Abstract
Following the success of and the high demand for recombinant protein-based therapeutics during the last 25 years, the pharmaceutical industry has invested significantly in the development of novel treatments based on biologics. Mammalian cells are the major production systems for these complex biopharmaceuticals, with Chinese hamster ovary (CHO) cell lines as the most important players. Over the years, various engineering strategies and modeling approaches have been used to improve microbial production platforms, such as bacteria and yeasts, as well as to create pre-optimized chassis host strains. However, the complexity of mammalian cells curtailed the optimization of these host cells by metabolic engineering. Most of the improvements of titer and productivity were achieved by media optimization and large-scale screening of producer clones. The advances made in recent years now open the door to again consider the potential application of systems biology approaches and metabolic engineering also to CHO. The availability of a reference genome sequence, genome-scale metabolic models and the growing number of various “omics” datasets can help overcome the complexity of CHO cells and support design strategies to boost their production performance. Modular design approaches applied to engineer industrially relevant cell lines have evolved to reduce the time and effort needed for the generation of new producer cells and to allow the achievement of desired product titers and quality. Nevertheless, important steps to enable the design of a chassis platform similar to those in use in the microbial world are still missing. In this review, we highlight the importance of mammalian cellular platforms for the production of biopharmaceuticals and compare them to microbial platforms, with an emphasis on describing novel approaches and discussing still open questions that need to be resolved to reach the objective of designing enhanced modular chassis CHO cell lines.
Highlights
Following the approval of the first biopharmaceutical products by regulatory authorities in the early 1980s [1], innovation in the biopharmaceutical field has triggered the generation of many novel compounds that demonstrated great therapeutic potential towards the treatment of existing and Processes 2020, 8, 643; doi:10.3390/pr8060643 www.mdpi.com/journal/processesProcesses 2020, 8, 643 emerging diseases [2]
The availability of a full genome sequence enables researchers to reconstruct cellular metabolism in silico. This knowledge is captured in genome-scale metabolic models (GSMMs), which are essential for the rational identification of engineering targets [38,39]
To succeed and to really take advantage of the full “design” space, it is necessary to have a collection of well-characterized synthetic biology parts, such as promoters, terminators, regulatory sequences, or genes encoding sensor proteins that can react to various stimuli. Any combination of these parts should result in predictable behaviour. Such a collection of parts is already available for bacteria http://parts.igem.org/Main_Page where one can choose from a wide selection of promoters, terminators and genes involved in various cellular processes, such as signalling, cell death, motility, recombination and many more
Summary
Following the approval of the first biopharmaceutical products by regulatory authorities in the early 1980s [1], innovation in the biopharmaceutical field has triggered the generation of many novel compounds that demonstrated great therapeutic potential towards the treatment of existing and Processes 2020, 8, 643; doi:10.3390/pr8060643 www.mdpi.com/journal/processes. The predominant host used in today’s industry are Chinese hamster ovary (CHO) cells [13,14,17,18], which have the advantage of low susceptibility to viral infection and a species specific glycosylation pattern that differs only minimally from human glycosylation [19] Due to their comparatively simple handling and their ability to grow in chemically defined media in suspension culture, CHO cell lines have proven extremely useful both for research and industrial applications [15]. The use of these tools is facilitated by the availability of the genetic information [22] as well as a genome-scale metabolic model of the target strain While many of these tools are already widely applied in the field of recombinant protein production or strain engineering in microbial research, up to the level of design of chassis strains, their application to mammalian production hosts is still fragmentary and lagging far behind. We discuss the open challenges and required tools that need to be solved and established to transfer these approaches to mammalian systems
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
