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New expression systems compete for attention.
New, alternative expression systems in various stages of development are showing their viability in large-scale protein manufacture. So, the question is no longer if an alternative platform will emerge, but which of the more than 340 expressions systems and associated genetic engineering technologies available for licensing will become the next common industry platform.1 In any case, it's very likely that the industry will be seeing broader diversity in the expression systems used at the commercial level over the next five years.
Eric S. Langer
Until recently, selecting one of the currently predominant expression systems for new products in development was the safe choice. But now, drug developers are realizing that old technologies can be more costly. Evaluating the best and newest technologies is prudent, and today most biopharmaceutical companies are considering the clinical, quality, and productivity implications of their expression system selections. Most manufacturers are considering options for their production technologies for a variety of reasons, including how biosimilar competitors might use alternative technologies that could undercut the prices of innovative products. This could affect exclusive worldwide suppliers' competitive positions in the long run if the biosimilar manufacturers can reduce production costs through use of new expression systems.
The benefits of newer expressions systems are likely to include improvements related to cost, such as increased protein yield and lower upfront investment. In addition, many offer more rapid scale-up, faster batch turnaround, and less costly supporting infrastructure, including physical space and land. Some systems are being developed for use with totally disposable manufacturing equipment, allowing further cost savings and convenience; and many are intended to avoid the use of animal products. Some newer expression systems incorporate fusion protein tag sequences that greatly facilitate simpler and cheaper downstream purification. Newer systems also often allow better control of various aspects of expression, notably control of glycolysis. Such unique molecular modifications enable the design and selection of therapeutics with optimal properties, efficacy, and safety, in addition to allowing proprietary (patented or not) customization of expressed proteins, providing a considerable barrier to the future development of competing biosimilar products. Many newer systems simply offer higher yields with less equipment and effort.
Most important perhaps is speed to market. Many new expression systems allow much faster cell line development, process scale-up, and testing; what might require months with current systems may take a fraction of that time with some of the newer technologies.
Competitiveness is one reason that companies like Lonza are actively developing new expression systems. "Success in this industry is directly related to innovative expression technologies," says John Birch, chief scientific officer at Lonza Biopharmaceuticals (Slough, UK). He adds that although the GS Gene Expression System has been widely accepted, they are also developing alternative mammalian and microbial systems.
A few novel expression systems are already well on track to become common industry platforms. For example, several biopharmaceuticals nearing approval are manufactured in insect cell culture using baculovirus vectors. These include: Cervarix, a human papillomavirus (HPV) vaccine from GlaxoSmithKline; Provenge, involving a GM-CSF–prostate tumor antigen fusion protein made by Dendreon for the treatment of prostate cancer; and FluBlok from Emergent Biosolutions, Inc. (developed by Proteins Sciences Corp.), a new cell-cultured influenza vaccine. Recombinant proteins expressed by transgenic animals also are entering the market, including the recently approved Atryn, containing goat-expressed antithrombin protein, from GTC Biotherapeutics.
The PER.C6 expression system from Crucell and DSM Biologics is already having a major impact. This is one of the most advanced of the various human cell line alternatives to Chinese hamster ovary (CHO) cells, and will probably become a major platform for recombinant monoclonal antibody manufacture. Many companies have already licensed PER.C6 for large-scale use and for internal production of therapeutic candidates; and yields over 30 g/L have been documented. Another expression system with high-visibility and many licensees is the Pfenex Pseudomonas bacterium being commercialized by Dowpharma. Other major companies getting involved in expression systems manufacturing platform technologies include Invitrogen and GE.
The commercial value of novel expression systems is evident in the marketplace. Merck acquired GlycoFi for over $400 million and developed its first biosimilar product, currently in development, using GlycoFi. This product will be comparable to Aranesp, Amgen's second-generation erythropoietin, but Merck's protein is expected to have an improved therapeutic profile. Merck will also use its proprietary technology to build in molecular modifications that will make it very difficult for those seeking to develop a competing biosimilar of an innovator product.
Table 1 lists some of the expression systems in development and their sources (the main commercial licensing organizations). These systems include an incredible variety of organisms being transformed for recombinant protein expression, including algae, both unicellular and whole plants; glycolysis in diverse yeasts, animal cells and even plants; moss; coconut cells; Drosophila mosquitoes; fungi, including unicellular and whole plants; chicken stem cells; tobacco and other agricultural commodity plants in cell culture, greenhouses and open fields; bacteria long used in for nonpharmaceutical industrial manufacture, including Bacillus subtilis; cell lines targeted as replacements for CHO cells, including NS0 and HEK-292 cell lines; diverse yeasts, including those engineered to have human-like glycosylation; shrimp and other aquatic animals; protozoa; transgenic animals of all types; novel bacteria, such as Caulobacter, Staphylococcus and Clostridia species; Pseudoalteromonas haloplanktis, a cold-growing bacterium from Antarctica; stripped-down E. coli; and even totally cell-free systems.
Table 1. Select novel expression systems and commercial sources1
As strange as it may now seem, in coming years, you will likely be using multiple expression systems. The biotechnology community should welcome these manufacturing platforms and follow their development because they offer wide-open options for improvements and alternatives to the currently dominant E. coli, yeast, and CHO systems. In many cases, the economics and increased simplicity and convenience of newer systems will expand their use. Currently, only a small portion of those involved in recombinant protein or MAb manufacture are familiar with more than just a few of the upcoming technologies. So, there are still ample opportunities to stake one's claim before others jump in and catch up by taking options to license effective expression systems.
Eric S. Langer is president and managing partner at BioPlan Associates, Inc., Rockville, MD, 301.921.5979, email@example.com He is also a member of BioPharm International's editorial advisory board.
1. Rader RA. Biopharmaceutical expression systems and genetic engineering technologies: current and future manufacturing platforms. BioPlan Associates. Rockville, MD; 2008 Oct. Available from: www.bioplanassociates.com/es/index.htm.