The European Medicines Agency's (EMEA) decision back in February on recombinant human antithrombin-α, an anticoagulant developed by GTC Biotherapeutics, was eagerly awaited because the product, known as Atryn, if approved, would be the first drug produced in a transgenic farm animal to reach the market. In the event, the EMEA did not approve the product, but not because of any direct concerns about its animal origins. Atryn was rejected because GTC simply did not present enough appropriate data to allay EMEA's concerns about its immunogenicity.
GTC has been developing Atryn since 1993 principally for treating patients suffering from hereditary antithrombin deficiency, a rare condition affecting one person in every 3,000–5,000 that puts them at increased risk of deep vein thrombosis. Over the years, Atryn has been given to over 200 patients. But in its submission GTC only presented data on 14 patients. This exceeds the minimum requirement of 12 laid out in the EMEA guidelines, but the authorities disallowed all but five of the cases on the basis that GTC's dosing regimen across the group of 14 had not been constant. GTC will appeal the decision. Ultimately, it may seek approval instead in the United States, where the compound is now in three phase 3 trials.
That bare-bones 'not enough data' conclusion rather skirts round some of the underlying issues that transgenic protein producers have to face.
Recombinant proteins produced in animals typically have altered glycosylation patterns compared with native proteins. This doesn't necessarily influence their pharmacological properties, of course, but in the case of Atryn, it clearly did. Compared with the conventional antithrombin-α product, which is extracted from bovine plasma, Atryn's serum half-life was reduced seven- to tenfold, necessitating infusion of the protein rather than a one-off injection.
But one of EMEA's principle concerns with Atryn was its potential immunogenicity. GTC claims that it has not observed adverse immunogenicity in any of the 200 patients who have received Atryn. It will be important not only for GTC but also for other animal transgenics companies to allay the concerns of regulators on this matter. The problem is that it is pretty difficult for transgenics producers to produce 'nature-identical' proteins in milk. In cows and sheep and GTC's bioreactor of choice, the goat, the oligosaccharide decoration on proteins typically contains N-glycolylneuraminic acid (NGNA), a monomer virtually absent in native human proteins. Furthermore, the high concentrations of protein produced in milk—around a gram per liter—stretches the glycosylation capacity of the mammary gland to its limits. In fact, only in rabbits and chickens are the oligosaccharides more human-like (containing N-acetylneuraminic acid).
Thus, if immunogenicity of milk-produced proteins turns out to be a generic problem, then a whole class of transgenic production methods may turn out to have a limited future. Chicken milk, anyone?
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Transgenic milk prospects turn sour. Nat Biotechnol 24, 368 (2006). https://doi.org/10.1038/nbt0406-368b