Project Grant R43CA287804

PROTEASOME INHIBITOR-LOADED ANTIBODY DRUG CONJUGATES WITH HIGH DRUG LOADING FOR TARGETED TREATMENT OF TRIPLE NEGATIVE BREAST CANCERS - PROJECT SUMMARY/ABSTRACT PROTEASOME INHIBITORS (PIS) ARE ONE OF THE MOST IMPORTANT CLASSES OF THERAPEUTICS TO HAVE EMERGED IN THE PAST TWO DECADES AND NOW SERVE AS THE BACKBONE OF MULTIPLE MYELOMA (MM) TREATMENT. THE FIRST-IN-CLASS PI, BORTEZOMIB (BTZ), TARGETS THE UBIQUITIN PROTEASOME PATHWAY (UPP), WHICH HAS LED TO TREMENDOUS EFFICACY IN INDUCING PLASMA CELL APOPTOSIS AND IN INHIBITING MM GROWTH. DESPITE THE UNIVERSAL NATURE OF PI AS A MECHANISM OF ACTION (MOA) AND STRONG PRECLINICAL RESULTS, THE CLINICAL USE OF THE PIS BORTEZOMIB, IXAZOMIB, AND CARFILZOMIB FOR SOLID CANCER INDICATIONS HAVE BEEN LARGELY UNSUCCESSFUL THUS FAR DUE TO SIGNIFICANT DOSE-LIMITING TOXICITY (DLT) AND EXCEEDINGLY NARROW THERAPEUTICS WINDOW. AS THE ENTIRE SOLID CANCER PATIENT POPULATION IS TREATMENT-NAIVE TO PIS, TECHNOLOGIES THAT CAN DELIVER BTZ IN A TARGETED MANNER, THEREBY CIRCUMVENTING ITS DLTS, WOULD BE HIGHLY DESIRABLE ESPECIALLY IN RECALCITRANT INDICATIONS SUCH AS TRIPLE NEGATIVE BREAST CANCER (TNBC). WE HAVE DEVELOPED A NOVEL ANTIBODY DRUG CONJUGATE (ADC) PLATFORM THAT ENABLES CONTROLLED DRUG RELEASE OF A COVALENTLY CONJUGATED PI IN TARGETED CANCER CELLS. ADDITIONALLY, OUR ADC PLATFORM HAS DRUG LOADINGS MULTI-FOLD HIGHER THAN WHAT IS USED IN STATE-OF-THE-ART FDA APPROVED ADCS LIKE ENHERTU AND TRODELVY. THUS FAR, WE HAVE SHOWN IN A LOW HER2 BREAST CANCER MODEL THAT AN ITERATION OF OUR PI-LOADED ADC CAN OUTPERFORM T-DXD, A BIOSIMILAR OF ENHERTU. OVER 12 MONTHS, WE INTEND TO SYNTHESIZE AND CHARACTERIZE A LIBRARY OF THESE PI-LOADED ADCS WITH VARYING TARGETS AND DRUG LOADINGS. BY USE OF IN VITRO SCREENING OF THEIR BINDING AFFINITIES, CELLULAR INTERNALIZATION, AND POTENCY, WE WILL SCREEN THIS LIBRARY FOR BEST PERFORMING CANDIDATES. FURTHER IN VIVO PK/BD AND EFFICACY STUDIES IN VARIOUS LOW-EXPRESSION TNBC MOUSE MODELS WILL ENABLE US TO FIND AN OPTIMAL PI-LOADED ADC LEAD CANDIDATE TO PUSH FORWARD. SUCCESS OF THIS PROJECT WILL BE DETERMINED BY THE DISCOVERY OF AT LEAST ONE WTX-ABC LEAD CANDIDATE THAT CAN BE FURTHER DEVELOPED FOR CLINICAL APPLICATION WITH A PHASE II SBIR.