Human cell lines for biopharmaceutical manufacturing: history, status, and future perspectives
Open accessAbstract
Biotherapeutic proteins represent a mainstay of treatment for a multitude of conditions, for example, autoimmune disorders, hematologic disorders, hormonal dysregulation, cancers, infectious diseases and genetic disorders. The technologies behind their production have changed substantially since biotherapeutic proteins were first approved in the 1980s. Although most biotherapeutic proteins developed to date have been produced using the mammalian Chinese hamster ovary and murine myeloma (NS0, Sp2/0) cell lines, there has been a recent shift toward the use of human cell lines. One of the most important advantages of using human cell lines for protein production is the greater likelihood that the resulting recombinant protein will bear post-translational modifications (PTMs) that are consistent with those seen on endogenous human proteins. Although other mammalian cell lines can produce PTMs similar to human cells, they also produce non-human PTMs, such as galactose-α1,3-galactose and N-glycolylneuraminic acid, which are potentially immunogenic. In addition, human cell lines are grown easily in a serum-free suspension culture, reproduce rapidly and have efficient protein production. A possible disadvantage of using human cell lines is the potential for human-specific viral contamination, although this risk can be mitigated with multiple viral inactivation or clearance steps. In addition, while human cell lines are currently widely used for biopharmaceutical research, vaccine production and production of some licensed protein therapeutics, there is a relative paucity of clinical experience with human cell lines because they have only recently begun to be used for the manufacture of proteins (compared with other types of cell lines). With additional research investment, human cell lines may be further optimized for routine commercial production of a broader range of biotherapeutic proteins.
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Murine myeloma cells (NS0 and Sp2/0) are used to produce commercial monoclonal antibodies such as Cetuximab and Palivizumab.
“Murine myeloma cells (NS0 and Sp2/0), derived from tumor cells that no longer produce their original immunoglobulins, also are being used to produce some commercial monoclonal antibodies such as Cetuximab (ERBITUX ® ) and Palivizumab (SYNAGIS ® ) (Barnes et al., 2000;Dumont et al., 2015).”
From Therapeutic glycoprotein production in mammalian cells (2017) · cites this paper as Dumont et al., 2015
Only two marketed recombinant glycoproteins are currently manufactured in BHK cells, Factor VIIa and Factor VIII.
“Only two marketed recombinant glycoproteins are currently manufactured in these cells, Factor VIIa (NovoSeven ® ) and Factor VIII (Kogenate ® and Kovaltry ® ), which are other clotting factors (Durocher and Butler, 2009;Dumont et al., 2015).”
From Therapeutic glycoprotein production in mammalian cells (2017) · cites this paper as Dumont et al., 2015
The non-human expression systems section lists NovoSeven and Kogenate among product references and defines BHK as baby hamster kidney, but the passages retrieved do not link either product to BHK manufacture or establish that only two marketed glycoproteins use those cells. The references to Kogenate and the comparison of factor VIII expression with BHK21 cells also do not establish the marketed-product claim. Searches for BHK, both factor names, and the product names did not settle it. (LLM, conf=0.68)
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Cites
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“Further, there is perceived species barrier protection with the use of hamster-derived cells, reducing the potential risk of transfer of contaminating adventitious agents to humans (Berting et al., 2010; Swiech et al., 2012).”
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- Authors
- Dumont, J., Euwart, D., Mei, B., Estes, S., & Kshirsagar, R.
- Affiliations
- Biogen (United States) (US)
- Corresponding author
- Dumont, Jennifer
- ORCID
- Estes, Scott
- Venue
- Critical Reviews in Biotechnology
- Publisher
- Informa UK Limited
- Published
- 2015-09-18
- Volume
- 36
- Issue
- 6
- Pages
- 1110-1122
- ISSN
- 0738-8551 (ISSN-L)
- 1549-7801
- PMC
- PMC5152558
- OpenAlex
- W1915519529
- Cited by
- 483
- References
- 7
- Citations by year
- 2026: 39 · 2025: 37 · 2024: 63 · 2023: 55 · 2022: 57 · 2021: 49 · 2020: 51 · 2019: 49 · 2018: 43 · 2017: 27 · 2016: 10 · 2015: 1
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Critical Reviews in Biotechnology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Biogen
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Transgenic Plants and Applications
- Keywords
- human cell lines, biopharmaceutical manufacturing, therapeutic proteins, recombinant protein expression, post-translational modification, N-glycolylneuraminic acid, immunogenicity, viral contamination, virus inactivation, serum-free suspension culture, CHO cells, NS0 cells, vaccine production
- MeSH terms
- Animals, Biological Products, Cell Line, Humans, Proteins, Metabolic Engineering
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