Project Grant R44AI179371

MONOCLONAL ANTIBODY COCKTAIL FOR TREATMENT OF MARBURG VIRUS DISEASE - PROJECT SUMMARY EBOLA (EBOV) AND MARBURG (MARV) VIRUSES CAUSE HEMORRHAGIC FEVER DISEASE IN HUMANS AND NONHUMAN PRIMATES (NHPS) WITH CASE-FATALITY RATES AS HIGH AS 90%. THE 2013-2016 EBOLA VIRUS DISEASE (EVD) OUTBREAK LED TO OVER 28,000 CASES AND 11,000 DEATHS AND TOOK AN ENORMOUS TOLL ON THE ECONOMY OF WEST AFRICAN NATIONS, IN THE ABSENCE OF ANY VACCINE OR THERAPEUTIC OPTIONS. THIS OUTBREAK SPURRED AN UNPRECEDENTED GLOBAL EFFORT FOR DEVELOPMENT OF VACCINES AND THERAPEUTICS FOR EVD AND LED TO AN APPROVED VACCINE AND TWO MONOCLONAL ANTIBODY (MAB) THERAPEUTICS. IMPORTANTLY STUDIES WITH EBOV MABS AND LATER SARS-COV2 MABS ESTABLISHED THE VALUE OF MAB COCKTAILS FOR EFFECTIVE TREATMENT OF VIRAL DISEASES. IN CONTRAST TO EVD, DEVELOPMENT OF THERAPEUTICS FOR MARBURG VIRUS DISEASE (MVD) HAS BEEN LAGGING DESPITE SEVERAL MVD OUTBREAKS INCLUDING ONE IN 2022. THE INVESTIGATORS ON THIS MPI PHASE I/II FAST TRACK SBIR APPLICATION HAVE DEVELOPED TWO CLASSES OF MABS TARGETING NON-OVERLAPPING EPITOPES WITHIN THE RECEPTOR BINDING SITE (RBS) AND THE INTERNAL FUSION LOOP (IFL) OF MARV GLYCOPROTEIN (GP). THE RBS-BINDING MAB (MR186), PROVIDES PROTECTION PRIMARILY THROUGH EFFECTOR FUNCTIONS, WHILE THE IFL-BINDER (R217) IS THE MOST POTENT NEUTRALIZING MARV MAB DISCOVERED TO-DATE. MR186 HAS BEEN ENGINEERED TO ENHANCE BIOAVAILABILITY USING YTE MUTATION IN THE FC PORTION, AND PRODUCED IN A FUCOSYL- TRANSFERASE DEFICIENT CHO CELL LINE TO ENHANCE EFFECTOR FUNCTIONS (MR186-YTEAF). WE ARE CURRENTLY INTRODUCING YTE MUTATIONS INTO R217 FC TO GENERATE THE THERAPEUTIC CANDIDATE R217-YTE. IN THIS PROPOSED PROJECT WE HARNESS THESE COMPLEMENTARY MECHANISMS OF ACTION TO DEVELOP A HIGHLY EFFECTIVE COCKTAIL OF THESE TWO MABS FOR MVD TREATMENT. USE OF MAB COCKTAIL IS ALSO EXPECTED TO REDUCE THE RISK OF ESCAPE VARIANT. THE PROPOSAL HAS FOUR SPECIFIC AIMS. IN AIM 1 (PHASE I PORTION), R217-YTE WILL BE PRODUCED IN EXPICHO CELLS AND FULLY CHARACTERIZED. SUPERIOR EFFICACY OF THE COCKTAIL WILL BE DEMONSTRATED IN A GUINEA PIG MODEL OF MARV-ANGOLA AND THIS MILESTONE WILL SERVE FOR TRANSITION TO PHASE II SBIR. PHASE II PORTION STARTS WITH AIM 2, IN WHICH THE EFFICACY OF THE COCKTAIL WILL BE TESTED IN NHP MODELS IN SERIES OF ADAPTIVELY DESIGNED NHP EXPERIMENTS AND FINALLY THE SUPERIOR EFFICACY WILL BE FORMALLY DEMONSTRATED IN COMPARISON WITH THE INDIVIDUAL MABS. IN AIM 3 WE WILL EVALUATE THE PHARMACOKINETICS (PK) AND PHARMACODYNAMICS (PD) OF THE ANTIBODIES IN SERA FROM A NUMBER OF NHP EFFICACY STUDIES INCLUDING STUDIES PERFORMED IN AIM 1. CORRELATIONS BETWEEN PK/PD DATA AND CLINICAL OUTCOME WILL BE EXPLORED. AIM 4 WE WILL BE FOCUSED ON GENERATION OF STABLE MANUFACTURING CELL LINES IN CHO CELLS AND AT LEASE FOUR CLONES OF EACH MAB WILL BE PRODUCED TO BE USED FOR FUTURE GMP CELL BANKS. IF SUCCESSFUL, WE ANTICIPATE FURTHER DEVELOPMENT OF THE PRODUCT UNDER DOD OR BARDA FUNDING AND APPROVAL UNDER FDA ANIMAL RULE.