Broadly Protective Bispecific Antibodies for Treatment of Ebola Virus Disease

DESCRIPTION provided by applicant The ebolaviruses and Marburg virus MARV constitute the family Filoviridae andquot filovirusesandquot that cause severe hemorrhagic fever with human case fatalities of The current epidemic in West Africa unprecedented in terms of geographic scope and size highlights the continued need for development of therapeutics Among the five ebolavirus species the Zaire and Sudan subtypes EBOV and SUDV respectively are the most pathogenic and both have resulted in recurring outbreaks Together EBOV and SUDV accounted for over of Ebola related deaths from In addition another ebolavirus subtype the Bundibugyo virus BDBV has caused two sizable outbreaks in and Current filovirus antibody therapies are narrowly strain specific and therefore have limited therapeutic utility The goal of this proposal is to use an innovative antibody technology platform bispecific antibody Bis mAb engineering to develop cross neutralizing therapeutic antibody cocktails effective against EBOV SUDV and BDBV We have produced several bispecific monoclonal antibodies Bis mAbs that can effectively neutralize EBOV and SUDV binding to a critical neutralization epitope at the viral glycoprotein GP base as well as a suite of novel cross reactive antibodies binding multiple filovirus species Notably one of these mAbs has shown in vivo protection in both EBOV and SUDV murine infection models This is the first report of a filovirus cross protective antibody Our preliminary data also reveal a series of novel conserved epitopes within the glycan cap and the fusion loop of filovirus GP We hypothesize that these key epitopes can be exploited in a synergistic manner when targeted by Bis mAbs Taking advantage of the enhanced avidity and synergistic neutralization that result from targeting multiple key epitopes such Bis mAbs will represent a novel class of highly effective broadly neutralizing filovirus therapeutics In Aim we will explore GP base binding Bis mAb designs to optimize potency and test them for neutralization in combination with a cross binding antibody that engages a second epitope in the glycan cap Aim will focus on developing novel Bis mAbs that target new highly conserved epitopes on GP that are present in multiple filovirus species The Bis mAbs will be tested for enhanced and broad neutralizing activity against EBOV SUDV and BDBV to select lead therapeutic candidates Phase I studies will lay the foundation for the anticipated Phase II component in which the most potent combinations of Bis mAbs will be evaluated for their ability to protect in vivo This approach can further be extended to create novel Bis mAb cocktails that can target all filovirus species including MARV This work represents a partnership between academic Einstein and commercial Integrated BioTherapeutics entities to develop cross neutralizing therapeutic Bis mAb cocktails The approach leverages proprietary antibodies technology platforms and complementary expertise from both partners These therapies will fill a major therapeutic gap and could not be obtained using conventional antibody isolation methods

PUBLIC HEALTH RELEVANCE Filoviruses ebolavirus and marburgvirus are among the deadliest viruses and a major threat to humans There are no approved treatment options for these diseases and the current experimental treatments are mostly specific to the Zaire strain of Ebola In this proposal we use a novel technology to engineer antibodies to achieve broad protection against multiple species of filoviruses