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.
BENEFITS OF NEWER 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
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.
NEW SYSTEMS ARE ALREADY HERE
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.