Multiplex secretome engineering enhances recombinant protein production and purity

Stefan Kol (), Daniel Ley, Tune Wulff, Marianne Decker, Johnny Arnsdorf, Sanne Schoffelen, Anders Holmgaard Hansen, Tanja Lyholm Jensen, Jahir M. Gutierrez, Austin W. T. Chiang, Helen O. Masson, Bernhard O. Palsson, Bjørn G. Voldborg, Lasse Ebdrup Pedersen, Helene Faustrup Kildegaard, Gyun Min Lee and Nathan E. Lewis ()
Additional contact information
Stefan Kol: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet
Daniel Ley: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet
Tune Wulff: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet
Marianne Decker: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet
Johnny Arnsdorf: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet
Sanne Schoffelen: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet
Anders Holmgaard Hansen: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet
Tanja Lyholm Jensen: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet
Jahir M. Gutierrez: The Novo Nordisk Foundation Center for Biosustainability at the University of California, San Diego, School of Medicine
Austin W. T. Chiang: The Novo Nordisk Foundation Center for Biosustainability at the University of California, San Diego, School of Medicine
Helen O. Masson: The Novo Nordisk Foundation Center for Biosustainability at the University of California, San Diego, School of Medicine
Bernhard O. Palsson: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet
Bjørn G. Voldborg: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet
Lasse Ebdrup Pedersen: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet
Helene Faustrup Kildegaard: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet
Gyun Min Lee: The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet
Nathan E. Lewis: The Novo Nordisk Foundation Center for Biosustainability at the University of California, San Diego, School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract Host cell proteins (HCPs) are process-related impurities generated during biotherapeutic protein production. HCPs can be problematic if they pose a significant metabolic demand, degrade product quality, or contaminate the final product. Here, we present an effort to create a “clean” Chinese hamster ovary (CHO) cell by disrupting multiple genes to eliminate HCPs. Using a model of CHO cell protein secretion, we predict that the elimination of unnecessary HCPs could have a non-negligible impact on protein production. We analyze the HCP content of 6-protein, 11-protein, and 14-protein knockout clones. These cell lines exhibit a substantial reduction in total HCP content (40%-70%). We also observe higher productivity and improved growth characteristics in specific clones. The reduced HCP content facilitates purification of a monoclonal antibody. Thus, substantial improvements can be made in protein titer and purity through large-scale HCP deletion, providing an avenue to increased quality and affordability of high-value biopharmaceuticals.

Date: 2020
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DOI: 10.1038/s41467-020-15866-w

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