CLERMONT-FERRAND and NANTES, France - A growing number of biotech companies are developing technologies for extracting therapeutic proteins from genetically modified plants and animals in preference to the manufacture of synthetic compounds.

In Clermont-Ferrand, the capital of the strongly agricultural Auvergne region in central France, Meristem Therapeutics extracts recombinant proteins from transgenic plants, while in Nantes, on France's Atlantic seaboard, Vivalis is obtaining the same kinds of proteins from transgenic animals, and could also use transgenic plants in the future.

Meristem is a spin-off from a major seed company based in the Clermont-Ferrand area, Limagrain, and has invented its own sobriquet to describe its technology, "molecular pharming." According to Chairman Bertrand Mirot, it was a question of "putting plants back at the heart of pharmaceutical development, with the focus on recombinant proteins." He said the world market for therapeutic recombinant proteins was some $18 billion to $20 billion. "Molecular pharming is a technological alternative" that had the advantage of permitting the unlimited production of complex proteins at very low cost, said Mirot, stressing that there was no risk of plant viruses being transmitted to humans.

Meristem is concentrating on therapeutic enzymes, anti-infective proteins and blood-derived proteins to target digestive and respiratory diseases, among others. Limagrain has already demonstrated the viability of cultivating genetically modified tobacco to produce synthetic human hemoglobin and gastric lipase (used to treat digestive problems related to cystic fibrosis), and Mirot said Meristem's first clinical trials would be of gastric lipase in the primary indication of cystic fibrosis, starting this year.

Meristem plans to confine itself to the industrial phase of the drug development process, from the insertion of the gene in the plant to the production of the therapeutic protein. It will then license these proteins out to pharmaceutical companies, which will take them into clinical development. It has so far developed more than 10 proteins in different types of plants.

The company has established an industrial extraction/purification plant complying with GMP standards for purifying kilograms of pharmaceutical-grade recombinant protein from plants. Its facilities also include 3,000 square meters of laboratory space and 550 square meters of greenhouse, in which it cultivates genetically modified versions of tobacco and corn. Tobacco is useful for research purposes but is not suitable for mass production, as it does not yield sufficient quantities of proteins, unlike corn or oil seed rape.

Limagrain remains the largest shareholder in Meristem, but when the company was spun off in 1998 it raised additional funding from four venture capitalists - Banexi (lead investor), 3i, and two regional funds, Sofipar and Sofimac. The company says it will seek a stock market listing "when the time seems appropriate, in three to five years." Its current funding will enable it to establish full-scale production facilities and achieve its medium-term objective of bringing its first protein to market through a pharmaceutical partner, between 2003 and 2005.

Vivalis Focuses On Use Of Transgenic Animals

Nantes-based Vivalis is a more recent start-up, set up in April 1999 with the technical support of the local university hospital. Using transgenic animals, it cultivates cells in the egg and in milk, from which it extracts recombinant proteins with therapeutic potential.

It was established by Groupe Grimaud, a local company specialized in genetic selection, together with three public research establishments that provided Vivalis with its core technology and remain its only other shareholders. They are the French Scientific Research Center (CNRS - Centre National de Recherche Scientifique), the National Agronomic Research Institute (INRA - Institut National de la Recherche Agronomique) and the Ecole Nationale Supirieure of Lyon, and they have granted Vivalis an exclusive worldwide license to the cell cultivation technology they developed between them. That technology entails cultivating embryonic strain cell lines into which human genes are inserted coding for a particular protein that expresses itself naturally in the egg.

The managing director of Vivalis, Franck Grimaud, said he expected to be asked to supply active compounds throughout the drug development cycle. He pointed out that the market for drugs incorporating recombinant proteins was well over $12 billion a year and that there were more than 170 proteins in clinical development. Within that market, the production of active proteins is a $2 billion-plus business.

The company's research and development program calls for spending of FFr30 million (US$4.6 million) over the first six years. As well as a laboratory in the Nantes university hospital complex, the company has established a large animal house outside the city.