Lundbeck Inc., the US subsidiary of the Danish pharmaceutical company H. Lundbeck A/S, launched this week ATryn (antithrombin recombinant), an anticoagulant used to prevent blood clots in patients with hereditary antithrombin deficiency, a rare blood-clotting disorder. Why is that noteworthy? ATryn is the first biologic product approved in the United States that is manufactured in a transgenic animal.

The US Food and Drug Administration approved ATryn in February 2009. The drug was developed and is manufactured by the biopharmaceutical company GTC Biotherapeutics. ATryn is made by processing the human antithrombin protein from the milk of a select herd of transgenic goats. The process for producing ATryn involves inserting DNA for the human antithrombin protein into a single-celled goat embryo. This embryo is implanted into a surrogate doe. The resulting transgenic offspring are able to produce high levels of human antithrombin in their milk. This protein is collected and purified from the milk to produce ATryn, which is administered to patients by intravenous infusion. A general guide for transgenic production is outlined here.

Purified recombinant antithrombin has the same amino-acid sequence as antithrombin derived from human plasma, outlines Lundbeck in a company press release. Antithrombin (recombinant) and plasma-derived antithrombin both contain six cysteine residues forming three disulfde bridges and 3–4 linked carbohydrate moieties. The glycosylation profile of ATryn is different from plasma-derived antithrombin, which results in an increased heparin affinity. When assayed in the presence of excess of heparin, the potency of the recombinant product is not different from that of the plasma-derived product, according to Lundbeck.

Transgenic animal production is a niche, but important tool in manufacturing proteins that would not otherwise be feasible to produce using more conventional technologies. In gaining marketing authorization for the drug, GTC Biotherapeutics, the manufacturer of ATryn, received approvals from two FDA centers. The Center for Biologics Evaluation and Research approved the human biologic based on its safety and efficacy, and the Center for Veterinary Medicine (CVM) approved the recombinant DNA (rDNA) construct in the goats that produce ATryn. As part of its review, CVM determined that introduction of the rDNA construct did not cause any adverse outcomes to the health of the goats over seven generations. CVM also determined that the manufacturer, GTC, has adequate procedures in place to ensure that food from these goats does not enter the food supply. As part of the approval, CVM specified that these goats cannot be used for food or feed and validated a method suitable for identifying the rDNA construct in both animals and their products. As required by the National Environmental Policy Act and its implementing regulations, CVM also determined that the genetically engineered goats do not cause any significant impact on the environment, according to FDA.

Making pharmaceuticals from transgenic animal production is likely to remain a niche technology, and the bioethical debate of creating and using genetically modified organisms will continue as well. But for the moment, we should step back and recognize a real accomplishment in pharmaceutical manufacturing.