Neutralising anti-drug antibodies in Fabry disease can inhibit endothelial enzyme uptake and activity.
Fabry disease
anti-drug antibodies
endothelium
enzyme replacement therapy
globotriaosylceramide
Journal
Journal of inherited metabolic disease
ISSN: 1573-2665
Titre abrégé: J Inherit Metab Dis
Pays: United States
ID NLM: 7910918
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
06
06
2019
revised:
22
08
2019
accepted:
24
09
2019
pubmed:
7
10
2019
medline:
3
7
2021
entrez:
7
10
2019
Statut:
ppublish
Résumé
Fabry disease (FD) is a lysosomal storage disease, treatable by enzyme replacement therapy (ERT) that substitutes deficient α-galactosidase A (AGAL). The formation of neutralising anti-drug antibodies (ADA) inhibiting AGAL activity during infusion is associated with disease progression in affected male patients. In this study we analysed if ADAs also inhibit endothelial enzyme uptake as well as intracellular enzyme activity. Therefore, fluorescence-labelled AGAL in combination with ADA-positive sera from FD patients (n = 8) was used to analyse enzyme uptake in endothelial and FD-specific cells. Furthermore, immune adsorption and a comprehensive ADA epitope mapping were performed. Pre-incubation of AGAL with ADAs significantly inhibited intracellular enzyme activity, which was rescued by immune adsorption (both P < .01). ADAs from some patients also inhibited enzyme uptake. ADA epitope mapping identified an epitope at position 121 to 140 aa potentially responsible for uptake inhibition for these patients. Further analyses revealed the presence of stable AGAL/ADA-immune complexes at pH 4.5 and decreased intracellular enzyme activity in endothelial cells (P < .001). Finally, the pre-incubation of AGAL with ADAs resulted in a reduced depletion of intracellular globotriaosylceramide in patient-derived AGAL-deficient cells, demonstrating a direct negative impact of ADAs on intracellular clearance. Neutralising ADAs may not only inhibit infused AGAL activity, but according to their epitopes can also inhibit endothelial AGAL uptake. Indeed, internalised AGAL/ADA-complexes may not dissociate, underlining the importance of novel therapeutic approaches for ADA reduction and prevention to increase therapy efficiency in affected patients.
Substances chimiques
Antibodies, Neutralizing
0
alpha-Galactosidase
EC 3.2.1.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
334-347Informations de copyright
© 2019 SSIEM.
Références
Zarate YA, Hopkin RJ. Fabry's disease. Lancet. 2008;372:1427-1435.
Eng CM, Guffon N, Wilco WR, et al. Safety and efficacy of recombinant human a-galactosidase A replacement therapy in Fabry's disease. N Engl J Med. 2001;345:9-16.
Schiffmann R, Kopp JB, Austin HA 3rd, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA. 2001;285:2743-2749.
Lenders M, Brand E. Effects of enzyme replacement therapy and antidrug antibodies in patients with Fabry disease. J Am Soc Nephrol. 2018;29:2265-2278.
Lenders M, Stypmann J, Duning T, et al. Serum-mediated inhibition of enzyme replacement therapy in Fabry disease. J Am Soc Nephrol. 2016;27:256-264.
Lenders M, Schmitz B, Brand SM, et al. Characterization of drug-neutralizing antibodies in patients with Fabry disease during infusion. J Allergy Clin Immunol. 2018;141:2289-2292.e7.
Linthorst GE, Hollak CEM, Donker-Koopman WE, et al. Enzyme therapy for Fabry disease: neutralizing antibodies toward agalsidase alpha and beta. Kidney Int. 2004;66:1589-1595.
Rombach SM, Aerts JMFG, Poorthuis BJ, et al. Long-term effect of antibodies against infused alpha-galactosidase A in Fabry disease on plasma and urinary (lyso)Gb3 reduction and treatment outcome. PLoS One. 2012;7:e47805.
van der Veen SJ, van Kuilenburg ABP, Hollak CEM, et al. Antibodies against recombinant alpha-galactosidase A in Fabry disease: subclass analysis and impact on response to treatment. Mol Genet Metab. 2019;126:162-168.
Vedder AC, Breunig F, Donker-Koopman WE, et al. Treatment of Fabry disease with different dosing regimens of agalsidase: effects on antibody formation and GL-3. Mol Genet Metab. 2008;94:319-325.
Arends M, Biegstraaten M, Wanner C, et al. Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study. J Med Genet. 2018;55:351-358.
Lenders M, Neußer LP, Rudnicki M, et al. Dose-dependent effect of enzyme replacement therapy on neutralizing antidrug antibody titers and clinical outcome in patients with Fabry disease. J Am Soc Nephrol. 2019a;29:2879-2889.
Mauhin W, Lidove O, Amelin D, et al. Deep characterization of the anti-drug antibodies developed in Fabry disease patients, a prospective analysis from the French multicenter cohort FFABRY. Orphanet J Rare Dis. 2018;13:127.
Bénichou B, Goyal S, Sung C, et al. A retrospective analysis of the potential impact of IgG antibodies to agalsidase beta on efficacy during enzyme replacement therapy for Fabry disease. Mol Genet Metab. 2009;96:4-12.
Desnick RJ, Allen KY, Desnick SJ, et al. Fabry's disease: enzymatic diagnosis of hemizygotes and heterozygotes. Alpha-galactosidase activities in plasma, serum, urine, and leukocytes. J Lab Clin Med. 1973;81:157-171.
Mayes JS, Scheerer JB, Sifers RN, et al. Differential assay for lysosomal alpha-galactosidases in human tissues and its application to Fabry's disease. Clin Chim Acta. 1981;112:247-251.
Edgell CJ, McDonald CC, Graham JB. Permanent cell line expressing human factor VIII-related antigen established by hybridization. Proc Natl Acad Sci U S A. 1983;80:3734-3737.
Lenders M, Stappers F, Niemietz C, et al. Mutation-specific Fabry disease patient-derived cell model to evaluate the amenability to chaperone therapy. J Med Genet. 2019b;56:548-556.
Fleit HB, Kobasiuk CD. The human monocyte-like cell line THP-1 expresses fc gamma RI and Fc gamma RII. J Leukoc Biol. 1991;49:556-565.
Debiec H, Valayannopoulos V, Boyer O, et al. Allo-immune membranous nephropathy and recombinant aryl sulfatase replacement therapy: a need for tolerance induction therapy. J Am Soc Nephrol. 2014;25:675-680.
Hunley TE, Corzo D, Dudek M, et al. Nephrotic syndrome complicating alpha-glucosidase replacement therapy for Pompe disease. Pediatrics. 2004;114:e532-e535.
Ronco P, Debiec H. Pathophysiological advances in membranous nephropathy: time for a shift in patient's care. Lancet. 2015;385:1983-1992.
Zhu X, Yin L, Theisen M, et al. Systemic mRNA therapy for the treatment of Fabry disease: preclinical studies in wild-type mice, Fabry mouse model, and wild-rype non-human primates. Am J Hum Genet. 2019;104:625-637.