GTC Biotherapeutics

A goat at GTC Biotherapeutics’ farm.

The New York Times, February 8, 2009, by Andrew Pollack — The 21st Century opens onto a new era in farming and pharmaceuticals, the Food and Drug Administration on Friday approved the first drug produced by livestock that have been given a human gene.

The drug, meant to prevent fatal blood clots in people with a rare condition, is a human protein extracted from the milk of genetically engineered goats.

At the same time, the F.D.A. also approved the goats used to make the drug, the first such animals cleared under guidelines the agency adopted only last month to regulate the use of transgenic animals in the nation’s drug and food supply.

Made by a company called GTC Biotherapeutics, the human anticlotting protein is produced by a herd of 200 bioengineered goats living under carefully controlled conditions on a farm in central Massachusetts.

Proponents say such “pharm animals” could become a means of producing biotechnology drugs at lower cost or in greater quantities than the existing methods — which include extracting proteins from donated human blood or growing them in large steel vats of genetically engineered cells.

The protein in the goat milk, antithrombin, is sometimes in short supply or unavailable for pharmaceutical use because of a shortage of human plasma donations. GTC Biotherapeutics said one of its goats can produce as much antithrombin in a year as can be derived from 90,000 blood donations. And if more drug is needed, the herd can be expanded.

“If you need more, you breed more,” said Thomas Newberry, a spokesman for GTC, which is based in Framingham, Mass.

Drugs have been derived from animals before, of course. Most insulin used by people with diabetes formerly came from pigs or cows. Genetically engineered mice are now used to develop some drug ingredients. But this is the first drug from a herd of genetically engineered animals created specifically to serve as living pharmaceutical factories.

Turning animals into walking drug producers does not sit well with some environmental advocates and animal rights activists.

“It is a mechanistic use of animals that seems to perpetuate the notion of their being merely tools for human use rather than sentient creatures,” the Humane Society of the United States says in its position paper on the practice.

There are other concerns: that the animals could be harmed, that animal germs might contaminate the drug, that the milk or meat from genetically engineered drug-producing animals might enter the food supply or that the animals might escape and breed with others, spreading the gene, with unpredictable consequences.

But the F.D.A. approval could now encourage drug makers to consider this type of production.

The F.D.A.’s move “really takes away one of the biggest issues that have always been on the table, which is how do regulatory agencies view this kind of technology,” said Samir Singh, president of the American operations of Pharming, another company using such technology.

Pharming, which is based in the Netherlands, plans to apply this year for approval of a drug, produced in the milk of transgenic rabbits, to treat hereditary angioedema, a protein deficiency that can lead to dangerous swelling of tissues.

Another company, PharmAthene, is developing a treatment for nerve gas poisoning in the milk of transgenic goats.

Still, it could be difficult to persuade established manufacturers to depart from their existing methods, which have improved markedly since GTC first began its work.

“I think we have very good ways of making therapeutic proteins today,” said Norbert Riedel, chief scientific officer at Baxter International, which makes proteins both from human plasma and in cell cultures grown in huge steel tanks.

Sales of the GTC drug, called ATryn, are expected to be modest, judging from the small sales so far in Europe, where the drug was approved in 2006.

ATryn will be sold in the United States by Ovation Pharmaceuticals, which said it had not yet set the price.

GTC’s stock, which was below 11 cents in mid-December, had risen recently on expectation of the F.D.A. approval. It traded above 90 cents a share earlier this week. On Friday, as investors evidently sold on the news, it fell more than 14 percent, closing at 70 cents.

The drug was approved to prevent blood clots in people born with a rare hereditary deficiency of antithrombin while they undergo surgery or childbirth. At other times such people can reduce their clotting risks by taking blood thinners like warfarin, but during surgery or childbirth blood thinners are typically avoided because of the risk of excessive bleeding.

To make its protein, GTC took the human gene for antithrombin and linked it to goat DNA that normally controls production of a protein found in milk. That ensured that the antithrombin would be produced only in the milk.

The gene was injected into a one-celled goat embryo, which was then implanted into the womb of a surrogate mother. After a goat was born that produced the protein in its milk, the herd was expanded by conventional breeding.

Many of the newer protein-based drugs, like the cancer drug Avastin and the arthritis drug Enbrel, are produced in genetically engineered Chinese hamster ovary cells that are grown in big stainless steel vats. But a cell culture factory can cost hundreds of millions of dollars to build. Using livestock shrinks the investment to tens of millions of dollars, said Geoffrey Cox, GTC’s chief executive.

GTC executives say the animal technology might be best suited to making proteins that cannot be produced well in cell cultures. Antithrombin, the protein in ATryn, is one such drug. Some other drugs require huge volumes that are impractical to achieve with cells.

Production in animal milk might also appeal to new companies hoping to make lower-priced copycat versions of biotechnology drugs, if the regulatory procedures are eventually adopted for approving generic versions of such drugs.

GTC itself is planning to make a copycat version of Rituxan, a cancer and arthritis drug sold by Biogen Idec and Genentech. It is also planning to make clotting factors for hemophilia treatment.

One risk of using animals is that drug production can be lost if a disease wipes out the herd. Mr. Newberry, the GTC spokesman, said the goats were fully vaccinated. Access to them by people is controlled and there is a double fence around the farm to keep out wildlife.

Mr. Newberry said that none of the goats in the herd, including nontransgenic ones used as surrogate mothers, would be allowed in the food supply. Nor will any of the milk.

The F.D.A. said it was confident that products from the goats would not enter the food supply or harm the environment. “There were no novel or controversial issues” with the goats, Bernadette Dunham, director of the agency’s Center for Veterinary Medicine, said Friday.

