Anti-α-galactosidase A antibody response to agalsidase beta treatment: Data from the Fabry Registry

Wilcox, William R.; Linthorst, Gabor E.; Germain, Dominique P.; Feldt‐Rasmussen, Ulla; Waldek, Stephen; Richards, Susan; Beitner‐Johnson, Dana; Cizmarik, Marta; Cole, J. Alexander; Kingma, Wytske; Warnock, David G.

doi:10.1016/j.ymgme.2011.12.006

Cited by 61 publications

(55 citation statements)

References 24 publications

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“…Initial studies addressing immune reactions to ERT in patients with FD suggested that up to 73% of newly ERT-treated patients with FD develop antibodies toward the infused enzyme over time, 2,10 resulting in short-term complications including acute allergic reactions, necessitating premedication with histamines, cortisone, etc. Two recent studies demonstrated that antibody formation results in serum-mediated ERT inhibition, affecting the Gb3 clearance in ERT i+ men with FD.…”

Section: Discussionmentioning

confidence: 99%

Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Lenders

Stypmann

Duning

et al. 2016

Journal of the American Society of Nephrology

106

113

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Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme replacement therapy (agalsidase). However, recent studies suggest an endogenous inhibition of agalsidase in patients with FD, as reported for other lysosomal storage diseases. To assess the clinical consequences of serum-mediated agalsidase inhibition in affected patients, we determined the agalsidase inhibition status of 168 patients (68 male) with FD and compared outcomes of inhibition-positive patients with those of inhibition-negative patients. The assessment included clinical events during time on agalsidase, determination of renal and cardiac function, and evaluation of FD-related symptoms. The frequency of serum-mediated agalsidase inhibition was 40% in agalsidase-treated males. Inhibition did not depend on the compound initially used (agalsidase-a or -b). Agalsidase inhibition was associated with higher lysoglobotriaosylceramide levels and worse disease severity scores in patients. Compared with agalsidase inhibition-negative men, agalsidase inhibition-positive men showed greater left ventricular mass (P=0.02) and substantially lower renal function (difference in eGFR of about -30 ml/min per 1.73 m 2 ; P=0.04), which was confirmed by a longitudinal 5-year retrospective analysis. Additionally, affected patients presented more often with FD-typical symptoms, such as diarrhea, fatigue, and neuropathic pain, among others. Therefore, patients with poor clinical outcome on agalsidase should be tested for agalsidase inhibition. Future studies are warranted to determine if affected patients with FD benefit from acute reduction of anti-agalsidase antibodies or long-term immune modulation therapies to suppress agalsidase inhibition and to identify mechanisms that minimize antibody generation against agalsidase.

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Section: Discussionmentioning

confidence: 99%

Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Lenders

Stypmann

Duning

et al. 2016

Journal of the American Society of Nephrology

106

113

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“…To date, in FD no standardized assay exists to detect the presence of anti-agalsidase antibodies (Schellekens 2008;Lidove et al 2010). In most of the trials and reports studying the IgG response against ERT, except those of the Dutch team of Aerts, Linthorst et al, antibody analyses were performed by the manufacturer of the infused agalsidase preparation (Linthorst et al 2004;Ohashi et al 2008;Vedder et al 2008;Bénichou et al 2009;Rombach et al 2010aRombach et al , 2012Lidove et al 2010;Wilcox et al 2012). Linthorst et al then Smid et al showed that all the antibody-positive patients (assessed by the gold standard ELISA) demonstrated a neutralizing activity (Linthorst et al 2004;Smid et al 2013).…”

Section: Ert In Fabry Diseasementioning

confidence: 99%

“…It could be the result of the production process using CHO, with a higher percentage of fully sialylated oligosaccharides and a higher level of phosphorylation (Lee et al 2003;Bekri 2006;Ohashi et al 2008;Deegan 2012;Ramaswami et al 2012). In the latest report of postmarketing surveillance database on agalsidase beta, 73% of the patients developed IgG antibodies towards the exogenous enzyme (Wilcox et al 2012). Concerning agalsidase alfa, 24% of the patients developed IgG antibodies (Lidove et al 2010;Keating 2012).…”

