PMC:2495071 / 31421-33446 JSONTXT

{"project":"2_test","denotations":[{"id":"18656179-17884403-2045970","span":{"begin":208,"end":210},"obj":"17884403"},{"id":"18656179-12501870-2045971","span":{"begin":510,"end":512},"obj":"12501870"},{"id":"18656179-17337334-2045972","span":{"begin":846,"end":848},"obj":"17337334"},{"id":"18656179-15283985-2045973","span":{"begin":968,"end":970},"obj":"15283985"},{"id":"18656179-8124728-2045974","span":{"begin":1133,"end":1135},"obj":"8124728"},{"id":"18656179-12119747-2045974","span":{"begin":1133,"end":1135},"obj":"12119747"},{"id":"18656179-15958824-2045974","span":{"begin":1133,"end":1135},"obj":"15958824"}],"text":"As of December, 2006, 65 new biopharmaceuticals had been approved in the U.S., European Union, and Japan since 1999. Like IFN-β, 47 of these new biopharmaceuticals are derived from recombinant DNA technology.22 Applications range from the treatment of more prevalent rheumatic diseases (Ethanercept) to rare acquired or inherited disease with protein deficiencies (Galsulfase). It is predicted that many more therapeutic proteins will become available in the near future for an even wider range of indications.10 Despite their therapeutic potential, immunogenicity is a common problem to most, if not all, protein-based biopharmaceuticals and an important aspect of their safety. Antibodies might not only lead to the loss of drug efficacy but may also induce severe allergic reactions or neutralize the activity of endogenously produced protein.23 It has been argued that in the absence of resilient predictors of immunogenicity, patients might be put at a high risk.24 Preparation, handling, packaging, dose, frequency, and route of administration and treatment duration seem to affect immunogenicity of biopharmaceuticals.25, 26, 27 However, the role of genetic factors in immunogenicity to protein-based therapeutics has not been addressed. In the present study we show that—besides the influence of different preparations on immunogenicity—genetic factors play an important role in the development of antibodies against protein therapeutics. Patients who carry the HLA-DRB1∗0401 or HLA-DRB1∗0408 allele show a 5- and 14-fold increased risk to develop antibodies to IFN-β, respectively. This results in an average relative risk of 2.07 for DRB∗0401- and DRB∗0408-positive patients. Although the HLA-DRB1∗0401 or HLA-DRB1∗0408 alleles increase the risk of developing antibodies in response to all IFN-β formulations, it remains to be determined, in further studies and with a different study design, whether formulations with higher immunogenicity are more affected by the HLA haplotype than those with low immunogenicity."}