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Editor's note: We're posting this story from our September 2006 issue because of recent FDA action on ATryn.
Proteins are biotechnology’s raw crude. For much of its 30-year history, the industry has struggled to come up with a steady source of supply, squeezing the maximum out of these large-molecule commodities from cell lines isolated from hamster ovaries and the like. In the late 1990s—with the advent of a new class of protein-based drugs, monoclonal antibodies—demand sometimes outstripped supply. For decades, the scientists who created recombinant erythropoietin to rejuvenate red blood cells and monoclonal antibodies to combat cancer have sought out alternative forms of manufacture.
A new bioreactor—an animal genetically engineered to produce a therapeutic protein in its milk—may finally be ready to fulfill its long-awaited promise. The European Medicines Evaluation Agency (EMEA) may decide early next year on approval of an anticoagulant protein, human antithrombin, that is produced in goat’s milk to treat a hereditary disorder. If the drug, ATryn, finally gets a nod from regulators, its approval will mark the culmination of a meandering 15-year journey for GTC Bio therapeutics, a Framingham, Mass., spin-off of the biotech giant Genzyme.
The idea of making transgenic drugs occurred to a number of scientists during the mid-1980s, when the new industry began to wrestle with the challenge of making complex proteins: ensuring that these big molecules were folded into the proper shape and that they had all their sugars in the right places on the surface of the proteins’ amino acids. Chinese hamster ovary cells do the job, but getting enough product has been a constant frustration and one reason why biotech drugs today cost so much. In addition, mammalian cell cultures are not always an ideal medium: at times, it is simply too hard to produce proteins in this manner.
In their quest for greater efficiencies, researchers noticed that the mammary glands of cows, rabbits and goats, among others, are capable of becoming ideal protein manufacturing plants because of their ability to make high volumes of complex proteins. Milk glands, moreover, do not need the constant coddling required for cell cultures. Genzyme got involved after its purchase in 1989 of Integrated Genetics, which had a portfolio of drugs and diagnostics products. To head up its program, Genzyme recruited one of the pioneers in this technology from another company, Biogen. Harry Meade, along with Nils Lonberg, had patented a method of extracting therapeutic proteins from mice.
In the early 1990s Genzyme’s program was targeted at producing drugs in goat’s milk. Genzyme, though, was not focusing on transgenics and decided to spin off its operation into a separate entity, Genzyme Transgenics (later renamed GTC Biotherapeutics), in which the parent still holds an equity interest. The new company could thus produce its drugs for other firms without the inevitable conflicts of interest that would have arisen had it remained within the bosom of a large drugmaker.
Goats as Drug Factories Initially, GTC generated transgenic goats by microinjecting into the developing nucleus of a one-cell embryo a gene encoding the desired human protein (along with DNA that promotes activation of that gene in milk). Such embryos were transferred into female goats, which produced offspring that were then tested for the presence of the newly integrated gene. The milk of these “founder” animals contains the therapeutic protein, which must then undergo a purification process. The mature transgenic animals were bred usually with nontransgenic goats as a first step toward producing a herd. Microinjection, however, is an inefficient process. Only 1 to 5 percent of the embryos result in transgenic animals. For newer drugs in its portfolio, GTC has adopted somatic cell nuclear transfer, a.k.a. cloning, which ensures that an animal will carry the desired transgene. Dolly the sheep was cloned, in fact, with the intention of eventually using this procedure to create transgenic animals having useful properties, not as a means to make carbon copies of baseball legend Ted Williams or a favorite dead pet.