG3/UH3 APPLICATION IS FOCUSED ON OBTAINING HUMAN VALIDATION FOR R-2487 BY COMPLETING A PHASE 1 SS PROOF-OF-CONCEPT CLINICAL TRIAL. THE SPECIFIC AIMS ARE: 1) ESTABLISH A SUCCESS-DRIVEN BIOMETRICS PLAN TO SUPPORT THE CLINICAL TRIAL, 2) PREPARE CLINICAL DOCUMENTATION AND FILE AN IND WITH THE FDA, 3) ESTABLISH R-2487 CLINICAL SAFETY, 4) EVALUATE R-2487 ACTIVITY AND CLINICAL BENEFIT IN SS, AND 5) CLOSE OUT THE PHASE 1 CLINICAL TRIAL TO SUPPORT FUTURE CLINICAL ENDEAVORS. SUCCESSFUL COMMERCIALIZATION OF R-2487 WILL PROVIDE A PROFOUND MEDICAL ADVANCEMENT FOR TREATING SS.