Dec 8, 2008

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Molecular Pharming

Pharma plants: Status report

Around the world, efforts are increasing to use genetically modified plants in the same way that e.g. bacteria and yeasts have been used until now, as production organisms for vaccines and other pharmaceutical substances. In the USA and Canada, but increasingly also in Europe, and especially France, pharma plants are being tested in release trials and the drugs they produce are already undergoing clinical tests. For biological safety, the cultivation of pharma plants poses completely new challenges.

Producing drugs using biotechnology is not new, but until now it has been restricted to production within closed systems using microbial, animal and – occasionally – plant cells or tissue (fermenter or bioreactor production). These drugs (biopharmaceuticals) are produced by inserting the genes that code for the desired substance into the production organism and expressing them there. The bacterium Escherichia coli in particular, is often used. Nearly two-thirds of licensed drugs produced using biotechnology are produced in E.coli, including human insulin, a recombinant drug that was first produced in 1982.

Seven of the 50 top-selling drugs in 2003 were biopharmaceuticals. They currently account for around seven per cent of the global pharmaceuticals market.

With suitable genetic modifications, plants too can be used as production organisms for biopharmaceuticals. The pharmaceutical substances produced in the plant are then extracted and purified. There has been talk of developing plants containing vaccines that would give protection when eaten, but these are a long way from becoming reality.

Releases of pharma plants

By the end of 2003 a total of 186 applications for releases of PMP plants had been submitted in the USA, Canada and the EU, the first of which were submitted in the USA as far back as 1991.

In Germany the first release of pharma plants was approved in 2006. Scientists at the University of Rostock want to investigate over several years to what extent potatoes are suitable as a production system for vaccines.

The main crops used for release trials are maize and tobacco, followed by oilseed rape and soya. Pharmaceuticals obtained from these include blood and blood coagulation proteins, vaccines, structural substances like collagen, antimicrobial and antiviral substances, growth hormones, various enzymes and, in particular, antibodies. Antibodies have been the most intensively studied in plant production systems. Therapeutic antibodies, e.g. for treating cancer, autoimmune diseases and infectious diseases are a key focus in the development of PMPs.

No PMP plants approved

The first pharmaceuticals produced in transgenic plants are already at various clinical trial phases (see table below). So far though, no PMP plant has yet been authorised anywhere in the world. Only a few proteins are commercially available that have been produced during experimental releases in the USA and which may be used for research or diagnosis purposes (e.g. trypsin from maize and lactoferrin from rice).

At the beginning of 2006 a first PMP, an animal vaccine produced by Dow AgroSciences, was approved in the USA. The vaccine was produced using plant cell cultures.

The most intensive PMP research and development is being conducted in the USA and Canada. But some European companies are also a step ahead. For instance, a French company, Meristem Therapeutics, is developing a PMP for treating cystic fibrosis. This PMP, a gastric lipase, is produced in maize and has already been tested in experimental releases. It could be the first application in Europe for approval of a drug produced by GM plants. This PMP was awarded “orphan drug status” in 2003. This means the company is guaranteed market exclusivity for up to ten years if the drug is approved. Another PMP was awarded this status in 2003 in the USA.

The debate about the possible advantages of plants compared with other production systems focuses on the following: The production even of large volumes of pharmaceutical substances could be adapted to market requirements more flexibly and cost-effectively through field cultivation; contamination with human pathogens could be avoided; since protein structures change inside the production organism and could therefore have an impact on the desired characteristics of the substances produced, plant cells may be better suited for production because they are more similar to human cells than e.g. bacteria.

Biosafety challenge

Biosafety challengePlants that form modified substances and pharmaceuticals present completely new safety challenges. Unlike first-generation GM plants, which mainly produce substances to combat chewing insects or are resistant to certain herbicides, pharma plants are used specifically to produce substances that have an effect on humans or on higher animal species. They are also optimised in terms of yield, i.e. the amount of active substance they produce is many times that produced in previous GM plants, and several genetic modifications are often carried out at once, e.g. to make the plants sterile for safety reasons, which means that the likelihood of unforeseen impacts is all the greater.

In 2002 a discussion flared up in the USA about the risks of released pharma plants when remains of genetically modified maize plants were found in soya beans. The Texan biotech company ProdiGene, one of the leading companies in PMP development, had released genetically modified maize that produces trypsin, a protein found in the pancreas. Trypsin is used to produce insulin, among other things. When the trial ended, soya for human consumption was planted on the field. When the harvested soya beans were tested, maize remains were found. ProdiGene was forced to buy up the harvest of around 13,500 tonnes of soya beans worth two million dollars and destroy it and was also made to pay a fine.

The conflict surrounding trypsin maize highlighted the fact that PMP plants require special safety measures in order to keep them strictly separate from food and feed crops. As well as various measures to contain these plants physically or biologically, another way of reducing the risks would be to use non-food plants. However, at the moment maize, oilseed rape, rice and potatoes are still the plants of choice for many PMP projects in the USA.