Prophylactic Immunotherapy for Marburg Virus Disease Outbreak Control

The ebolaviruses (EBOV, SUDV, BDBV) and marburgviruses (MARV and RAVV), cause periodic outbreaks of
severe viral hemorrhagic fever with very high mortality rates. The 2013-2016 Ebola virus disease (EVD) outbreak
in West Africa highlighted the serious nature of a filovirus epidemic and its regional and global implications. This
outbreak took an enormous toll on people at the front line of the epidemic control, i.e., physicians, nurses, hospital
personnel, social workers, and other support staff. Many nurses and physicians lost their lives helping patients
and many left their profession out of fear of exposure. The near breakdown of the local healthcare system further
fueled the spread of the virus across the region. Therefore, protection of the first responders must be a high
priority and is critical for successful outbreak control. Currently, while a prophylactic vaccine is available for
EVD, there are no therapeutic or prophylactic countermeasures available for Marburg virus disease (MVD) which
has led to many outbreaks and as recently as June 2022. The objective of this proposal is to develop an effective
immunoprophylactic for protection of first responders against MVD. Such a product mut be 1) extremely potent
to enable economically affordable low dose levels, and 2) have extended bioavailability to provide a reasonably
long duration of protection. We and others have isolated several classes of neutralizing monoclonal antibodies
(mAbs) for ebolaviruses. However, for marburgviruses only a single class of mAbs against the glycoprotein (GP)
has been described that all target a single epitope within the receptor binding site (RBS) of MARV and RAVV
GP. Now, using a novel immunization and B cell selection approach with rationally designed antigens we have
succeeded in identifying a new class of mAbs that bind to a novel epitope and neutralize marburgviruses at sub-
to low-nM concentrations and are up to 100-fold more potent than the RBS binders. A lead antibody, R217, has
been selected and shown to protect against MVD in mice, guinea pigs, and nonhuman primates (NHPs). In this
SBIR project we propose to engineer the Fc portion of this macaque-human chimeric antibody by introducing
mutations (YTE) in the FcRn binding region to extend the half-life of the antibody and evaluate the efficacy of
the product. In Aim 1 R217-YTE will be produced in ExpiCHO cells and fully characterized. Pharmacokinetics
(PK) will be evaluated in NHPs. In Aim 2, the efficacy of R217-YTE against MVD will be evaluated in the settings
of pre- and post-exposure prophylaxis and the required dose level and serum neutralization activity required for
protection will be determined. Aim 3 will be focused on generation of a stable manufacturing cell line in CHO
cells and a research cell bank to be used for production of future GMP cell banks. If successful, we anticipate
further development of the product under DoD or BARDA funding and approval under FDA Animal Rule.

Grant Number: 5R44AI177045-03
NIH Institute/Center: NIH
Principal Investigator: M Aman