RAPID: Novel Bioreactor-Based Systems for Producing Anti-Ebola Monoclonal Antibodies in Nicotiana benthamiana Plant Cell Suspension Culture

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This NSF RAPID project will contribute to the development of new biomanufacturing processes for proteins used in the treatment of Ebola that will dramatically increase the production capacity during the current crisis. Currently, antibodies against Ebola (the ZMapp antibodies) are produced in a relative of the tobacco plant. Antibody production in the whole plant is relatively slow. In the proposed work, investigators will move production from the whole plant into plant cells that can then be grown in large fermenters, much like other biopharmaceutical products. By optimizing the manufacturing conditions, the investigators believe that they can obtain a 100 fold increase in productivity for the same mass of plant material. The work will contribute to the Nation's ability to respond to other global health crises in the future by creating new biomanufacturing platforms and the capacity to rapidly increase production.Technical: This NSF Rapid Response Research (RAPID) project will support the development of a new biomanufacturing process for the mixture of three monoclonal antibodies (ZMapp) that has been used to successfully treat patients infected with the Ebola virus. Currently, ZMapp is produced in Nicotiana benthamiana (N. benthamiana) in whole plants using vacuum agroinfiltration. This mode of production is dependent upon transient agroinfiltration of indoor or greenhouse grown plants, and is severely limited in production capacity relative to traditional stainless steel fermenter types of biomanufacturing processes. However, production of the ZMapp antibodies in more traditional hosts such as Chinese hamster ovary cells (CHO) had led to less effective monoclonal antibodies (lower survival rates and higher doses needed in animal studies) compared to the N. benthamiana produced antibodies. The researchers in this project will develop methods for large-scale suspension culture production of ZMapp antibodies from N. benthamiana cells. These methods will employ novel techniques for culturing agroinfiltrated plant cells in batch and semi-continuous modes. The work performed will enable the rapid production of the antibodies in the same types of large-scale facilities available for other biotherapeutics, while retaining the desirable antibody properties associated with proteins produced from N. benthamiana. The project is appropriate for the RAPID mechanism based on the urgency of need to develop scalable biomanufacturing methods to produce Ebola therapeutics that are already known to be effective. The project will contribute to our understanding and ability to design new biomanufacturing platforms that use plant cells, and enable the advance of synthetic biology in plant cells. Beyond the Ebola crisis, this work should help develop capacity for rapid biomanufacturing in response to future threats to global health.