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

NSF RAPID项目将有助于开发用于治疗埃博拉病毒的蛋白质的新生物制造工艺，这将大大提高当前危机期间的生产能力。 目前，针对埃博拉病毒的抗体（ZMapp抗体）是在烟草植物的亲属中产生的。 整个植物中的抗体产生相对缓慢。在拟议的工作中，研究人员将把整个工厂的生产转移到植物细胞中，然后可以在大型发酵罐中生长，就像其他生物制药产品一样。 通过优化生产条件，研究人员认为，对于相同质量的植物材料，他们可以将生产率提高100倍。 这项工作将通过创建新的生物制造平台和快速提高产量的能力，为国家应对未来其他全球健康危机做出贡献。技术：NSF快速反应研究（RAPID）项目将支持开发一种新的生物制造工艺，用于三种单克隆抗体（ZMapp）的混合物，该混合物已用于成功治疗埃博拉病毒感染患者。 目前，ZMapp是在本塞姆氏烟草（Nicotiana benthamiana）（N. Benthamiana）在整个植物中进行。 这种生产模式依赖于室内或温室生长的植物的瞬时农杆菌渗透，并且相对于传统的不锈钢发酵罐类型的生物制造工艺，其生产能力受到严重限制。 然而，与N. benthamiana产生抗体。 该项目的研究人员将开发从N.本氏细胞 这些方法将采用新技术以分批和半连续模式培养农杆菌渗入的植物细胞。所进行的工作将能够在可用于其他生物治疗的相同类型的大规模设施中快速生产抗体，同时保留与从N.本萨米亚纳 该项目适合快速机制，因为迫切需要开发可扩展的生物制造方法，以生产已知有效的埃博拉治疗药物。 该项目将有助于我们理解和设计使用植物细胞的新生物制造平台的能力，并促进植物细胞合成生物学的发展。 除了埃博拉危机之外，这项工作还应有助于发展快速生物制造能力，以应对未来对全球健康的威胁。

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.