But Gregory Jaffe of the Center for Science in the Public Interest, a Washington consumer group, called for assurances that the milk or meat would be safe if it did inadvertently enter the food supply.

“Humans are fallible; accidents happen,” he said.

Target Health Inc. is involved with similar cutting edge biogenetic engineering research, through one client, Protalix Biotherapeutics and their ProCellEx products.

Read about Protalix Biotherapeutics


Protalix Biotherapeutics is a biopharmaceutical company focused on the development and commercialization of recombinant therapeutic proteins based on our proprietary ProCellEx™ protein expression system. Using our ProCellEx™ system we are developing a pipeline of proprietary recombinant therapeutic proteins based on our plant cell-based expression technology that target large, established pharmaceutical markets and that rely upon known biological mechanisms of action. Our initial commercial focus has been on complex therapeutic proteins, including proteins for the treatment of genetic disorders, such as Gaucher disease and Fabry disease. We believe our ProCellEx™ protein expression system will enable us to develop proprietary recombinant proteins that are therapeutically equivalent or superior to existing recombinant proteins currently marketed for the same indications. Because we are targeting biologically equivalent versions (“Biosimilar versions”) of highly active, well-tolerated and commercially successful therapeutic proteins, we believe our development process is associated with relatively less risk compared to other biopharmaceutical development processes for novel therapeutic proteins.

ProCellEx™ Overview:

ProCellEx™ is our proprietary production system that we have developed based on our plant cell culture technology for the development, expression and manufacture of recombinant proteins. Our expression system consists of a comprehensive set of capabilities and proprietary technologies, including advanced genetic engineering and plant cell culture technology, which enables us to produce complex, proprietary and biologically equivalent proteins for a variety of human diseases. Our protein expression system facilitates the creation and selection of high expressing, genetically stable cell lines capable of expressing recombinant proteins. The entire protein expression process, from initial nucleotide cloning to large-scale production of the protein product, occurs under cGMP-compliant, controlled processes. Our plant cell culture technology uses plant cells, such as carrot and tobacco cells, which undergo advanced genetic engineering and are grown on an industrial scale in a flexible bioreactor system. Cell growth, from scale up through large-scale production, takes place in flexible, sterile, polyethylene bioreactors which are confined to a clean-room environment. Our bioreactors are well-suited for plant cell growth using a simple, inexpensive, chemically-defined growth medium as a catalyst for growth. The reactors are custom-designed and optimized for plant cell cultures, easy to use, entail low initial capital investment, are rapidly scalable at a low cost and require less hands-on maintenance between cycles. Our protein expression system does not involve mammalian or animal components or transgenic field-grown, whole plants at any point in the production process.

Our ProCellEx™ system is capable of producing proteins with an amino acid structure practically equivalent to that of the desired human protein, and with a very similar, although not identical, glycan, or sugar, structure. Our internal research and external laboratory studies have demonstrated that ProCellEx™ is capable of producing recombinant proteins that exhibit a glycan and amino acid structure similar to their naturally-produced human counterparts. In addition, proteins produced by our ProCellEx™ system maintain the biological activity that characterizes the biological activity of naturally-produced proteins. In collaboration with Israel’s Weizmann Institute of Science, we have demonstrated that the three-dimensional structure of a protein expressed in our proprietary plant cell-based expression system retains the same three-dimensional structure as exhibited by the mammalian cell-based expressed version of the same protein (Shaaltiel et al, Plant Biotechnology J. 2007). Based on these results, we believe that proteins developed using our ProCellEx™ protein expression system have the intended composition and correct biological activity of their human equivalent proteins.

Platform Technology:

Protalix’s novel bioreactor plant cell system, based on disposable plastic vials, is the first of its kind. The closed system provides stable, optimized conditions, with manufacturing capabilities for the entire range of proteins, including antibodies, complex enzymes, and plant-derived pharmaceuticals.

Plant cell cultures are grown on aqueous media consisting of highly purified water and defined inorganic nutrients in a completely closed and controlled environment. Protalix’s patented bioreactor system utilizes sterilized, large flexible plastic containers for culturing and harvesting cells in consecutive cycles, with a central unit providing oxygen and nutrients. The vials have been designed to allow for the removal of excess air and waste gases, as well as the introduction of inoculants and culture media.

The entire process is conducted in a GMP (Good Manufacturing Practice)-approved production suite with optimized temperature, lighting, air and nutrient supplies. Because all components of the system are fixed, purification techniques for each specific protein are highly efficient.

Protein Production:

Plant-based recombinant protein production systems offer distinct advantages over mammalian cell culture systems:

Cost-Effective Protein Production

Plant-based systems are capable of producing high quantities of complex proteins at a dramatically lower cost than mammalian cell culture systems. Such plant-based systems offer greater scalability than alternative systems and almost unlimited capacity, while incurring relatively small increases in cost as production ramps.


There are no known risks of contamination from animal, bacterial, or viral pathogens in a plant-based system.

Protein Assembly & Post-Translation Modifications

In contrast to bacterial fermentation techniques, plant-based systems are able to maintain antibody assembly and function. In addition, they are capable of carrying out a number of post-translation modifications, such as glycosilation, in a manner similar to that performed in the human body. This enables the production of more complex proteins such as those used for human therapeutics.

Range of Expression

Plant-based systems are capable of expressing unique antibody subtypes and other proteins not expressed in mammalian cell culture system. We have been successful in expressing proteins that have yet to be successfully expressed in any other production systems.

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