Human cell lines for biopharmaceutical manufacturing: history, status, and future perspectives

Abstract

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.

A long non-coding SINEUP RNA boosts semi-stable production of fully human monoclonal antibodies in HEK293E cells

“…Recently, biotherapeutics produced in HEK293, HT1080 and PER C6 human cell lines have been approved by FDA or the European Medicines Agency 7 . Although the generation of a stable cell line expressing high levels of mAbs is the final goal for clinical development, it still remains time-consuming and expensive during the development phases of the research, before occurrence of preclinical and clinical studies.…”

Impaired antiviral response of adenovirus-transformed cell lines supports virus replication

“…So far, only a few cell lines, such as Vero cells, which are unable to produce IFN, support the propagation of IFN-sensitive viruses (Barrett et al, 2009;Emeny & Morgan, 1979;Stewart et al, 2014). However, not all viruses replicate in these African green monkey cells and some properties of the virus, such as the glycan structures of viral surface proteins, can be altered by propagation in cells that do not originate from natural host organisms (Dumont et al, 2015;Genzel et al, 2012; Schwarzer et al, 2009). Thus, there is a need to provide flexible host cell systems for the propagation of IFN-sensitive viruses.…”

Production of recombinant coagulation factors: Are humans the best host cells?

“…This cell line possesses good characteristics for commercial exploitation for recombinant protein production: ability to grow under serum-free suspension conditions, amenability to transfection, high yield protein production, apart from human-like posttranslational modifications. 49 Besides rFVIII and rFIX-based products, a Glucagon-1-like peptide (GLP-1) Fc fusion protein, Trulicity Ò (Eli Lilly), has been commercially produced in this cell line. 48,49 Xigris Ò , activated protein C, was the first recombinant therapeutic protein produced in Hek293 cells approved by the FDA (2001); however, it was voluntarily withdrawn from market in 2011 by its manufacturer (Eli Lilly).…”

“…49 Besides rFVIII and rFIX-based products, a Glucagon-1-like peptide (GLP-1) Fc fusion protein, Trulicity Ò (Eli Lilly), has been commercially produced in this cell line. 48,49 Xigris Ò , activated protein C, was the first recombinant therapeutic protein produced in Hek293 cells approved by the FDA (2001); however, it was voluntarily withdrawn from market in 2011 by its manufacturer (Eli Lilly). 50 In addition to Hek293 cells, novel human cell lines have been explored for improved recombinant FVIII production.…”