Author: Séverine Fagète, Ph.D.
The commercial production of recombinant proteins, including antibodies and enzymes, hinges on the generation and maintenance of specific cell lines designed for these specialized molecules. This complex and time-intensive process often leads businesses to partner with contract development and manufacturing organizations (CDMOs) for their cell line development (CLD) needs. This decision is crucial, as a stable, high-quality cell line is essential for transitioning a protein from development to commercialization. This article highlights key indicators that a CDMO is the right fit for a company's CLD partnership.
A significant majority of clinical and commercial proteins are produced in Chinese hamster ovary (CHO) cells due to their numerous beneficial characteristics. These include a reduced susceptibility to human viruses, robust large-scale proliferation, suitability for suspension cultures, and the ability to perform post-translational modifications similar to native proteins. These traits make CHO cells a solid foundation for protein expression, adaptable to much of the commercial and therapeutic protein market.
However, variability exists within various CHO cell lines, and CDMOs often show differing success levels in optimizing their cells for protein production. CDMOs with deep sequencing knowledge and proprietary cell lines outperform those relying on third-party technologies. Understanding the genome and epigenome enables CDMOs to place transgene of interest in highly expressed genomic regions, boosting overall protein production. Skilled CDMOs can create favorable genomic microenvironments for efficient transcription factor recruitment, further enhancing protein production. Comprehensive genetic knowledge also supports using powerful bioinformatic tools to strengthen the cell-line development process, particularly for enhanced protein expression or monoclonality assessment. Therefore, the depth of a CDMO's knowledge about their cell lines is a crucial factor for biopharmaceutical companies when selecting a protein production partner.
Successfully expressing the gene of interest is insufficient for large-scale production. Post-translational modifications (PTMs) such as linkages, cleavages, and chemical alterations must occur for a protein to be functional. PTMs are highly individualized to each protein and vital to its functionality. Thus, CDMOs must tailor their CLD process to the molecule's unique requirements. The CLD process should also be integrated with other CDMO components, such as analytics or formulation development, to limit tech transfers and streamline development.
This is particularly relevant for bispecific proteins, a rapidly evolving class of structurally complex therapeutics. Bispecific proteins are primarily heterodimeric, adding complexity to the production process. CDMOs should offer early-stage CLD solutions to ensure heterodimeric bispecific protein production is fine-tuned to produce high-quality therapeutics.
Proteins can also aggregate, fragment, or degrade due to reactions within the cell culture or protein purification process, potentially affecting stability, immunogenicity, and functionality. A competent CDMO can provide customized solutions, such as chaperone proteins, to facilitate the production of challenging proteins. Therefore, biopharma companies should seek CDMOs willing to design a bespoke approach to CLD, ensuring protein production is not hindered by unforeseen complexity.
When selecting a CDMO, biopharmaceutical companies must consider microbial contamination and impurities within the cell line and expressed protein. CDMOs must routinely test throughout CLD to ensure cell cultures are free of microbes, with rigorous quality control processes being paramount.
Contamination can also arise from impurities within the cell line and expressed protein. For example, monoclonal antibodies not produced from a single progenitor cell or mixed with another antibody are considered contaminated. A good CDMO should have well-defined separations between CLD processes to prevent cross-contamination. Genetic and molecular tests can confirm the correct molecule production and single-parent cell origin. The safety of biopharmaceutical products is critical, and companies should partner with CDMOs that prioritize contamination issues as seriously as they do.
Scientific expertise is crucial in determining the right CDMO partner, but the human element should not be overlooked. Biopharma companies make significant investments when choosing a CLD collaborator and should seek a CDMO with top-quality customer service. The ability to discuss concerns with subject matter experts, receive regulatory compliance guidance, and establish a productive relationship with a project manager are essential components of a successful partnership.
Finding the right CDMO may require significant time and resources, but CLD is at the heart of biologics development. Companies must identify organizations with extensive CLD expertise to navigate regulatory milestones and scientific challenges easily. The upfront investment in finding a high-quality CDMO will pay off with a stable, high-quality cell line, ensuring confidence in development, manufacturing, and commercialization of a biotherapeutic.
More information on KBI Biopharma's Cell Line Development capabilities and our SUREtechnology Platform™, powered by Selexis®, can be found here.
Séverine is the Vice President of Mammalian Cell Line Development (CLD) at KBI Biopharma’s Geneva Facility. Prior to the operational consolidation with KBI, Séverine held multiple leadership roles with escalating responsibilities at Selexis. She brings nearly two decades of experience in the pharmaceutical industry, and deep expertise in early drug discovery, antibody engineering (bispecifics), stable cell line development, and project management.
Séverine holds a master’s in biotechnology from L’Ecole Nationale Supérieure de Technologie des Biomolécules de Bordeaux (ENSTBB) and a PhD in protein engineering from University of Geneva, acquired through NovImmune (now Light Chain Bioscience). She subsequently held a postdoctoral position at the University of Geneva where she designed a novel phage display platform for accelerating bispecific antibody development.