Project Grant R43AI179510

INTEGRIN-TARGETED NOVEL ORAL THERAPEUTICS FOR LUPUS NEPHRITIS - PROJECT SUMMARY LUPUS NEPHRITIS (LN) REMAINS THE STRONGEST PREDICTOR OF MORBIDITY AND MORTALITY FOR PEOPLE WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), AN AUTOIMMUNE DISEASE DISPROPORTIONATELY AFFECTING WOMEN AND MINORITIES. THE CURRENT STANDARD OF CARE FOR LN, GLUCOCORTICOIDS AND IMMUNOSUPPRESSIVE AGENTS, HAS MANY SIDE EFFECTS AND LONG-TERM TOXICITY. THEREFORE, THERE IS AN URGENT AND UNMET NEED FOR TARGETED THERAPIES. SLE IS CHARACTERIZED BY AN ABERRANT ACTIVATION OF TOLL-LIKE RECEPTOR (TLR) SIGNALING IN IMMUNE CELLS THAT DRIVES INFLAMMATORY LEUKOCYTE ACTIVATION AND INFLUX INTO MAJOR ORGANS, WITH APPROX. 40% OF LUPUS PATIENTS SHOWING GLOMERULAR INJURY AND RENAL DISEASE, LN. THE INTEGRIN CD11B, EXPRESSED PRIMARILY ON MYELOID CELLS, IS AN IMMUNE RECEPTOR THAT MODULATES FUNCTIONS OF THESE CELLS. AMONG ITS MANY ROLES, IT MEDIATES LEUKOCYTE INFLUX IN TISSUES AND HAS RECENTLY BEEN SHOWN TO ALSO CONTROL OVERACTIVE TLR SIGNALING IN THESE CELLS. RECENT GWAS STUDIES SHOWED HIGH CORRELATION BETWEEN PATIENTS WITH SNPS IN ITGAM, WHICH CODES FOR CD11B, AND INCIDENCE OF SLE AND LN. STUDIES ALSO SHOWED THAT THE THREE MOST COMMON CODING ITGAM SNPS PRIMARILY REDUCE CD11B'S ROLE AS A RHEOSTAT OF TLR- SIGNALING, WITHOUT AFFECTING ITS SURFACE EXPRESSION, SUGGESTING REDUCED CD11B FUNCTION AS A CONTRIBUTOR TO SLE AND LN. IT ALSO SUGGESTED THAT CD11B ACTIVATION COULD SERVE AS A POTENTIAL THERAPEUTIC STRATEGY FOR LN. TOWARDS THAT, OUR CO-FOUNDER (VINEET GUPTA) DISCOVERED THAT ALLOSTERIC ACTIVATION OF INTEGRIN CD11B IS A NOVEL THERAPEUTIC STRATEGY AND IS AN EFFECTIVE METHOD TO TARGET THIS INTEGRIN FOR REDUCING LEUKOCYTE ACTIVATION AND TISSUE INFLUX. HE AND HIS TEAM DEVELOPED A FIRST-GENERATION CD11B SMALL MOLECULE ALLOSTERIC AGONIST, CALLED LA1, THAT SELECTIVELY ENGAGES CD11B IN VIVO, IS ORALLY BIOAVAILABLE, NON-TOXIC, REDUCES AUTOIMMUNE DISEASE AND SIGNIFICANTLY REDUCES INFLUX OF INFLAMMATORY MYELOID CELLS INTO TISSUES. DRS GUPTA, BARBOSA AND THE TEAM ALSO DEVELOPED AN LA1 ANALOG, CALLED GB1275, THAT HAS BEEN TRANSLATED AS AN ORAL THERAPEUTIC THAT IS CURRENTLY UNDER PHASE 1/2 CLINICAL TRIALS IN CANCER PATIENTS. THE PRIMARY GOAL OF THIS PROPOSAL IS TO FIND AND DEVELOP A NEW SERIES OF ALLOSTERIC AGONISTS OF CD11B WITH TRACTABLE SAR, DRUG-LIKE PROPERTIES AND WITH ENHANCED POTENCY OVER THE FIRST-GENERATION COMPOUNDS THAT CAN BE ADMINISTERED CHRONICALLY FOR TREATING AUTOIMMUNE DISEASES, LIKE LN. WE HAVE DEVELOPED AN ASSAY PLATFORM AND A FOCUSED INTEGRIN TARGETING LIBRARY OF ~800 COMPOUNDS THAT CAN BE USED TO RAPIDLY IDENTIFY AND DEVELOP NOVEL, HIGHLY POTENT CD11B AGONIST CANDIDATES WITH HIGH CONFIDENCE. HERE, WE PROPOSE TWO SPECIFIC AIMS TO DESIGN, SCREEN AND IDENTIFY NOVEL CD11B AGONISTS WITH IMPROVED POTENCY OVER LA1 AND TO CHARACTERIZE THEM IN VITRO AND IN VIVO FOR THEIR READINESS FOR DRUG DEVELOPMENT. OUR LONG-TERM GOAL IS TO DEVELOP THE NEW COMPOUNDS INTO A NEXT GENERATION OF THERAPEUTICS TO TREAT LUPUS NEPHRITIS IN HUMANS.