Mammalian cells as biopharmaceutical production hosts in the age of omics

Abstract

Mammalian cells are important hosts for the production of a wide range of biopharmaceuticals due to their ability to produce correctly folded and glycosylated proteins. Compared to microbes and yeast, however, the productivity of mammalian cells is low because of their comparatively slow growth rate, tendency to undergo apoptosis, and low production capacities. While much effort has been invested in the engineering of mammalian cells with superior production characteristics, the success of these approaches has been limited to date. One factor responsible for this lack of success is our limited understanding of the cellular basis for high productivity, and of how discrete mechanisms within a cell contribute to the overall phenotype. Aiming to measure and characterize all cellular components at different functional levels, omics technologies have the potential to improve our understanding of mammalian cell physiology, elucidating new targets for the generation of a superior host cell line. This review provides a comprehensive analysis of recent examples of omics studies in the context of mammalian cells as production hosts, highlighting both the challenges and successes in the application of these powerful technologies.

Generation of monoclonal antibody-producing mammalian cell lines

“…Increased knowledge of the CHO genome [28,74,75], transcriptome [69,76] and proteome [77] would allow greater understanding of the complex interactions taking place for improved cell engineering approaches. Construction of dynamic computational models has worked well in the production of microbial cells and this extra information will eventually allow similar implementation in mammalian cells [39,78,79].…”

Advances in affinity ligand‐functionalized nanomaterials for biomagnetic separation

“…Owing to the requirements of post translational modifications, such as glysocsylation of the CH2 domain, full-length antibodies must be expressed in mammalian cell culture. Mammalian cell culture facilities cost several hundred million dollars, require years to establish, and the cell culturing is typically slow, expensive and plagued with issues such as cellular toxicity and apoptosis (Dietmair et al 2012). Due to advancements in antibody engineering in recent years, fulllength antibodies can now be dissected, and expressed as minimal binding fragments, lacking the glycosylated constant domains.…”

Emerging synthetic biology tools for engineering mammalian cell systems and expediting cell line development

“…Specifically, efficient mammalian cell engineering requires precise, reliable genome editing techniques to enable the expression of heterologous genes and deletion of unwanted genes. In contrast to the ease of genome editing in microbial systems, mammalian cell engineering still relies heavily on semi-random integration [3,5] and low probability homologous recombination events [6][7][8] coupled with laborious screening [3,[9][10][11]. However, classes of enzymes naturally exist which can recognize specific DNA sequences and modify those genomic loci.…”

“…This review concludes with a perspective for future directions and advances. These advancements, coupled with a better understanding of cell systems captured through omics approaches [3,4], facilitate faster and more flexible cell line development, ultimately reducing cost and time.…”