Mortality rates associated with Marburg virus (MARV) outbreaks range from 20% to over 90%. MARV is included by the Centers for Disease Control and Prevention as among the Category A agents, or high- priority agents ... that pose a risk to national security. MARV not only causes acute and terrifying disease, but it is relatively stable in wet or dry aerosols; it is highly infectious whether infection occurs parenterally or by aerosol-- 1 LD50 is approximately 1 plaque-forming unit; it is subject to nosocomial and iatrogenic spread to and by health care personnel; and as an endemic African virus it could be acquired from recurrent natural outbreaks by a resourceful individual or group. There are currently no drugs available for preventing or treating infections with MARV. There is a clear unmet need for a MARV immunoprotectant to address biowarfare threats as well as public health concerns raised by naturally occurring outbreaks. Passive immunization with antibodies has been shown to be effective against a wide variety of viruses. Because of their excellent safety profile and efficacy mAbs are a rapidly growing class of therapeutic drug. We have shown that a cocktail of mAbs can provide post-exposure and therapeutic protection against lethal challenge with another filovirus (Ebola) in the non-human primate (NHP) model (i.e. the model most representative of humans). As a result of successful completion of our Phase 1 SBIR efforts, we have identified six potent anti-MARV mAbs that protect mice from lethal challenge. Further, in this proposal we are combining forces with Integrated Biotherapeutics (Dr. Kelly Warfield; Gaithersburg, MD) and the Public Health Agency of Canada (PHAC; Dr. Gary Kobinger), whose teams have identified additional protective mAbs via separate funding. Together with Dr. Tom Geisbert (UTMB; Galveston, TX) we will determine which of these combinations of mAbs is the most appropriate for continued development. The Long Range Objective of this project is to develop a safe and effective immunoprotectant for Marburg virus.
In Specific Aim 1, the existing protective mAbs will be produced using a well-characterized transient Nicotiana production system. Experiments in rodents will be used to select a lead mAb cocktail for advancement to non-human primate (NHP) testing.
In Specific Aim 2, the cocktail will be evaluated in NHPs against lethal MARV challenge.
In Specific Aim 3 IND-enabling testing will be completed and an IND submitted.

Public Health Relevance

The efforts in this proposal will help in the development of a drug product for preventing and treating infection with Marburg virus, a highly lethal virus that causes sporadic outbreaks and is a biowarfare threat.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44AI082744-04
Application #
8874839
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Repik, Patricia M
Project Start
2009-04-01
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Mapp Biopharmaceutical, Inc.
Department
Type
DUNS #
137551797
City
San Diego
State
CA
Country
United States
Zip Code
92121
Mire, Chad E; Geisbert, Joan B; Borisevich, Viktoriya et al. (2017) Therapeutic treatment of Marburg and Ravn virus infection in nonhuman primates with a human monoclonal antibody. Sci Transl Med 9: