Analysis of immunotherapeutics to native Marburg virus epitopes

Scripps Research Institute, The, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): The Category A Marburg virus causes a severe hemorrhagic fever. The virus was weaponized by the Soviet Union for aerosol distribution and recent natural outbreaks in Africa have achieved ~90% lethality. No treatments against Marburg virus are yet available for human use. Antibodies could provide immediate immunity: some antibodies against the related Ebola virus are protective even 48 hours after exposure, and antibodies are a key component of post-exposure vaccination/prophylaxis for viruses such as rabies. However, very few monoclonal antibodies against Marburg virus exist from which we can develop emergency treatments or even improved antigen-capture diagnostics. We propose development of an extensive panel of monoclonal antibodies (mAbs) against Marburg virus, and thorough evaluation of these mAbs alone and in oligoclonal combinations, in vitro and in vivo. This work will provide a broad array of mAbs against different epitopes on Marburg virus, will explain which epitopes among this landscape of immune responses lead to the most effective in vitro neutralization and in vivo protection, and which mAbs function synergistically to achieve highest protection against the range of Marburg virus sequences. An appended product development plan delineates how our two corporate partners will combine forces to manufacture and develop these immunotherapeutics as tangible products. A unique strength of this proposal is the use of three-dimensional structural information to frame and interpret the functional analysis. Perplexingly, for the filoviruses, antibodies that are effective in vitro are not always useful in vivo, and vice versa, antibodies that are protective in vivo, do not neutralize in vitro. Hence, a third approach, in which we can directly look at the antibody and antigen complexes, will provide additional insight to reconcile in vitro and in vivo results and guide future studies. The structures already determined and proposed here will establish 3D maps to the most effective epitopes and propose ground rules for why some antibodies work better than others. Another chief advantage of this proposal is the unique and extensive expertise of the consortium members in high-throughput antibody development and in vitro analysis, as well as development and use of novel animal models of live, in vivo Marburg virus for physiologically relevant BSL4 evaluation. Innovative FMAT, SAXS, and microscale microfluidic techniques and our newly developed Marburg virus models, combined with an initial in-hand, starting panel of mAbs mitigate risk and ensure the success of this proposal. Our efforts here will result in a complete set of well-characterized antibodies against MARV GP. Of these, we will carefully select the most promising candidates for advanced development towards our ultimate goal of an efficacious post-exposure treatment for Marburg virus infection.