Category A filoviruses and arenaviruses cause severe and rapidly progressing hemorrhagic fever, for which no specific treatments or vaccines are available. Among the possible pre- and post-exposure treatments vetted, monoclonal antibodies are currently thought to be the most effective, provide the longest window for post-exposure treatment, and be most likely to achieve FDA approval for reasons of safety, availability and efficacy. In the last year, members of our team were first to identify specific antibodies and cocktails of antibodies that confer effective post-exposure protection against Ebola virus and Lassa virus in multiple animal models. We will translate these therapies and fill critical resource gaps in antibodies against other pathogenic filoviruses (Sudan, Marburg and Bundibugyo) and arenaviruses (Lujo, Machupo, Junin, etc.). this proposal describes a large, multidisciplinary consortium from academic and industrial investigators. We have gathered -315 monoclonal antibodies against the filoviruses and -100 monoclonal antibodies against the arenaviruses. These are the largest antibody pools ever assembled for these viruses and include the most potent antibodies known. The consortium includes directors of three BSL4 laboratories - experts in post exposure therapeutic development and evaluation; other leaders in high-throughput and human antibody discovery and analysis with access to unique, large cohorts of human survivors of outbreaks in 2012; structural biologists with intimate knowledge of the filovirus and arenavirus glycoproteins able to map the epitope of nearly every antibody in the pools during the course of the project; and industrial scientists who are experts in large-scale production and evaluation of therapeutics for human use. Our consortium is open to all investigators and to all antibodies they wish to contribute. We will provide a public, comprehensive and definitive analysis of which antibodies are most effective against these antibodies and why, which antibodies can be combined for greatest synergy and why, and which epitopes lead to broad-spectrum reactivity. The over-arching goal is to advance mAb-based immunotherapeutic products to fill the need for treatments against these families of viruses and to file one or more Investigational New Drug applications by year 5.

Public Health Relevance

This project will perform an unprecedented, field-wide analysis of antibodies against viral hemorrhagic fevers and will translate the most effective antibody cocktails to clinical use. These products will provide a much needed pre- or post-exposure therapy against some of the word's most lethal viruses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI109762-04
Application #
9231360
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Program Officer
Parker, Tina M
Project Start
2014-03-15
Project End
2019-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
4
Fiscal Year
2017
Total Cost
$5,799,280
Indirect Cost
$739,093
Name
Scripps Research Institute
Department
Type
Research Institutes
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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
Zhu, Wenjun; Zhang, Zirui; He, Shihua et al. (2018) Successful treatment of Marburg virus with orally administrated T-705 (Favipiravir) in a mouse model. Antiviral Res 151:39-49
Wong, Gary; Mendoza, Emelissa J; Plummer, Francis A et al. (2018) From bench to almost bedside: the long road to a licensed Ebola virus vaccine. Expert Opin Biol Ther 18:159-173
Wong, Gary; Qiu, Xiangguo (2018) Funding vaccines for emerging infectious diseases. Hum Vaccin Immunother 14:1760-1762
Hastie, Kathryn M; Saphire, Erica Ollmann (2018) Lassa virus glycoprotein: stopping a moving target. Curr Opin Virol 31:52-58
Gunn, Bronwyn M; Yu, Wen-Han; Karim, Marcus M et al. (2018) A Role for Fc Function in Therapeutic Monoclonal Antibody-Mediated Protection against Ebola Virus. Cell Host Microbe 24:221-233.e5
King, Liam B; West, Brandyn R; Schendel, Sharon L et al. (2018) The structural basis for filovirus neutralization by monoclonal antibodies. Curr Opin Immunol 53:196-202
Amanat, Fatima; Duehr, James; Oestereich, Lisa et al. (2018) Antibodies to the Glycoprotein GP2 Subunit Cross-React between Old and New World Arenaviruses. mSphere 3:
Flyak, Andrew I; Kuzmina, Natalia; Murin, Charles D et al. (2018) Broadly neutralizing antibodies from human survivors target a conserved site in the Ebola virus glycoprotein HR2-MPER region. Nat Microbiol 3:670-677
Murin, Charles D; Bruhn, Jessica F; Bornholdt, Zachary A et al. (2018) Structural Basis of Pan-Ebolavirus Neutralization by an Antibody Targeting the Glycoprotein Fusion Loop. Cell Rep 24:2723-2732.e4

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