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: 8.56). 10/2004; 66(4):1589-95. DOI: 10.1111/j.1523-1755.2004.00924.x
Source: PubMed


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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Available from: Carla E Hollak, May 30, 2014
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    • "This patient had experienced an allergic reaction to agalsidase-β, which took the form of allergic rhinitis during administration of the infusion, but he did not develop an infusion-related reaction to agalsidase-α. Crossreactivity against agalsidase-α and -β has been observed for IgG antibodies28; however, an IgE antibody response has only been reported for agalsidase-β, and so IgE crossreactivity has not been reported to date.29 A switch to agalsidase-α may be appropriate for some patients who experience an infusion-related allergic reaction to agalsidase-β. "
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    ABSTRACT: Background:Between 2009 and 2012, there was a worldwide shortage of agalsidase-β for the treatment of Fabry disease. Therefore, alternative treatments were needed, including switching to a different enzyme-replacement therapy.Purpose:This is an ongoing observational study assessing the effects of switching from agalsidase-β (1.0 mg/kg every other week) to agalsidase-α (0.2 mg/kg every other week) in 11 patients with Fabry disease.Methods:Clinical data were collected for 5 years-2 years before switching and 3 years after switching.Results:Measures of renal function such as estimated glomerular filtration rate remained stable during the 3 years after switching to agalsidase-α. Improvements in cardiac mass were recorded in both male and female patients 12 months after switching to agalsidase-α, and the benefit was maintained during 36 months of follow-up. There was no significant difference in the severity of pain experienced by patients before and after switching enzyme-replacement therapy, and no difference in quality-of-life parameters. Agalsidase-α was generally well tolerated, and no patients experienced allergy or developed antibodies to agalsidase-α.Conclusion:This observational study supports the safety of switching from agalsidase-β to agalsidase-α at the approved doses, with no loss of efficacy. It also suggests that if an infusion-related allergic reaction occurs in a patient receiving agalsidase-β, switching to agalsidase-α may be a viable option.Genet Med advance online publication 20 March 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.28.
    Genetics in medicine: official journal of the American College of Medical Genetics 03/2014; 16(10). DOI:10.1038/gim.2014.28 · 7.33 Impact Factor
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    • "However, underpowered studies for rare diseases are justified and ethical in that they allow clinical data to be amassed over time and these data can then be consolidated in meta-analyses, thereby increasing the power and strength of the findings and adding to the clinical evidence base. Development of neutralizing IgG or IgE antibodies to agalsidase alfa or agalsidase beta were not determined in this study, although switching treatments is not expected to prevent IgG antibody formation or related adverse effects because of complete cross reactivity (Linthorst et al. 2004). Nevertheless, our study is the first MRI study reporting positive long-term effects of switching therapy ERT on cardiac performance in patients with Anderson-Fabry disease. "
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    ABSTRACT: Anderson-Fabry disease (AFD) is a multiorgan X-linked lysosomal storage disease that particularly affects the heart, kidneys, and cerebrovascular system. Current treatment is enzyme replacement therapy (ERT) with agalsidase beta (Fabrazyme(®), Genzyme Corporation, Cambridge, MA, USA) or agalsidase alfa (Replagal(®), Shire Human Genetic Therapies AB, Lund, Sweden). It was recommended that patients switch to agalsidase alfa due to a manufacturing shortage of agalsidase beta beginning in June 2009. This study assessed the effect of switching to agalsidase alfa on clinical outcomes in patients with AFD previously treated with agalsidase beta. Ten patients (seven male, three female) with genetically confirmed AFD and at least 48 months' continuous data collected during treatment with agalsidase beta 1 mg/kg every other week were switched to agalsidase alfa 0.2 mg/kg every other week for at least 20 months, with prospective clinical evaluations every 6 months. Pre-switch data was collected retrospectively from patient charts. Cardiac functional parameters were assessed using magnetic resonance imaging. Results showed that renal function was normal (estimated glomerular filtration rate ≥90 mL/min/1.73 m(2)) in 8 of 10 patients prior to agalsidase alfa and generally remained stable after the switch. Cardiac mass decreased significantly (p < 0.05 vs pre-ERT) after agalsidase beta and remained unchanged after switching to agalsidase alfa. Symptoms of pain and health status scores did not deteriorate during agalsidase alfa therapy. Adverse events were mostly mild and infusion related. In conclusion, switching to agalsidase alfa was relatively well tolerated and associated with stable clinical status and preserved renal and cardiac function.
    02/2013; 9:41-8. DOI:10.1007/8904_2012_177
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    • "The development of neutralizing antibodies is a consideration with respect to recombinant proteins such as agalsidase alfa and agalsidase beta. Cross-reactivity of IgG antibodies has been observed against agalsidase alfa and agalsidase beta in patients with Fabry disease.21 However, the IgE antibody response to ERT, and possible cross-reactivity of IgE antibodies to agalsidase alfa and agalsidase beta, does not appear to have been reported. "
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    ABSTRACT: Purpose: Fabry disease is a rare, X-linked, inherited lysosomal storage disorder that can be treated with the enzymes agalsidase alfa (Replagal) and agalsidase beta (Fabrazyme). Currently, there is a global shortage of agalsidase beta, and this has increased global demand for agalsidase alfa. We assess the feasibility of switching patients on agalsidase beta treatment to agalsidase alfa instead. Methods: This analysis is part of an ongoing observational study involving 11 patients with Fabry disease in whom the treatment was switched from agalsidase beta (1 mg/kg every other week) to agalsidase alfa (0.2 mg/kg every other week). Data were collected for a minimum of 36 months: 24 months before and 12 months after the switch. Serial data were evaluated with respect to renal function, cardiac mass, pain, quality of life, and tolerability/safety. Results: Indexes of renal function (estimated glomerular filtration rate) and cardiac mass (left-ventricular mass index), pain (Brief Pain Inventory), and quality of life (EuroQoL-Dimensions) clearly showed that, in patients switched to agalsidase alfa, Fabry disease stabilized during the 12 months of follow-up. Conclusion: Despite the limitations of this preliminary observational study, it was found that all the patients maintained disease stability when treated with agalsidase alfa, as evidenced by estimated glomerular filtration rate, left-ventricular mass index, pain scores, and quality-of-life indexes, throughout 12 months of follow-up.
    Genetics in medicine: official journal of the American College of Medical Genetics 04/2012; 14(9):779-86. DOI:10.1038/gim.2012.39 · 7.33 Impact Factor
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