Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012;7(10):e47805.
doi: 10.1371/journal.pone.0047805. Epub 2012 Oct 19.

Long-term effect of antibodies against infused alpha-galactosidase A in Fabry disease on plasma and urinary (lyso)Gb3 reduction and treatment outcome

Saskia M Rombach  1 , Johannes M F G Aerts, Ben J H M Poorthuis, Johanna E M Groener, Wilma Donker-Koopman, Erik Hendriks, Mina Mirzaian, Sijmen Kuiper, Frits A Wijburg, Carla E M Hollak, Gabor E Linthorst
Affiliations

Long-term effect of antibodies against infused alpha-galactosidase A in Fabry disease on plasma and urinary (lyso)Gb3 reduction and treatment outcome

Saskia M Rombach et al. PLoS One. 2012.

Abstract

Introduction: Enzyme replacement therapy (ERT) with alpha-Galactosidase A (aGal A) may cause antibody (AB) formation against aGal A in males with Fabry disease (FD). Anti agalsidase ABs negatively influence globotriaosylceramide (Gb3) reduction. We investigated the impact of agalsidase AB on Gb3 and lysoGb3 and clinical outcome in Fabry patients on ERT.

Methods: Adult male and female patients on ERT for at least one year were included. Urinary Gb3 was measured by HPLC, plasma lysoGb3 by LC-ESI-MS/MS and AB with a neutralization assay.

Results: Of the 59 patients evaluable patients, 0/30 females and 17/29 males developed anti-agalsidase antibodies (AB+). Only 3/17 males had transient (low) titers (tolerized). All AB+ patients developed antibodies during the first year of treatment. Change of agalsidase preparation (or dose) did not induce antibody formation. AB+ males had significant less decline in plasma lysoGb3 compared to AB- males (p = 0.04). Urinary Gb3 levels decreased markedly in AB- but remained comparable to baseline in AB+ males (p<0.01). (Lyso)Gb3 reduction in plasma and urine on ERT was correlated with LVmass reduction in females and development white matter lesions and stroke.

Conclusion: In male patients antibodies against aGal A remained present up to 10 years of ERT. The presence of these antibodies is associated with a less robust decrease in plasma lysoGb3 and a profound negative effect on urinary Gb3 reduction, which may reflect worse treatment outcome.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: GEL, FAW, JMA and CEMH have received reimbursement of expenses and honoraria for lectures on the management of from Genzyme, Actelion and Shire HGT. GEL, JMA and CEMH donated the honoraria to the Gaucher Stichting, a foundation that supports research in the field of lysosomal storage disorders. All other authors declare no conflicts of interest. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Plasma lysoGb3 and Gb3 in Fabry males.
LysoGb3 (A) and plasma Gb3 (B) in 23 classic Fabry males, treated for at least one year (AB+ group n = 12, AB− group n = 11), depicting mean and 95% confidence intervals.
Figure 2
Figure 2. Plasma lysoGb3 and Gb3 in Fabry females.
Plasma lysoGb3 in 27 (A) and Gb3 (B) in 28 Fabry females, treated for at least one year, depicting mean and 95% CI.
Figure 3
Figure 3. Urinary Gb3 in males and females.
A. Urinary Gb3 in classic Fabry males, treated for at least one year (AB+ group n = 11, AB− group n = 11). B. Urinary Gb3 in classic Fabry females treated for at least one year (n = 28), depicting mean and 95% confidence interval. The dotted line denotes upper limit of normal in healthy controls: 18–90 nmol/24 uur.
Figure 4
Figure 4. LVMass reduction and LysoGb3.
LVMass decreases as lysoGb3 decreases. The dot represents the mean lysoGb3 and mean LVmass in females at start of ERT treatment, the square depicts mean lysoGb3 one year after start of ERT.
Figure 5
Figure 5. Risk to develop white matter lesions and LysoGb3.
The hazard ratio to develop a (additional) white matter lesion or stroke decreases as the absolute value of lysoGb3 decreases. The dot represents mean lysoGb3 for males and females at start of ERT. The square depicts mean lysoGb3 level one year after start of ERT.
See this image and copyright information in PMC

References

    1. Schiffmann R, Warnock DG, Banikazemi M, Bultas J, Linthorst GE, et al. (2009) Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy. Nephrol Dial Transplant (7): 2102–11. - PMC - PubMed
    1. Vedder AC, Linthorst GE, van Breemen MJ, Groener JEM, Bemelman FJ, et al. (2007) The Dutch Fabry cohort: diversity of clinical manifestations and Gb3 levels. J Inherit Metab Dis 30(1): 68–78. - PubMed
    1. Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, et al. (2001) Safety and efficacy of recombinant human alpha-galactosidase A--replacement therapy in Fabry's disease. N Engl J Med 345(1): 9–16. - PubMed
    1. Schiffmann R, Kopp JB, Austin HA, Sabnis S, Moore DF, et al. (2001) Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA 285(21): 2743–2749. - PubMed
    1. Linthorst GE, Hollak CEM, Donker-Koopman WE, Strijland A, Aerts JMFG (2004) Enzyme therapy for Fabry disease: neutralizing antibodies toward agalsidase alpha and beta. Kidney Int 66(4): 1589–1595. - PubMed

Publication types

MeSH terms