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

Linthorst, Gabor E.; Hollak, Carla E. M.; Donker‐Koopman, Wilma E.; Strijland, Anneke; Aerts, Johannes M. F. G.

doi:10.1111/j.1523-1755.2004.00924.x

Cited by 236 publications

(250 citation statements)

References 17 publications

(17 reference statements)

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“…The number of samples that test positive for neutralizing activity and/or inhibition of uptake is dependent on the sensitivity and specificity of the method (Fabrazyme ® Prescribing information, last updated May 2010). Thus, it is not surprising that neutralizing antibody activity results from this study differ from results reported by other groups (Linthorst et al 2004;Lenders et al 2015). Studies have demonstrated that both agalsidase alfa and agalsidase beta are structurally equivalent and, on a milligram basis, induce similar, fully cross-reactive, antibody responses in vivo (Blom et al 2003;Lee et al 2003;Linthorst et al 2004), refuting the suggestion that variation in glycosylation patterns between agalsidase beta and agalsidase alfa may have implications for the long-term safety of ERT (Barbey et al 2008).…”

Section: Discussioncontrasting

confidence: 41%

Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

Göker-Alpan

Gambello

Maegawa³

et al. 2015

JIMD Reports

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Introduction: Agalsidase alfa and agalsidase beta, recombinant enzyme preparations for treatment of Fabry disease (FD), have different approved dosing schedules: 0.2 mg/kg and 1.0 mg/kg every other week (EOW), respectively.Methods: This open-label, multicenter, exploratory phase 4 study evaluated plasma globotriaosylsphingosine (lyso-GL-3) and plasma and urine globotriaosylceramide (GL-3) levels at baseline and 2, 4, and 6 months after the switch from agalsidase alfa (0.2 mg/kg EOW for !12 months) to agalsidase beta (1.0 mg/kg EOW) in 15 male patients with FD. Immunoglobulin (Ig)G antidrug antibody titers were assessed, and safety was monitored throughout the study.Results: Plasma lyso-GL-3 concentrations decreased significantly within 2 months after switch and reductions continued through month 6 (mean absolute changes, À12.8, À16.1, and À16.7 ng/mL at 2, 4, and 6 months, respectively; all P < 0.001). The mean percentage reduction from baseline was 39.5% (P < 0.001) at month 6. For plasma GL-3, the mean absolute change from baseline (À0.9 mg/mL) and percentage reduction (17.9%) at month 6 were both significant (P < 0.05). Urine GL-3 measurements showed intra-patient variability and changes from baseline were not significant. No clinical outcomes were assessed in this 6-month study, and, therefore, no conclusions can be drawn regarding the correlation of observed reductions in glycosphingolipid concentrations with clinically relevant outcomes. There were no differences in IgG antidrug antibody titers between the two enzymes. The switch from agalsidase alfa to agalsidase beta was well tolerated.Conclusion: Plasma lyso-GL-3 and GL-3 levels reduced after switching from agalsidase alfa to agalsidase beta, indicating that agalsidase beta has a greater pharmacodynamic effect on these markers at the recommended dose. These data further support the use of agalsidase beta 1.0 mg/kg EOW as enzyme replacement therapy in FD.

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Section: Discussioncontrasting

confidence: 41%

Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

Göker-Alpan

Gambello

Maegawa³

et al. 2015

JIMD Reports

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“…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.…”

Section: Discussionmentioning

confidence: 92%

Effects of Switching from Agalsidase Beta to Agalsidase Alfa in 10 Patients with Anderson-Fabry Disease

et al. 2012

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“…To analyze serum-mediated ERT inhibition as previously reported, 4,7 we tested sera of 168 patients with FD using an in vitro GLA inhibition assay. Patients had been consecutively recruited at the Fabry center of the University Hospital Muenster (IFAZ) between 2001 and 2014.…”

Section: Ert Inhibition Status In Patients With Fdmentioning

confidence: 99%

“…2,3 Recent studies suggested that infusion of recombinant enzyme may lead to formation of antibodies, resulting in short-term acute complications, 2 as well as deleterious long-term effects by therapy inhibition, resulting in severely decreased Gb3 and lyso-Gb3 depletion. [4][5][6][7] Reduced lyso-Gb3 clearance, as a marker of disease progression, may be accompanied by a deterioration of clinical manifestations and symptoms in affected patients. Until now, only indirect associations between ERT inhibition and end-organ manifestations have been shown, in that elevated lyso-Gb3 levels of inhibition-positive patients were associated with left ventricular mass (LV mass ) and the formation of whitematter lesions.…”

mentioning

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

104

110

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

Cited by 236 publications

References 17 publications

Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

Effects of Switching from Agalsidase Beta to Agalsidase Alfa in 10 Patients with Anderson-Fabry Disease

Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

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