Section: Ert In Fabry Diseasementioning

confidence: 99%

“…In males, FD is diagnosed by demonstrating a deficiency of a-GalA in plasma or leukocytes (Winchester and Young 2006). In heterozygous females, the gold standard is the genetic analysis since enzymatic assays fail to detect one third of the patients because of the residual enzyme activity (Linthorst et al 2010;Wang et al 2007;Wilcox et al 2012). Whereas "classical FD" consists in a multi-organ pathology, single organ variants are more and more evoked, following systematic investigations in specific medical conditions such as hypertrophic cardiomyopathies, cryptogenic strokes or isolated renal disease (Nakao et al 2003;Chimenti et al 2004;Rolfs et al 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Actually, immune reactions are described in both treatment-naive and agalsidase-treated FD patients (Rozenfeld et al 2009;De Francesco et al 2013). Antibodies against agalsidase are notably well described, but their role remains unclear (Linthorst et al 2004;Bénichou et al 2009;Wilcox et al 2012). In this review we present the spectrum of the immunological reactions, both innate and adaptive, observed in the natural history of FD and developed against agalsidase therapy, and their impact on outcome in FD.…”

Section: Introductionmentioning

confidence: 99%

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Innate and Adaptive Immune Response in Fabry Disease

et al. 2015

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Fabry disease is an X-linked lysosomal storage disease in which mutations of the gene (GLA) cause a deficiency of the lysosomal hydrolase α-galactosidase A (α-Gal). This defect results in an accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3) which causes a multisystemic vasculopathy. Available since 2001 in Europe, enzyme replacement therapy consists in the administration of agalsidase, a recombinant form of α-galactosidase A. Enzyme replacement therapy was shown to improve the global prognosis but allowed partial success in preventing critical events such as strokes and cardiac arrests. As in most lysosomal storage diseases, frequent immune reactions have been described in naive Fabry disease patients. Humoral immune responses following enzyme replacement therapy have also been described, with unclear consequences on the progression of the disease. While cost-effectiveness of enzyme replacement therapy in Fabry disease begins to be questioned and new therapeutic strategies arise such as chaperone or gene therapy, it appears necessary to better understand the immune responses observed in the treatment of naive patients and during enzyme replacement therapy with agalsidase. We propose a comprehensive review of the available literature concerning both innate and adaptive responses observed in Fabry disease. We particularly highlight the probable role of the toll-like receptor 4 (TLR4) and CD1d pathways triggered by Gb3 accumulation in the development of local and systemic inflammation that could lead to irreversible organ damages. We propose an immunological point of view of Fabry disease pathogenesis involving immune cells notably the invariant natural killer T cells. We finally review anti-agalsidase antibodies, their development and impact on outcomes.

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An expert consensus document on the management of cardiovascular manifestations of Fabry disease

Linhart

Germain

Olivotto

et al. 2020

European J of Heart Fail

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140

119

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Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the-galactosidase A (GLA) gene that leads to reduced or undetectable-galactosidase A enzyme activity and progressive accumulation of globotriaosylceramide and its deacylated form globotriaosylsphingosine in cells throughout the body. FD can be multisystemic with neurological, renal, cutaneous and cardiac involvement or be limited to the heart. Cardiac involvement is characterized by progressive cardiac hypertrophy, fibrosis, arrhythmias, heart failure and sudden cardiac death. The cardiac management of FD requires specific measures including enzyme replacement therapy or small pharmacological chaperones in patients carrying amenable pathogenic GLA gene variants and more general management of cardiac symptoms and complications. In this paper, we summarize current knowledge of FD-related heart disease and expert consensus recommendations for its management.

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Anti-α-galactosidase A antibody response to agalsidase beta treatment: Data from the Fabry Registry

Cited by 61 publications

References 24 publications

Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Innate and Adaptive Immune Response in Fabry Disease

An expert consensus document on the management of cardiovascular manifestations of Fabry disease

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