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Abstract
Antibody combination therapeutics (ACTs) are polyvalent biopharmaceuticals that are uniquely suited for the control of complex diseases, including antibiotic resistant infectious diseases, autoimmune disorders and cancers. However, ACTs also represent a distinct manufacturing challenge because the independent manufacture and subsequent mixing of monoclonal antibodies quickly becomes cost prohibitive as more complex mixtures are envisioned. We have developed a virus-free recombinant protein expression platform based on adeno-associated viral (AAV) elements that is capable of rapid and consistent production of complex antibody mixtures in a single batch format. Using both multiplexed immunoassays and cation exchange (CIEX) chromatography, cell culture supernatants generated using our system were assessed for stability of expression and ratios of the component antibodies over time. Cultures expressing combinations of three to ten antibodies maintained consistent expression levels and stable ratios of component antibodies for at least 60 days. Cultures showed remarkable reproducibility following cell banking, and AAV-based cultures showed higher stability and productivity than non-AAV based cultures. Therefore, this non-viral AAV-based expression platform represents a predictable, reproducible, quick and cost effective method to manufacture or quickly produce for preclinical testing recombinant antibody combination therapies and other recombinant protein mixtures.
Disclosure of Potential Conflicts of Interest
All authors were employees of Excelimmune, Inc. during the research period. G.M.W., K.L.C., H.H.R., A.B.C., and E.E.R. own Excelimmune stock and/or stock options. This research was funded internally as an Excelimmune research project.
Acknowledgments
The authors would like to acknowledge Vincent Coljee for leadership on the project. We would also like to thank Theresa A. Towle, Marina D. Capacian, and Jeffrey Neale for help with antibody purification, Christy Manchester, Amanda L. St. Germain, and Virginia Lai for help cloning and preparing the vectors and Arnaud Colantonio, Samuel Ayisi, Anna M. Hall, and Meghan Rego for helpful discussions. Finally, we would like to thank the excellent support team. This research was funded internally as an Excelimmune research project.