Broadly Protective Bispecific Antibodies for Treatment of Ebola Virus Disease

PROJECT SUMMARY The family of Filoviridae consisting of five ebolaviruses and two marburgviruses are causative agents of severe hemorrhagic fever with human case fatality rates ofTheepidemic of Ebola virus disease in West Africa was unprecedented both in geographic scope and size and highlighted the extent of the threat filoviruses could pose to global public health and the urgent need for development of therapeuticsAmong the five ebolavirus speciesthe Zaire and Sudan subtypesEBOV and SUDVrespectivelyare the most pathogenic and both have resulted in recurring outbreaksFurthermoreBundibugyo virusBDBVhas also caused two sizable outbreaks over the past decadeHowevercurrent filovirus antibody therapies are narrowly specific to Zaire Ebola virus and ineffective against SUDV and BDBVThe goal of this proposal is to develop a bispecific antibodyBis mAbtherapeutic with broad protection against all ebolaviruses that have caused human diseaseIn the Phase I of this STTR we created a prototype Bis mAb that combines the antigen binding variable domains of a non neutralizing pan ebolavirus antibody with an antibody against a cryptic epitope within the receptor binding site of ebolavirus glycoprotein that becomes exposed only within the endosomesThe BismAb colocalizes to the endosomes with the virus where the antibody against the cryptic epitope becomes effective due to proteolytic cleavage of the glycoprotein by cysteine cathepsinsThis approach enabled us to generate aTrojan Horsethat co opts the virus to deliver a lethal weapon into the endosomes leading to effective virus neutralizationThis prototypic pan ebolavirus Bis mAbFVMMRpotently neutralized all five ebolavirus species while a cocktail of the parental IgGs was ineffectiveIn miceFVMMRprotected against lethal challenge with EBOV and SUDVthe most divergent ebolavirusesIn the Phase II projectwe propose to demonstrate protective efficacy of the product in nonhuman primates and ferrets to achieve a critical milestone that would justify clinical developmentIn Aimwe will produce the Bis mAb in CHO cells by transient transfection at scale required for large animal studiesStable cell lines will be also generated for use in future manufacturing of the productIn Aimwe will evaluate the pharmacokinetics of the Bis mAb and conduct proof of principal efficacy against SUDV and EBOV in NHPs and against BDBV in ferretsThis work represents a partnership between academicEinsteinand commercialIntegrated BioTherapeuticsentities to develop a cross neutralizing therapeutic Bis mAbThe approach leverages proprietary antibodiestechnology platformsand complementary expertise from both partners