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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Available from: Carla E Hollak, May 30, 2014
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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.
    01/2013; 9:41-8. DOI:10.1007/8904_2012_177
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    • "Therefore, concern exists that these antibodies may interfere with the clinical benefit that is hoped to be gained through ERT; the antibody level and the dose of ERT administered to seropositive patients may be important factors to consider in treatment. Increased urinary GL3 levels have been demonstrated in seropositive patients compared to antibody negative patients, although some seropositive patients do demonstrate normalization of urinary GL3 levels after 12 months of ERT (Linthorst et al. 2004; Ohashi et al. 2007). Fabry mice had reduced a-galactosidase activity within their major organs (including heart and kidneys) after infusion of Agalsidase beta incubated with serum from seropositive patients, compared to those treated with an equal dose of enzyme pre-incubated with serum from seronegative patients (Ohashi et al. 2008). "
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    ABSTRACT: Background: In Australia, enzyme replacement therapy (ERT) for Fabry Disease (FD), both Agalsidase alfa (Replagal, Shire HGT) and beta (Fabrazyme, Genzyme), is funded and monitored through a specific government program. Agalsidase beta supply has been rationed by Genzyme since 2009 due to manufacturing issues. Consequently, the Australian Fabry Disease Advisory Committee has treated patients on Agalsidase beta at 50% of their usual dose from mid-2009, with a further reduction to 30% for some patients from late 2009. Aim: To determine the clinical effect of Agalsidase beta dose reduction in the Australian FD patient cohort. Methods: A questionnaire assessing FD symptoms was administered to 40 patients on long-term ERT. Clinical data from The Fabry Registry for patients receiving Agalsidase alfa or beta, for at least 2 years prior to the time of enforced Agalsidase beta dose reduction, were reviewed. Disease burden and quality of life (QOL) were graded using the Disease Severity Scoring System, Mainz Severity Score Index, Brief Pain Inventory and Short Form 36 Health Survey at 2 years before dose reduction, at the time of dose reduction and at the most recent clinical review following dose reduction. Results: Disease severity and QOL scores did not change between the ERT groups. Males on Agalsidase beta reported lower energy levels after dose reduction, while no change was reported by females on either product or by males on a stable dose of Agalsidase alfa. Conclusion: This study suggests that energy levels in male patients worsen after dose reduction of Agalsidase beta.
    01/2012; 3:33-43. DOI:10.1007/8904_2011_44
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    • "However, discerning the specific effect of ERT from that of other interventions, for example the use of renin–angiotensin inhibitors, remains a challenge [35]. It has been documented that a large portion of Fabry hemizygotes develops antibodies against the recombinant enzymes during ERT [36] [37] [38]. In addition, it has been hypothesized that the formation of antibodies possibly affects outcome [39] [40]. "
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    ABSTRACT: Fabry disease is treated by two-weekly infusions with α-galactosidase A, which is deficient in this X-linked globotriaosylceramide (Gb3) storage disorder. Elevated plasma globotriaosylsphingosine (lysoGb3) is a hallmark of classical Fabry disease. We investigated effects of enzyme replacement therapy (ERT) on plasma levels of lysoGb3 and Gb3 in patients with classical Fabry disease treated with agalsidase alfa at 0.2mg/kg, agalsidase beta at 0.2mg/kg or at 1.0mg/kg bodyweight. Each treatment regimen led to prominent reductions of plasma lysoGb3 in Fabry males within 3 months (P=0.0313), followed by relative stability later on. Many males developed antibodies against α-galactosidase A, particularly those treated with agalsidase beta. Patients with antibodies tended towards smaller correction in plasma lysoGb3 concentration, whereas treatment with high dose agalsidase beta allowed a reduction comparable to patients without antibodies. Pre-treatment plasma lysoGb3 concentrations of Fabry females were relatively low. In all females and with each treatment regimen, ERT gave reduction or stabilisation of plasma lysoGb3. Our investigation revealed that ERT of Fabry patients reduces plasma lysoGb3, regardless of the recombinant enzyme used. This finding shows that ERT can correct a characteristic biochemical abnormality in Fabry patients.
    Biochimica et Biophysica Acta 01/2011; 1812(1):70-6. DOI:10.1016/j.bbadis.2010.09.007 · 4.66 Impact Factor
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