The Future of Raw Material Sources for mAbs

Published on: 
BioPharm International, BioPharm International-03-01-2020, Volume 33, Issue 3
Pages: 16–17

The future of raw material sourcing for mAb production may lay in the sustainability of the source and the added benefits of newer technologies.

There are ongoing efforts to continually refine and enhance monoclonal antibody (mAb) production, driven in part by the pipeline of upcoming biologic drugs that features many new mAbs in development as well as biosimilar mAbs. To stay competitive, mAb manufacturing processes must maintain desired quality attributes while reducing time to market, being cost effective, and providing manufacturing flexibility. One concern in upstream processing lies in the raw materials used in cell culture. Not only is it critical to have validated sources of purity and quality, it is also important to have sustainable sources.

The mammalian legacy

Today, commercial mAb production relies heavily on animal-derived source material, particularly in the cell line source. Mammalian expression systems have been the workhorse of mAb bioprocessing, typically using Chinese hamster ovary (CHO) cells. Other mammalian expression systems used include NS0 murine myeloma cells and PER.C6 human cells (1).

Murine cells, however, produce some byproduct (i.e., alpha-Gal-alpha(1,3) Gal linkages) (1) that were found to instigate an antibody response in patients against the murine-cell derived therapeutic mAb. As a result, mAb production based on murine cells has been limited in the industry.

Meanwhile, PER.C6 human cells are derived from transfected human embryonic retina cells. These cells are known to multiply indefinitely in suspension culture under serum-free conditions, making them a suitable and practical host for mAb production. The use of human host cells for mAb manufacture is being explored, with one advantage believed to be the compatibility of using a human-cell-derived therapeutic to treat humans. Any residual host cell protein still present in the recombinant product, for example, would be of human origin, thereby lowering the risk that an unwanted or unpredicted immune response may be triggered in the patient against the therapeutic.

Presently, CHO cells are the predominant cell source used in commercial mAb bioprocessing. CHO-derived cell lines have proven to be robust and high-yielding, or at least easily transfected to be high-yielding. However, production using CHO cells is still costly, and biomanufacturers are seeking ways to cut down on costs. In addition, there has been some evidence that residual CHO host cell proteins in the recombinant end product may have caused an undesired immune response in recipients (2). 

Insects instead of mammals?

Alternatives to mammalian cell sources are being explored, including the use of insect cells. In one study (3), product yield, specificity, and glycosylation patterns were compared between insect-cell-based bioprocessing versus CHO-cell-based bioprocessing. The researchers achieved “comparable” amounts of secreted antibodies in the insect-cell-based systems as in the CHO-cell-based system. The antibodies expressed by all the insect cell lines used also successfully displayed highly specific antigen binding. The glycosylation profiles of the antibodies produced in the insect-cell-based systems were also similar to the glycosylation patterns in CHO-cell-based expression.

The use of insect sources for cell-line starting material can potentially lower production costs for mAbs. Specifically, insect cells used in conjunction with a baculovirus is promising. Such a system is known to be safe because baculoviruses have a very restricted host range (i.e., are highly preferential to a specific range of invertebrate host organisms) and are therefore not pathogenic to plants or vertebrate animals. The major advantage of a baculovirus/insect cell system, however, is the speed with which the system can produce stable, recombinant viruses capable of yielding fully active protein product. An added bonus is that the protein produced would have an easily modulated glycosylation profile. This would mean the product can be easily manipulated to closely resemble human proteins (4).


The baculovirus/insect cell system is also a familiar one because it has already been in use to product recombinant proteins for research, diagnostics, and for some therapeutics and vaccines. However, further study is required to determine how effective baculovirus/insect-cell-derived antibodies would be in treating diseases, and whether their therapeutic effects would be comparable to the more commonly used CHO-cell-derived antibodies. 

Animal-free alternatives and future prospects

Although the use of animal-derived raw materials for mAb cell culture has been the dominant practice in the biopharma industry, there is interest and some movement away from the dependency on animal-sourced material (5). There is already use in the industry of animal-component-free biochemicals and supplements for cell culture media. 


For example, fetal bovine serum (FBS), traditionally a preferred supplement mammalian cell culture, has largely been replaced by serum-free media and supplements, which tend to be more chemically defined, allowing for greater consistency from lot to lot. Another advantage is the traceability of serum-free, chemically defined media (versus media of animal origin), which supports compliance with global regulatory standards. Serum-free media also provides high biological activity, stable supply, and predictable prices (6). 

Other attempts to shift away from animal-derived sources involve the use of plant-derived technology. For example, Agenus, a Lexington, MA-based immuno-oncology company, is developing a plant-cell-culture based process to manufacture an adjuvant molecule for use in the production of vaccines (7). The company’s efforts are supported by a $1-million grant from the Bill & Melinda Gates Foundation (8). 

Meanwhile, iBio, a plant-based biopharmaceutical contract development and manufacturing organization, has been applying its plant-based protein production technologies to advancing the development of rituximab biosimilar and biobetter products (9,10). The company’s technology does not require a cell-line development phase as in traditional mammalian expression systems, which saves time and cost. 

Another player making inroads with a non-animal-derived cell culture technology is biotechnology company Dyadic International, whose technology revolves around the use of a fungus-based source. The company has developed its C1 expression system based on the Myceliophthora thermophila fungus. The technology can produce proteins at a large scale. The C1 cell line doubles cells in about two hours, which provides two to 10 times higher productivity. Fermentation time is also reduced by one-third to one-half the time needed in a CHO-based system, with the added benefit of accruing only about one-tenth the media cost as CHO (2). 

Although the prospects for future alternatives to mammalian, and specifically CHO-based, bioprocessing looks promising, the adoption of such processes will not happen overnight. At present, there are many well-established mAbs in the market produced via traditional methods and dependent on mammalian-derived raw materials. However, the shift toward non-animal derived components in some aspects of the cell culture process demonstrate that the industry is actively looking to make a transition, particularly if yield, quality, and cost needs are met.


1. L. Feng, et al., MAbs2 (5) 466–477 (2010).
2. F. Mirasol, BioPharm International31 (11) 18–19 (2018).
3. D . Palmberger, et al., J Biotechnol.153 (3–4) 160-166 (2011).
4. M. Cérutti and J. Golay, MAbs4 (3) 294–309 (2012).
5. VWR, “Upstream Processing for MAbs,”, accessed Feb. 10, 2020.
6. MilliporeSigma, “Serum-Free Stem Cell Media & Supplements,”, accessed Feb. 17, 2020.
7. F. Mirasol, “Turning to Plant Cell Culture for Sustainability,”, Sept. 1, 2019.
8. Agenus, “Agenus Awarded Grant to Enable QS-21 Innovations,” Press Release, Jan. 3, 2019.
9. iBio, “iBio’s Collaboration with South Africa’s AzarGen Biotechnologies Advances to Next Stage,” Press Release, Sept. 18, 2019.
10. iBio, “iBio Reports Progress on Its Bio-Better Rituximab Collaboration with CC-Pharming,” Press Release, Dec. 16, 2019.

Article Details

BioPharm International
Vol. 33, No. 3
March 2020
Pages: 16–17


When referring to this article, please cite it as F. Mirasol, “The Future of Raw Material Sources for mAbs,” BioPharm International 33 (3) 2020.