SBIR Phase II: Plant Bioproduction of Therapeutics and Antibodies for the Treatment of Ebola and Other Diseases

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project will be the development of genetically engineered tobacco plants that produce antibodies for the treatment of individuals infected with the Ebola virus. In the recent Ebola outbreak, a new antibody-based drug was shown to be effective in treating infected patients that was based on a transient tobacco-produced Ebola antibody cocktail called ZMapp (Mapp Biopharmaceutical, Inc, San Diego, CA). Unfortunately, Mapp Biopharmaceutical's supply of antibody was quickly depleted, as the manufacturing method was not able to keep up with demand. The technological innovation in this proposal is the targeted production of antibodies within the gland cells of the tobacco leaf surface structures called glandular secreting trichomes. The research objectives will be to demonstrate the secretion of antibodies to the Ebola virus from tobacco trichome glands. The goal is to generate a line of N. tabacum plants that is optimized for antibody production in plant trichomes to provide a biomanufacturing platform for the large-scale production of antibodies that may be used in the treatment of Ebola infection, and in the future, other diseases. This SBIR Phase II project proposes to use a recently developed plant-based biomanufacturing system to scale-up the production of antibodies to the Ebola virus for use as a therapeutic treatment. Mapp Biopharmaceutical has produced a drug based on antibodies to the Ebola virus produced in a tobacco plant transient gene expression system. Using this system, they have identified a glycosylated antibody variant (glycoform) with enhanced antibody-dependent cell cytotoxicity. Using glycosyl-transferase knockout lines of N. benthiamiana and transient expression strategies, the company utilizes plants to produce glycosylated antibodies that produce optimal recruitment of natural immune effector cells (Olinger et al., 2012). Other expression hosts (Chinese hamster ovary cells, yeast) yield product with reduced potency, and are not suitable alternatives. To recover active antibody with their current plant expression technology, Mapp Biopharmaceutical must destructively harvest plants, and isolate antibody from plant tissue homogenates. Unfortunately, this method has not been able to produce enough antibodies to satisfy the demand. The proposed method will allow for the production of antibodies in tobacco plants in large scale. In addition, the proposed system will use antibody harvesting strategies that do not require destructive homogenization as the antibodies will be secreted onto the surface of the leaf, and recovered by washing. The goals of this project are to increase the functionality of plant-produced antibodies, scale-up production, and reduce the costs of production further through system optimization.