Project Grant R43HL154867

DEVELOPMENT OF A TARGETED TGF-B THERAPEUTIC THAT SELECTIVELY BLOCKS LUNG FIBROSIS IN IDIOPATHIC PULMONARY FIBROSIS (IPF) PATIENTS - SYNTHIS PROJECT SUMMARY/ABSTRACT PHASE I NHLBI IPF IS A CHRONIC, IRREVERSIBLE FIBROTIC LUNG DISEASE DRIVEN BY REPEATED INJURY, RESULTING IN PROGRESSIVE STIFFENING AND ULTIMATELY, LOSS OF LUNG FUNCTION. WITH 130,000 IPF PATIENTS ANNUALLY AND A 5 YEAR MORTALITY RATE OF 80%, THERE IS SIGNIFICANT NEED FOR NEW THERAPIES. TO DATE, CONVENTIONAL THERAPIES HAVE NOT HALTED DISEASE PROGRESSION. RECENTLY 2 NEW IPF DRUGS WERE APPROVED: PIRFENIDONE, AN ANTI-FIBROTIC AGENT AND, NINTEDANIB, A TYROSINE KINASE INHIBITOR, BUT BOTH ONLY MODESTLY DELAY DISEASE PROGRESSION. TGF- IS ONE OF THE KEY DRIVERS OF FIBROSIS IN IPF PATIENTS, DUE TO ITS ELEVATED AND PROLONGED LEVELS IN THE LUNG. ON A CELLULAR LEVEL, TGF- DRIVES ACTIVATED MYOFIBROBLASTS, THE MAJOR PERPETRATORS OF DISEASE, TO OVER-PRODUCE COLLAGEN AND INCREASE FIBRONECTIN DEPOSITION IN THE EXTRACELLULAR MATRIX (ECM), WHICH PROGRESSIVELY BLOCKS LUNG FUNCTION. INHIBITION OF TGF-- MEDIATED FIBROSIS COULD POTENTIALLY STOP OR EVEN REVERSE DISEASE IN IPF PATIENTS. HOWEVER, TGF- IS WIDELY EXPRESSED AND HAS ESSENTIAL ROLES IN MAINTAINING TISSUE HOMEOSTASIS. THUS, ALTHOUGH TGF- INHIBITORS ARE OF SIGNIFICANT INTEREST TO TREAT FIBROSIS, DEVELOPMENT OF THERAPIES HAS BEEN HINDERED DUE TO SIGNIFICANT HOST (I.E., CARDIAC) TOXICITY. SAFER TGF- INHIBITORS THAT SELECTIVELY BLOCK FIBROSIS IN IPF PATIENTS, BUT STILL PROTECT HOST TISSUES, WOULD PROVIDE DIFFERENTIATED TREATMENT OPTIONS TO FILL THIS SIGNIFICANT UNMET NEED. IN THIS SBIR AWARD, WE ARE DEVELOPING A FIRST IN CLASS ANTIBODY DRUG CONJUGATE (ADC) PLATFORM TO SELECTIVELY INHIBIT TGF- DRIVEN FIBROSIS IN IPF PATIENTS. IN AIM 1, WE WILL DEVELOP OUR NOVEL ADC THERAPEUTIC (SYN301) AND DEMONSTRATE INHIBITION OF FIBROSIS IN FIBROBLASTS DERIVED FROM IPF PATIENTS, AS ASSESSED BY A DECREASE IN PROCOLLAGEN EXPRESSION AND ALPHA SMOOTH MUSCLE ACTIN IN VITRO, CLINICAL MARKERS OF FIBROTIC DISEASE. IN AIM 2, WE WILL ASSESS THE EFFICACY OF SYN301 IN AN INDUSTRY STANDARD, IN VIVO MODEL OF BLEOMYCIN INDUCED LUNG FIBROSIS. SYN301 WILL BE ASSESSED FOR INHIBITION OF DISEASE PROGRESSION AND LUNG FIBROSIS AS MEASURED BY LUNG HISTOPATHOLOGY, INFLAMMATORY INFILTRATES, COLLAGEN DEPOSITION AND BALF IMMUNE CELL COMPOSITION. WE ANTICIPATE THAT SYN301 WILL REDUCE MARKERS OF FIBROSIS BOTH IN VITRO AND IN VIVO, COMPARED TO STANDARD OF CARE THERAPIES. SYN301 IS A FIRST IN CLASS THERAPY THAT WILL SAFELY BLOCK TGF- INDUCED FIBROSIS IN IPF PATIENTS. IT IS THE FIRST ADC MOLECULE BEING DEVELOPED TO SELECTIVELY BLOCK TGF- DRIVEN FIBROSIS. MOREOVER, SYN301 COULD ALSO BE USED IN COMBINATION WITH CURRENT FIBROSIS THERAPIES, TO INCREASE OVERALL PATIENT RESPONSE RATES. TISSUE FIBROSIS IS A WIDE SPREAD ISSUE IN MULTIPLE OTHER DISEASES, SUCH AS NASH, KIDNEY FIBROSIS AND CARDIAC FIBROSIS, OF WHICH TGF- IS ALSO INSTRUMENTAL IN DRIVING DISEASE. THUS, OUR THERAPEUTIC PLATFORM IS WIDELY APPLICABLE TO FIBROSIS IN MULTIPLE DISEASES, PROVIDING NOVEL THERAPEUTIC OPTIONS FOR PATIENTS THAT NEED IT THE MOST.