Project Grant R43AI162111

ECIRP-NEUTRALIZING MAB FOR ACUTE LUNG INJURY IN SEPSIS - PROJECT DESCRIPTION: THE PRIMARY OBJECTIVE OF THIS PROJECT IS TO DEMONSTRATE THE FEASIBILITY OF DEVELOPING THE EXTRACELLULAR COLD-INDUCIBLE RNA-BINDING PROTEIN (ECIRP)-NEUTRALIZING MONOCLONAL ANTIBODY #14 (MAB14) AS A NOVEL TREATMENT FOR SEPTIC PATIENTS WITH ACUTE LUNG INJURY (ALI). ALI IS A CRITICAL COMPONENT OF THE ELEVATED MORTALITY RATE IN SEPSIS NO SPECIFIC TREATMENT HAS YET BEEN APPROVED TO REDUCE THE MORTALITY OF SUCH PATIENTS. WE HAVE DISCOVERED THAT ECIRP IS A CRITICAL INDUCER OF ALI CAUSED BY SEPSIS AND OTHER INFLAMMATORY DISEASES. IN OUR RECENT STUDIES, WE HAVE SHOWN THAT INCREASED LEVELS OF ECIRP AGGRAVATED ALI IN MICE WITH SEPSIS INDUCED BY CECAL LIGATION AND PUNCTURE (CLP). INJECTION OF RECOMBINANT ECIRP WAS SUFFICIENT TO INDUCE ALI IN OTHERWISE HEALTHY MICE. IN OUR PRELIMINARY STUDIES, WE HAVE GENERATED A LARGE PANEL OF ANTI-ECIRP MONOCLONAL ANTIBODIES TO DEVELOP AN ECIRP-TARGETING TREATMENT FOR ALI, AND SCREENED THEM FOR THEIR INHIBITION OF ECIRP-INDUCED RELEASE OF TNF-A BY MACROPHAGES. WE THEN USED THE MOST EFFECTIVE ANTI-ECIRP MONOCLONAL ANTIBODY, MAB14, TO TREAT MICE WITH CLP-INDUCED ALI. COMPARED WITH NON-IMMUNIZED IGG (CONTROL), CLP MICE TREATED WITH MAB14 HAD ATTENUATED LUNG INFLAMMATION AS INDICATED BY THE DECREASED LUNG GENE AND PROTEIN LEVELS OF TNF-A, IL-1SS, IL-6, CXCL1, AND CXCL2, AS WELL AS THE DECREASED NEUTROPHIL INFILTRATION OF THE LUNGS AS INDICATED BY THE MYELOPEROXIDASE ACTIVITY. BASED ON THESE NOVEL FINDINGS, WE HYPOTHESIZE THAT MAB14 CAN BE DEVELOPED AS A NEW AND EFFECTIVE DRUG TO TREAT ALI CAUSED BY SEPSIS. IN THIS PROJECT, WE WILL FURTHER DETERMINE MAB14'S ECIRP NEUTRALIZATION ABILITY IN VITRO AND IN VIVO. WE WILL THEN OPTIMIZE MAB14'S DOSE TO ATTENUATE SEPSIS-INDUCED ALI AND THERAPEUTIC WINDOW TO IMPROVE THE SURVIVAL OF SEPTIC MICE. WE WILL ALSO EVALUATE MAB14'S PHARMACOKINETICS (PK) AND PHARMACOTOXICITY PROPERTIES. OUR FUTURE STEPS WILL INCLUDE DEVELOPING A HUMANIZED FORM OF MAB14 AND THEN CONDUCTING ITS ADME, PK, ADVANCED TOXICOLOGY, AND IMMUNOGENICITY STUDIES. WE WILL THEN FILE WITH THE FDA AN INVESTIGATIONAL NEW DRUG (IND) APPLICATION TO INITIATE CLINICAL TRIALS TO TREAT ALI IN PATIENTS WITH SEPSIS. OUR ULTIMATE GOAL IS TO OBTAIN COMMERCIAL UTILIZATION OF MAB14 AS A SAFE AND EFFECTIVE DRUG TO TREAT PATIENTS WITH ALI IN THE CONTEXT OF SEPSIS.