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