Inhibition of microRNA-let-7a Increases the Specific Productivity of Antibody-Producing CHO Cell Lines  

Lydia Greenlees1 , Robert W Georgantas, III1 , Jie Zhu1 , Huifang Dong1 , Gargi Roy1 , Jonathan Jacobs2 , Lori Clarke1 , Christina Stracener1 , Hui Feng1 , Yihong Yao1 , Michael A Bowen1 , Koustubh Ranade1 , Katie Streicher1
1. MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878. USA
2. MRI Global, Rockville, MD, USA
Author    Correspondence author
Genomics and Applied Biology, 2014, Vol. 5, No. 1   doi: 10.5376/gab.2014.05.0001
Received: 14 Mar., 2014    Accepted: 28 Mar., 2014    Published: 28 Mar., 2014
© 2014 BioPublisher Publishing Platform
This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Preferred citation for this article:

Greenlees et al., 2014, Inhibition of microRNA let-7a Increases the Specific Productivity of Antibody-Producing CHO Cell Lines, Genomics and Applied Biology, Vol.5, No.1, 1-15 (doi: 10.5376/gab.2014.05.0001)

Abstract

Chinese hamster ovary cells (CHO) are the preferred cell line for the production of recombinant biopharmaceuticals, which constitutes a multi-billion dollar global market. Major challenges to improving protein productivity of CHO in large-scale production cultures include growth level, cellular stress, and translation rate. Because microRNA (miR, miRNA) can simultaneously perturb multiple pathways by inhibiting translation or destabilizing different mRNAs, we explored their utility to extend the cell growth phase or alter protein production per cell (specific productivity) with the goal of enhancing current optimization techniques to increase the production capacity of CHO cell cultures. To investigate the effect of altered microRNA expression on CHO cell viability and specific productivity, two clinically relevant antibody-producing CHO cell lines were stably transduced with lentiviral vectors encoding nine different miRNAs or anti-miRNAs based on their potential involvement in pathways critical for recombinant protein production. Inhibition of miR-let-7a led to a 50%~68% increase in specific productivity in two recombinant antibody-producing cell lines. Furthermore, following miR-let-7a inhibition, we identified increased expression of its targets HMGA2, MYC, NF2, NIRF, RAB40C, and eIF4a which are important mediators of apoptosis, protein translation, and cellular metabolism. Overall, this work provides proof of concept that exogenous microRNA modifications can positively affect specific productivity of CHO cell cultures and highlights the potential of miR-let-7a to have a broad impact on the complex biological functions necessary for improving the capabilities of CHO cell lines.

Keywords
microRNA; miR-let-7a; CHO cells; Productivity
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