Enzyme therapy for Fabry disease: neutralizing antibodies toward agalsidase alpha and beta.

Department of Internal Medicine/Clinical Hematology, Academic Medical Center, Amsterdam, The Netherlands.
Kidney International (Impact Factor: 8.52). 10/2004; 66(4):1589-95. DOI: 10.1111/j.1523-1755.2004.00924.x
Source: PubMed

ABSTRACT Fabry disease is an X-linked inherited disorder that is caused by excessive lysosomal globotriaosylceramide (CTH) storage due to a deficiency in alpha-galactosidase A (alpha-Gal A). Two recombinant enzyme preparations have been approved as treatment modality. We studied emergence and properties of alpha-Gal A antibodies in treated patients.
During the first 6 to 12 months of intravenous administration of recombinant enzymes (rh-alpha-Gal A) formation of antibodies was studied in 18 adult Fabry patients (two females).
The female patients did not develop detectable amounts of antibodies following enzyme therapy. After 6 months of treatment with either agalsidase alpha or beta, 11/16 male patients showed high titers of immunoglobulin G (IgG) antibodies that cross-react in vitro similarly with both recombinant enzymes. The anti-rh-alpha-Gal A IgG neutralizes rh-alpha-Gal A activity in vitro for 65% to 95%. During infusion with rh-alpha-Gal A, circulating enzyme-antibody complexes are formed and these complexes are taken up by leukocytes in the peripheral blood. After 6 months of treatment all IgG-negative patients showed a significant (P < 0.01) reduction of urinary CTH (1890 +/- 797 to 603 +/- 291 nmol CTH/24hr urine), compared to IgG-positive patients (mean increase from 2535 +/- 988 to 2723 +/- 1212), suggesting a negative effect of circulating antibodies on renal tubular CTH clearance.
Emergence of antibodies with in vivo neutralizing capacities is frequently encountered in treated Fabry disease patients. Complete cross-reactivity of these antibodies suggests that it is unlikely that switching from one to the other recombinant protein prevents the immune response and related effects. Further studies on the clinical implications of alpha-Gal A antibodies are essential.

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    ABSTRACT: Anderson-Fabry disease (AFD) is a rare, X-linked lysosomal storage disorder that leads to accumulation of globotriasylceramide throughout the body. The disease usually presents in childhood, is progressive and results in increasing disability and premature death. Female carriers tend to be less severely affected. Treatment used to be entirely symptomatic, but the advent of enzyme replacement therapy has made it necessary to have explicit guidelines for the diagnosis, assessment, treatment and follow up of patients and families.
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    ABSTRACT: Background Management of Anderson–Fabry disease (AFD) is contentious, particularly regarding enzyme replacement therapy (ERT). We report results of a Delphi consensus panel on AFD management. Methods A survey to gauge consensus among AFD experts was distributed online and responses were analysed. Statements on: 1) diagnosis; 2) when starting ERT; 3) management of ERT infusion and adverse reactions; and 4) follow-up/monitoring response to therapy and progression of disease were included. Responses without consensus were discussed with an enlarged panel and modified to reach consensus. Results 15 experts responded to the survey. After plenary discussion among the enlarged panel, consensus was reached on most statements. Key points were the use of a target organ biopsy to show Gb3 deposits in symptomatic women with negative molecular analysis, the need for ERT in symptomatic women and in all patients with persistent signs and symptoms ± organ damage. It was agreed to assess vital signs before ERT administration and use a 0.2 μL filter on infusion to reduce the risk of adverse reactions, that serum should be drawn prior to the first infusion for anti-agalsidase antibody analysis to have a baseline value if a subsequent adverse reaction appears, and that pre-medication is required in those with prior infusion reactions. Holter ECG monitoring, cardiac and brain MRI, renal parameters, and abdominal ultrasound were considered important for the assessment of disease progression and response at ERT. Conclusions This consensus supplies guidance to healthcare providers on best practice in the management of patients with AFD and indicates a need for more guidance.
    European Journal of Internal Medicine 08/2014; 25(8). DOI:10.1016/j.ejim.2014.07.009 · 2.30 Impact Factor
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    ABSTRACT: Fabry disease is an X-linked inborn error of glycolipid metabolism caused by deficiency of the human lysosomal enzyme, α-galactosidase A (αGal), leading to strokes, myocardial infarctions, and terminal renal failure, often leading to death in the fourth or fifth decade of life. The enzyme is responsible for the hydrolysis of terminal α-galactoside linkages in various glycolipids. Enzyme replacement therapy (ERT) has been approved for the treatment of Fabry disease, but adverse reactions, including immune reactions, make it desirable to generate improved methods for ERT. One approach to circumvent these adverse reactions is the development of derivatives of the enzyme with more activity per mg. It was previously reported that carboxyl-terminal deletions of 2 to 10 amino acids led to increased activity of about 2 to 6-fold. However, this data was qualitative or semi-quantitative and relied on comparison of the amounts of mRNA present in Northern blots with αGal enzyme activity using a transient expression system in COS-1 cells. Here we follow up on this report by constructing and purifying mutant enzymes with deletions of 2, 4, 6, 8, and 10 C-terminal amino acids (Δ2, Δ4, Δ6, Δ8, Δ10) for unambiguous quantitative enzyme assays. The results reported here show that the kcat/Km approximately doubles with deletions of 2, 4, 6 and 10 amino acids (0.8 to 1.7-fold effect) while a deletion of 8 amino acids decreases the kcat/Km (7.2-fold effect). These results indicate that the mutated enzymes with increased activity constructed here would be expected to have a greater therapeutic effect on a per mg basis, and could therefore reduce the likelihood of adverse infusion related reactions in Fabry patients receiving ERT treatment. These results also illustrate the principle that in vitro mutagenesis can be used to generate αGal derivatives with improved enzyme activity.
    PLoS ONE 01/2015; 10(2):e0118341. DOI:10.1371/journal.pone.0118341 · 3.53 Impact Factor

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