Filoviruses are Category A pathogens which cause a severe and rapidly fatal disease with human case fatality rates of 30-90%. The 2013-2016 epidemic in Western Africa, with over 28,000 cases, was caused by one of these agents, Ebola virus (Zaire species, EBOV), and highlights the urgent need for new countermeasures targeting all virulent filoviruses. Monoclonal antibodies (mAbs) have emerged as the most promising therapeutic platform for treatment and prevention of Ebola virus disease. However, most mAbs and mAb cocktails are narrowly specific for a single filovirus, and are thus of limited use in outbreaks caused by other filoviruses with epidemic potential, including Bundibugyo virus (BDBV), Sudan virus (SUDV), and Marburg virus (MARV). A major gap in the filovirus mAb therapeutic pipeline is the lack of broad- spectrum therapies that are active against multiple disease-causing filoviruses. This proposal leverages an innovative technology platform, bispecific antibody engineering, along with proprietary mAbs from academic (Einstein), government (USAMRIID/Geneva), and commercial (Integrated Biotherapeutics; Mapp Biophamaceutical) partners to develop bispecific antibodies (bis-mAbs) as cross-protective filovirus antibody therapies. We build on a new approach recently developed by our team?a `Trojan Horse' bis-mAb that can copt virus particles themselves to `hitch a ride' into cellular endosomes, where it targets crucial and highly conserved viral epitopes that are normally hidden from antibodies. This bis-mAb shows potent, broad neutralization of all ebolaviruses in vitro and provides cross-protection against EBOV and SUDV in mice, thus providing proof-of-concept that bis-mAbs engineered to localize to endosome with viral particles can effectively target sequestered epitopes (Wec et al., Science 2016). Furthermore, this bis-mAb is broadly protective as a single component, thus avoiding the manufacturing and development hurdles of cocktails of mAbs that have been previously shown to be required for broad filovirus protection. To further develop this therapeutic bis-mAb modality, we will expand the range of highly conserved external and endosomal epitopes that are targeted. The goal of this proposal is to optimize and advance bis-mAbs as single component, pan-ebolavirus or pan-filovirus immunotherapies.

Public Health Relevance

Filoviruses, including ebolaviruses and marburgviruses, cause a rapidly progressing and fatal disease in humans, for which no FDA-approved treatments are available. The 2013?2016 West African epidemic high- lights the potential for these viruses to cause widespread disease. Monoclonal antibody (mAb) therapies have shown promise as post-exposure therapeutics for Ebola (Zaire) virus, but there are currently no mAbs that are effective against multiple filoviruses. The goal of this work is to use state-of-the-art protein engi- neering techniques to develop a broad therapeutic mAb therapy against all filoviruses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI132256-01
Application #
9363173
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Repik, Patricia M
Project Start
2017-07-14
Project End
2022-06-30
Budget Start
2017-07-14
Budget End
2018-06-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine, Inc
Department
Type
DUNS #
079783367
City
Bronx
State
NY
Country
United States
Zip Code
10461
Nyakatura, Elisabeth K; Zak, Samantha E; Wec, Anna Z et al. (2018) Design and evaluation of bi- and trispecific antibodies targeting multiple filovirus glycoproteins. J Biol Chem 293:6201-6211