November 17, 2023
It’s no secret that mammalian cell culture is the predominant production system in the biopharmaceutical industry. Microbial expression has been around longer, not least because of the early influence of the brewing industry. But once Chinese hamster ovary (CHO) and other animal cells could be cultured at scale with reliable results, that approach soon “disrupted the paradigm,” as our friends in marketing like to say. Before long, products from mammalian cell culture were dominating the development pipeline — despite the challenges in applying the technology.
Mammalian cells are fragile and finicky. Anyone who’s worked with them knows well their “high-maintenance” needs when it comes to temperature, feeding, mixing methods, and other aspects of a culture environment. The cells are also vulnerable to attack by adventitious agents, many of which can present a threat to recipients of mammalian-expressed protein drugs. But the capabilities of such cells for assembling complex proteins in increasingly large amounts make up for all that.
Or do they? Over the years, the amenability of CHO cells to advanced genetic-engineering techniques has given them adaptability to high-density, serum-free suspension culture while increasing productivity and improving cell-line stability and efficiency. Expression titers since the turn of the century have risen geometrically, from measurements in milligrams to grams and then multiple grams per liter of culture. But some things haven’t changed: primarily the vulnerability of mammalian cells to infection and environmental stresses.
For decades, a few biotechnologists have sought to avoid those concerns by using other means of protein expression. In the late 1990s, most notably, some in the industry were excited about the potential of transgenic animals to produce large volumes of recombinant protein in their milk. Microbiologists have since touted the capabilities of yeast-based systems and widening applicability of bacteria. Entomologists offered up the baculovirus expression vector system (BEVS) based on lepidopteran insect cells. And botanists weighed in with seemingly far-fetched ideas about plant-based expression. None of the associated advancements have been truly disruptive yet, and mammalian cell culture still dominates the industry.
But that might be about to change. In preparation for this featured report, we editors delved into the world of alternative expression technologies and discovered that, while many of us weren’t paying enough attention, some of those systems have taken great strides toward truly disrupting the norms of biopharmaceutical production. Canadian company Future Fields recently launched a contract development and manufacturing organization (CDMO) service using fruit flies for recombinant protein production. A SARS-CoV2 vaccine made by Nicotiana benthamiana plants was approved for market. LFB USA has an approved factor VIIa product expressed in transgenic rabbit milk. A recent publication by a European consortium boldly predicted that “CHO dominance has peaked and . . . the coming years will see a gradual shift back toward microbial-based pharmaceutical protein production” (1). Both rice and algal cell-culture systems are showing great promise. And you’ll read about more progress in the remaining pages of this report. Is one of these options the “next big thing,” or could they collectively disrupt the state of biopharmaceutical production as we know it? Only time will tell.
Reference
1 Rettenbacher LA, et al. Microbial Protein Cell Factories Fight Back? Trends Biotechnol. 40(5) 2022: 576–590; https://doi.org/10.1016/j.tibtech.2021.10.003.
Cheryl Scott is cofounder and senior technical editor of BioProcess International (part of Informa Connect Life Sciences); 1-212-600-3429; [email protected].
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