Managed Care - March 2009 - (Page 46) TOMORROW’S MEDICINE Transgenic Goats Are Key To Antithrombin Production With their high milk production and short generational time, these bovids are ideal bioreactors able to dramatically increase the protein yield Thomas Morrow, MD S anofi-Aventis CEO Chris Viehbacher told the Financial Times that his company had “missed the boat” when it comes to diversifying into biologics. He expressed his realization that biologic drugs have revolutionized the pharmaceutical industry. But the biotech industry has just had a development that may be even more revolutionary. The purest definition of a biologic drug is one that is derived from a living organism or cell. Their manufacture requires a large cell culture, the extraction of the active ingredient from the media or cell, and its purification in a facility called a bioreactor. Three different protein production techniques have been the mainstay of manufacturing in the United States. These methods require large capital outlays to build the facility to grow the tissue cultures — think brewery-size vats — and result in relatively low yields. Transgenic animals Transgenic animals were first developed in 1985 and were useful in the production of biopharmaceuticals shortly thereafter. The ideal transgenic animal produces plenty of milk, and has relatively short generation times. Typically, dairy animals are used because of their high volume of milk production. Goats have been selected for a number of reasons, the chief of which is the short generational time of 18 months. Goats produce about 800 liters of milk per year. Using goats has been shown to dramatically increase the yield of the active protein by more than 10 times that from the cell culture model. An initial “founder” transgenic animal is created by first injecting an engineered segment of Thomas Morrow, MD, is the immediate past president of the National Association of Managed Care Physicians. He has 24 years of managed care experience at the payer or health plan level. DNA into the pronucleus of a one-cell embryo. This DNA segment contains a mammaryspecific promoter sequence that codes for the protein of interest and the regulatory DNA that tells the cell how to manufacture the protein. The embryo is then transferred into a surrogate female animal, resulting in a transgenic offspring. If, after maturing and being induced to produce milk, the animal expresses the desired protein in the milk in sufficient quantity and quality, it can be included in the producing pool of animals. The key to this method of drug development is the use of the mammary gland. The major function of the mammary gland is to produce a solution that is loaded with a variety of proteins. Some of the proteins that can be created in milk are difficult or impossible to create in tissue culture-based bioreactors. Also, the mammary gland is capable of processing completed proteins through glycosylation and gamma carboxylation, functions that occur after translation of the DNA into proteins. Transgenically produced proteins are isolated from milk in a multistep process that includes methods normally used by cell culture bioreactors as well as processes adapted from the dairy industry. The resulting proteins are held to the same standards as any other recombinant protein. Obviously safety concerns have been addressed: All goats are certified to be free of scrapie by the United States Department of Agriculture, the farm is inspected by the FDA, and the goats receive superb medical care. Hereditary antithrombin deficiency On Feb. 9, the FDA approved ATryn, recombinant antithrombin manufactured by GTC Biotherapeutics in Massachusetts. While the approval of this agent may not be particularly revolutionary (human-derived antithrombin 46 MANAGED CARE / MARCH 2009
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