For approximately 15 years, two different enzyme replacement therapy (ERT) preparations have been licensed in Europe to treat Fabry disease: agalsidase-alfa (Replagal, Shire) and agalsidase-beta (Fabrazyme, Sanofi Genzyme). In 40-70% of male patients with classical disease treatment is complicated by the formation of antibodies that inhibit the recombinant enzyme in vitro (inhibiting antidrug antibodies, iADAs). The vast majority of female Fabry patients do not develop ADAs since, due to the presence of residual endogenous enzyme, the immune system does not recognize the recombinant enzyme as foreign.
Background
The slow disease progression and heterogeneity of the disease makes it difficult to determine the clinical significance of the presence of iADAs in Fabry disease. iADAs have already been shown to reduce (lyso)Gb3 clearance, but a long term clinical follow up study with proper classification of patients into classical and non-classical disease, is still lacking. Furthermore, the exact timing of antibody formation, antibody subtypes and their exact relation to the biochemical response to treatment are only partially known.
Objectives of the study
To characterize the antibody response to recombinant αGAL in order to be able to predict in which patients a clinically significant antibody response will occur and guide potential measures to prevent the negative effect of this response by:
- Determining in which patients and in which timeframe ADAs develop and what type of antibodies are formed (IgM, IgA, IgG subclasses).
- Comparing the results of the antibody assays (measuring the presence of antibodies) to functional in vitro assays (measuring the inhibitory effect of antibodies on enzyme activity)
- Studying the effect of different types and titers of antibodies on treatment efficacy (biochemical response, clinical response)
- Mapping the epitopes on the recombinant enzyme against which the ADAs are targeted
- Identify which factors predict the formation of ADAs in treatment naïve patients
Methods
A retrospective study will be carried out in male patients with classical FD, treated with ERT. Before and at every 6-12 months during treatment the following data will be collected: lysoGB3 levels, iADAs Ig subtypes (measured by Elisa) and inhibitory titer. We will correlate the results to clinical data of these patients. To develop a prediction model for iADA development in naïve patients we will use machine learning. For epitope mapping we will generate a system producing different parts of the recombinant enzyme, followed by a read out system to asses which part of the enzyme is responsible for the immune response.
Inclusion and exclusion criteria
Inclusion
- Male patients with classical Fabry disease treated with enzyme replacement therapy
- Signed informed consent
Exclusion
- Female Fabry patients
- A non-classical disease phenotype
Study type
Single center. Retrospective cohort. Basic laboratory
Start date/expected completion
Start date: 09-2017
Expected completion: 09-2020
Contact
S.J. van der Veen, PhD student
M. Langeveld, principal investigator
Dept of Internal Medicine, div of Endocrinology and Metabolism, F5-169
Amsterdam University Centers, location AMC
Meibergdreef 9
1105 AZ Amsterdam
T 0031-20-5666071 E s.j.vanderveen@amc.uva.nl/m.langeveld@amc.uva.nl