Fabry disease, enzyme replacement therapy and the significance of antibody responses
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Fabry disease is an X-linked disorder caused by a deficiency of α-galactosidase A. This leads to a progressive accumulation of globotriaosylceramide in tissues throughout the body. Cardiac, renal and neurological manifestations are common and life expectancy is significantly reduced relative to the general population. Management of Fabry disease involves the administration of intravenous enzyme replacement therapy (ERT). Two forms – agalsidase alfa and agalsidase beta – have been licensed in certain jurisdictions and are generally well tolerated; however, some patients develop antibodies to the infused enzyme, which may impair the efficacy and safety of treatment. Agalsidase alfa and agalsidase beta are produced in different systems; this leads to certain differences in post-translational modification that may affect immunogenicity. Immunoglobulin (Ig) G antibodies have frequently been reported in patients with Fabry disease receiving ERT; IgG responses are reported in a greater proportion of patients receiving agalsidase beta than in patients receiving agalsidase alfa. IgE antibodies are less common than IgG antibodies, and have not been observed in patients receiving agalsidase alfa. However, these data are difficult to interpret due to methodological differences in the assessment of seropositivity, and in the doses of enzyme used. The clinical impact of the development of IgG antibodies to ERT in patients with Fabry disease remains unclear, due to lack of data and to the marked heterogeneity of patients both in terms of disease manifestations and response to therapy. Further studies that examine the development of antibodies in patients with Fabry disease and the potential impact of such antibodies on the outcome of ERT are necessary.
KeywordsEnzyme Replacement Therapy Fabry Disease Gauche Disease Antibody Formation Lysosomal Storage Disorder
The author would like to thank Dr Rainer Döffinger for his advice regarding immunological perspectives.
Medical writing support to the author during the preparation of the manuscript was provided by Harriet Crofts, PhD, of Oxford PharmaGenesis Ltd and was sponsored by Shire Human Genetic Therapies, Inc. (Shire HGT). The sponsor had no influence on the contents or direction of the manuscript. The author takes full responsibility for the content of the paper.
Conflict of interest
Dr Patrick Deegan has been an investigator in clinical trials sponsored by Shire, Genzyme, Actelion, Protalix and Amicus and has received travel support for meeting attendance from each company. He has also received laboratory research grants from Shire and Genzyme and speaker honoraria from Shire, Genzyme and Actelion.
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