Project Grant R41CA265512

A NOVEL MONOBODY-DRUG CONJUGATE TO TREAT MUTANT KRAS PANCREATIC CANCER. - PROJECT SUMMARY: TEZCAT LABORATORIES LLC IS AN EARLY-STAGE, AUSTIN-BASED BIOTECHNOLOGY COMPANY DEVELOPING NOVEL BIOLOGICS WITH A UNIQUE MECHANISM OF ACTION TO TREAT THE MOST RECALCITRANT CANCERS, SUCH AS MUTANT KRAS PANCREATIC CANCER. AS AN ALTERNATIVE TO TARGETING MUTANT KRAS ITSELF, MUCH ATTENTION HAS BEEN PAID TO TARGETING CELLULAR EVENTS THAT ARE A RESULT OF MUTANT KRAS. NEW EFFORTS ARE UNDERWAY TO EXPLOIT PREVIOUSLY UNRECOGNIZED VULNERABILITIES. WE HAVE OBSERVED THAT MUTANT KRAS PANCREATIC CANCER CELLS DISPLAY HIGH LEVELS OF A PROTEIN SCAVENGING PROCESS. HARNESSING THIS METABOLIC ADAPTATION, WE HAVE CREATED PROTEIN-DRUG CONJUGATES THAT CARRY AN FDA-APPROVED CYTOTOXIC PAYLOAD. IN VITRO AND IN VIVO ASSAYS DEMONSTRATE THAT THE PROTEIN-DRUG CONJUGATES SHOW SELECTIVITY FOR MUTANT KRAS CANCER CELLS AND MAINTAIN POTENCY IN THE LOW NANOMOLAR RANGE. THE PROTEIN-DRUG CONJUGATES DISPLAY RELATIVELY FAST SYSTEMIC CLEARANCE BUT MAINTAIN BENEFICIAL CHARACTERISTICS OF BIOLOGICS SUCH AS DECREASED SYSTEMIC TOXICITIES AND TUMOR ACCUMULATION. THUS, WE HYPOTHESIZE THAT OUR NOVEL CONJUGATES WILL REDUCE ON-TARGET AND OFF-TARGET EFFECTS OFTEN SEEN WITH TRADITIONAL ANTIBODY-DRUG CONJUGATES AND FILL A VOID OF THERAPEUTIC OPTIONS FOR PATIENTS WITH MUTANT KRAS PANCREATIC CANCER. WE HAVE PROPOSED A PHASE I STTR PROGRAM FOR INVESTIGATORS AT TEZCAT LABORATORIES AND NEW YORK UNIVERSITY LANGONE HEALTH TO ADVANCE THIS LEAD THROUGH SPECIFIC AIMS THAT EVALUATE THE ABILITY OF THE LEAD DRUG CANDIDATE TO CONTROL CANCER GROWTH IN MOUSE MODELS OF PANCREATIC CANCER. WE FURTHER PROPOSE TO USE AN ADMINISTRATIVE SUPPLEMENT TO 1) TEST OUR LEAD AGAINST OTHER PROPRIETARY PROTEIN- DRUG CONJUGATES THAT UTILIZE THE SAME MECHANISM OF ACTION, AND 2) TEST OUR LEAD IN COMBINATION WITH IMMUNOTHERAPY IN THE MOST CLINICALLY-RELEVANT MOUSE MODEL OF PANCREATIC CANCER. THE COMMERCIALIZATION STRATEGY WILL BE BASED ON ESTABLISHING INITIAL EFFICACY AND NONTOXICITY OF THE LEAD COMPOUND IN RELATION TO MUTANT KRAS STATUS IN PHASE I STTR STUDIES, FURTHER DEVELOPMENT TOWARDS IND STATUS IN PHASE II SBIR STUDIES, AND THEN FIRST-IN-HUMAN CLINICAL TRIALS. THUS, WE EXPECT PHASE I STTR AND THE ADMINISTRATIVE SUPPLEMENT TO PROVIDE THE BASIS FOR PURSUIT OF ADDITIONAL DATA IN PHASE II AIMED AT GMP PROTOCOLS AND FURTHER NON-GLP AND GLP SAFETY AND TOXICITY STUDIES.