P15E ANALOGUES AS IMMUNOREGULATING AGENTS

THE OBJECTIVES OF THIS APPLICATION ARE TO OPTIMIZE AND TO BEGIN THE PHARMACEUTICAL DEVELOPMENT OF TWO NOVEL THERAPEUTICS FOR THE TREATMENT OF ALLOGRAFT REJECTION OR AUTOIMMUNE OR INFLAMMATORY DISEASES. SPECIFICALLY, WE WILL: 1) OPTIMIZE AS TO LENGTH AND AMINO ACID COMPOSITION A HOMODIMER OF A HEPTADECAPEPTIDE (CKS-17) WHICH ALREADY HAS DEMONSTRABLE ACTIVITY IN IN VIVO ANIMAL STUDIES; 2) PURITY TO HOMOGENEITY A 10KDA PROTEIN FRAGMENT (RP15E-10) WHICH INCLUDES THE CKS-17 SEQUENCE AND WHICH IS 1000X AS POTENT AS THE CKS-17 HOMODIMER IN IN VITRO ASSAYS OF IMMUNE FUNCTION; AND 3) CONFIRM ACTIVITY OF "OPTIMIZED" PEPTIDES AND PURIFIED RP15-10 IN BOTH IN VITRO AND IN VIVO ASSAYS OF CELL-MEDIATED IMMUNE FUNCTION AND INFLAMMATION. SUCH ASSAYS WILL INCLUDE MONONUCLEAR CELL PROLIFERATION TO MITOGENS AND ANTIGENS, NEUTROPHIL AND MONOCYTE CHEMOTACTIC RESPONSES, TOLERANCE TO ALLOGENEIC SKIN GRAFTS, ACCUMULATION OF NEUTROPHILS OR MONOCYTES AT IN VIVO INFLAMMATORY FOCI, AND CARRAGEENAN-INDUCED PAW EDEMA. BOTH THESE NOVEL COMPOUNDS HAVE THE POTENTIAL FOR ACTING AT AN EARLY STAGE IN THE DEVELOPMENT OF IMMUNE OR INFLAMMATORY REACTIONS AND THUS MAY MODIFY DISEASE AS OPPOSED TO AMELIORATE SYMPTONS. BOTH COMPOUNDS OFFER POTENTIAL ADVANCES FOR COMMERCIAL DEVELOPMENT, PARTICULARLY FOR THE LONG-TERM TREATMENT OF CHRONIC DISEASES SUCH AS ARTHRITIS.