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European Biopharmaceutical Review

Moving on Up: The Cultivation of Upstream Strategies

Andreas Herrmann at Celonic discusses the latest advances enabling swift and cost-effective production of cell lines

In recent decades, biopharmaceutical proteins have become the largest group of new therapeutic compounds in early and late clinical development. Since many of these therapeutics especially the antibody based approaches require a high-dose treatment in patients, efficient technologies for the production of recombinant proteins are needed in order to overcome the shortage in production capacities and to keep the cost of goods (COGs) as low as possible. Therefore, powerful upstream strategies have been developed for the fast track and efficient generation of high yield mammalian production cell lines by genetic engineering. Moreover, innovative fermentation technologies have been established to increase the production titre.

The correct choice of host cell line for the establishment of the production cell line is essential to ensure product quality and quantity. As an example, production cell lines that are often used for the production of biopharmaceuticals include the Chinese hamster ovarian (CHO) and hybridoma cell lines like SP2/0 or NS1, specifically dedicated for the production of antibodies. Since most of the antibodies that are currently under development are humanised or fully human antibodies, their production in CHO cells, which is currently the gold standard, became more and more popular.

But while hybridoma cells, which are derived from B-cells, are by nature dedicated to producing high volumes of antibodies, CHO cells often show poor cell-specific production rates. Recent improvements to increase the yield of fermentation processes are therefore focused on:

  • Improved vector systems for the rapid development of stable, high-yield expression cell lines

  • Engineered CHO cell lines in order to get robust, high viable cultivations

  • Methods for the high-density cultivation of cells

MAMMALIAN EXPRESSION VECTORS

Vectors for the high-yield expression of heterologous transcripts in mammalian cells consist of an expression cassette comprised of a promoter, the gene of interest and a polyadenylation sequence, a gene-selectable marker and a vector backbone for the amplification of said plasmid in bacteria. In order to generate stable, high-producing cell lines, integration of said cassette into the genome is required: a process that takes place randomly and with very low frequency. Finally, more than 99 per cent of the resulting clones show negligible productivity due to integration in unfavourable chromosomal regions that are not accessible for the transcriptional machinery. Thus, although most commonly used expression cassettes include strong constitutive promoters such as cytomegalovirus (CMV) or elongation factor 1 alpha (EF-1) promoter, very low expression is observed due to this so-called position effect.


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Dr Andreas Herrmann has been Managing Director of Celonic since 2003. Prior to this, he was Vice President of Manufacturing Operations and Process Development for Cardion AG, Germany. Between 1995 and 1998, he served as an Associate Professor at the University of Düsseldorf, where he established a research group in the field of vascular gene therapy. Andreasreceived his PhD in Chemistry from the University of Cologne in 1995.
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Dr Andreas Herrmann
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