Project Grant F31HL188853

NONINVASIVE DETECTION OF MYOCARDITIS VIA IMMUNE-PET IMAGING - PROJECT SUMMARY / ABSTRACT PATHOLOGIC INFLAMMATION IS A COMMON DENOMINATOR OF HUMAN DISEASE, CONTRIBUTING TO OVER HALF OF GLOBAL MORTALITY ACROSS CANCER, CARDIOVASCULAR, AUTOIMMUNE, AND NEURODEGENERATIVE DISORDERS. DESPITE ITS UBIQUITY, CLINICIANS STILL LACK TOOLS TO DIRECTLY VISUALIZE IMMUNE ACTIVITY IN REAL-TIME. THIS DIAGNOSTIC GAP IS PARTICULARLY CRITICAL FOR IMMUNE CHECKPOINT INHIBITOR (ICI)-ASSOCIATED MYOCARDITIS, A FATAL COMPLICATION OF WIDELY USED CANCER IMMUNOTHERAPIES THAT REMAINS DIFFICULT TO DIAGNOSE EVEN WITH BIOPSY. MY RESEARCH AIMS TO ADDRESS THIS UNMET NEED BY DEVELOPING AN IMMUNE-TARGETED POSITRON EMISSION TOMOGRAPHY (IMMUNE-PET) STRATEGY THAT NON- INVASIVELY VISUALIZES LEUKOCYTE INFILTRATION IN THE MYOCARDIUM AND ESTABLISHES THE FOUNDATION FOR ITS CLINICAL TRANSLATION. USING NANOBODY-BASED TRACERS, THE SMALLEST NATURALLY-DERIVED ANTIBODY FRAGMENTS, I WILL ESTABLISH A CD45-PET APPROACH THAT TARGETS A PAN-LEUKOCYTE SURFACE MARKER TO QUANTIFY IMMUNE CELL ACTIVITY AND IDENTIFY HIGH-RISK INFLAMMATORY PATTERNS OF DISEASE WITH SPATIAL AND TEMPORAL RESOLUTION. BUILDING ON PRELIMINARY DATA SHOWING THAT CD45-PET SENSITIVELY DETECTS MYOCARDITIS IN PRECLINICAL MODELS, I PROPOSE TWO INTEGRATED AIMS: (1) TO ESTABLISH A DIAGNOSTIC IMAGING FRAMEWORK DEFINING QUANTITATIVE THRESHOLDS, SPATIAL RESOLUTION, AND BIOLOGICAL CORRELATES OF DISEASE; AND (2) TO GENERATE A FULLY HUMANIZED NANOBODY WITH MINIMAL IMMUNOGENICITY, IMPROVED RADIOCHEMISTRY, AND OPTIMIZED PHARMACOKINETIC PROPERTIES COMPATIBLE WITH GMP-GRADE MANUFACTURING FOR HUMAN TRANSLATION. TOGETHER, THESE STUDIES WILL ESTABLISH A FIRST-IN-CLASS IMMUNE-IMAGING STRATEGY THAT INTEGRATES CHEMICAL BIOLOGY, RADIOPHARMACEUTICAL ENGINEERING, AND IMMUNOLOGY. THE RESULTS OF THIS WORK WILL TRANSFORM THE DIAGNOSTIC LANDSCAPE OF MYOCARDITIS AND LAY THE FOUNDATION FOR REAL-TIME IMMUNE IMAGING ACROSS A SPECTRUM OF INFLAMMATORY DISEASES, INCLUDING AUTOIMMUNITY, INFECTION, AND TRANSPLANT REJECTION.