Editor's Note: Since this article was written, European regulators have recommended the use, and paved the way for approval, of GTC Biotherapeutics' ATryn, which would become the first transgenics-derived product on the market. Click here for more information.
To say that therapeutic protein production in transgenic plants and animals has been long on promise, short on products, is an understatement. Nineteen years after demonstrating proof of principle, in transgenic mice, we still await the first transgenic protein product approval.
Transgenics — put simply, modifying the genetic material of one organism with that of another — should be a paradigm-buster, with greater potential for lowering cost of goods for biologicals than all the buzzwords of the last decade combined. Compared with cell culture and fermentation, transgenics offers numerous process advantages:
- Lower capital and operating costs upstream, especially during expression;
- Depending on the source, easier downstream separations;
- The manufacture of proteins that are poorly expressed, if at all, in mammalian cell culture, yeast, or bacteria;
- Elimination of risky, unreliable sourcing for some biologicals from animal and human tissue;
- Long-term stabilization of proteins in seeds or plant tissues;
- Proteins in physical forms that require less downstream manipulation.
Although the science and engineering have been validated elegantly and repeatedly, transgenics has encountered an entrenched fermentation culture, technical difficulties, and regulatory hurdles that at times appear insurmountable. Biotech’s primary expression model, mammalian cell culture, has spawned dozens of products, billions of dollars of revenue, and a warm, cozy environment in which regulators, manufacturers and vendors can operate. Transgenics represent an abrupt departure — a new set of manufacturing and regulatory challenges, and untold potential.
|Inoculum build-up. Courtesy of Biolex Therapeutics.
Biotechnology has previously faced paradigm shifts of similar magnitude. Experts recoiled at the prospect of manufacturing injectible drugs in yeast, pathogenic bacteria, and especially in cancer cells. Eventually, good science rendered these objections moot. Ironically, one of the battlegrounds in transgenics today is the source of transgenically produced proteins — food plants and animals that humans have ingested safely since time immemorial, but which present difficulties within the predominant GMP culture.
Protein expression in cultured cells is an uphill battle in every sense. Because cells exist out of their biological context, processors must pour nutrients and energy into bioreactors to keep cells alive and growing, and to fuel their protein-making apparatus. Cultured cells were not meant to express foreign proteins, even less so at production-worthy titers. Moreover, mammalian cells prefer to attach to the sides of vessels, much as they stick to other cells in tissues, rather than grow in suspension as bioprocessors prefer.
Animals and plants naturally make high-abundance proteins in specific tissues or fluids — blood, milk, eggs, leaves, seeds. As complex organisms, they are able to sequester therapeutic proteins and still go about their normal existence. Contrast this with fermentation, where exposure to foreign proteins by the entire organism or cell often spells trouble.
Most obvious benefits upstream
With transgenics, upstream operations are greatly simplified and reduced in terms of time, cost and complexity. At the development stage, when cell culture engineers are specifying stainless steel vessels, bioreactors, control equipment, piping, clean-in-place rigs, and a hundred-million-dollar facility, transgenics is concerned with agricultural issues — acquiring land, veterinary and husbandry expertise in the case of animals or plant specialization for food crops, and simple processing equipment for grinding grains or separating milk.
“Transgenic expression systems can be so much more attractive, financially, than CHO [Chinese hamster ovary] cells,” says Tom Newberry, VP at GTC Biotherapeutics (Framingham, Mass.). Economic benefits include flexibility of capital and operations, profitability even at low volumes, and lower cost of goods. Scaleup involves breeding more animals or growing more crops, compared with designing, building and validating a larger facility. Without the facility and equipment overhead, early-stage companies enjoy the freedom to allocate resources optimally.
GTC, formerly Genzyme Transgenics, concentrates on proteins that express poorly in cells, for example blood proteins, which are isolated from animal or human blood serum. GTC’s lead product, ATryn (recombinant human anti-thrombin), a plasma protein with anti-coagulant and anti-inflammatory properties, is currently under development in Europe, the Middle East and Canada with Leo Pharma (Ballerup, Denmark).
Even as FDA urges pharm/biotech to embrace and manage risk, companies have seemingly become more risk-averse. Nowhere is this more evident than in transgenics, where “nobody wants to be first,” says Newberry. In February 2006, the European Medicines Agency (EMEA) turned down GTC’s marketing application for ATryn, citing an insufficient number of patients in clinical studies and a minor discrepancy between the submitted purification methodology and the one used for the Phase III study. GTC and Leo Pharma have re-submitted their application. GTC has invested $200 million in ATryn and plans to pursue FDA approval, regardless of EMEA’s final decision.