Deep characterization of the anti-drug antibodies developed in Fabry disease patients, a prospective analysis from the French multicenter cohort FFABRY.

Autor: Mauhin W; Sorbonne Université, INSERM, UMR 974, Centre of Research in Myology, Association Institut de Myologie, Pitié-Salpêtrière University Hospital, 75013, Paris, France. wladimir.mauhin@aphp.fr., Lidove O; Sorbonne Université, INSERM, UMR 974, Centre of Research in Myology, Association Institut de Myologie, Pitié-Salpêtrière University Hospital, 75013, Paris, France.; Internal Medicine and Rheumatology Department, Diaconesses-Croix Saint Simon Hospital Group, Paris, France., Amelin D; Sorbonne Université, INSERM, UMR 974, Centre of Research in Myology, Association Institut de Myologie, Pitié-Salpêtrière University Hospital, 75013, Paris, France., Lamari F; Metabolic Biochemistry Department, Pitié Salpêtrière University Hospital, AP-HP, Paris, France.; GRC13-Neurometabolisme- Sorbonne Universités UPMC, Paris 06, Paris, France., Caillaud C; Biochemistry, Metabolomic and Proteomic Department, Necker Enfants Malades University Hospital, AP-HP, Paris, France.; INSERM U1151, Institute Necker Enfants Malades, Paris Descartes University, Paris, France., Mingozzi F; Sorbonne Université, INSERM, UMR 974, Centre of Research in Myology, Association Institut de Myologie, Pitié-Salpêtrière University Hospital, 75013, Paris, France., Dzangué-Tchoupou G; Sorbonne Université, INSERM, UMR 974, Centre of Research in Myology, Association Institut de Myologie, Pitié-Salpêtrière University Hospital, 75013, Paris, France., Arouche-Delaperche L; Sorbonne Université, INSERM, UMR 974, Centre of Research in Myology, Association Institut de Myologie, Pitié-Salpêtrière University Hospital, 75013, Paris, France., Douillard C; Reference Center for Inborn Metabolic diseases, Jeanne de Flandres Hospital, Lille, France., Dussol B; Nephrology Department, Aix Marseille Université et Centre d'Investigation Clinique 1409, INSERM/AMU/AP-HM, Marseille, France., Leguy-Seguin V; Internal Medicine and Clinical Immunology Department, Francois Mitterrand Hospital, Dijon, France., D'Halluin P; Nephrology and Clinical Immunology Department, Tours University Hospital, François Rabelais University, Tours, France., Noel E; Internal Medicine Department, Strasbourg University Hospital, Strasbourg, France., Zenone T; Internal Medicine Department, Valence Hospital, Valence, France., Matignon M; Nephrology and Renal Transplantation Department, Institut Francilien de Recherche en Néphrologie et Transplantation (IFRNT), Henri-Mondor/Albert-Chenevier University Hospital, APHP, Créteil, France.; University of Paris-Est-Créteil (UPEC), DHU (Département Hospitalo-Universitaire) VIC (Virus-Immunité-Cancer), IMRB (Institut Mondor de Recherche Biomédicale), Team 21, INSERM U 955, Créteil, France., Maillot F; Internal Medicine Department, Tours University Hospital, University of Tours, UMR INSERM 1253, Tours, France., Ly KH; Internal Medicine Department, Dupuytren University Hospital, Limoges, France., Besson G; Neurology Department, Grenoble University Hospital, Grenoble, France., Willems M; Medical Genetics and Rare Diseases Department, Montpellier University Hospital, Montpellier, France., Labombarda F; Cardiology Department, Caen University Hospital, Caen, France., Masseau A; Internal Medicine Department, Hôtel-Dieu University Hospital, Nantes, France., Lavigne C; Internal Medicine and Vascular Diseases Department, Angers University Hospital, Angers, France., Froissart R; Laboratory for Inborn Errors of Metabolism, East Hospital, Hospices Civils de Lyon, Bron, France., Lacombe D; Medical Genetics Department, CHU Bordeaux, INSERM U1211, Bordeaux University, Bordeaux, France., Ziza JM; Internal Medicine and Rheumatology Department, Diaconesses-Croix Saint Simon Hospital Group, Paris, France., Hachulla E; Internal Medicine Department, Huriez Hospital, University of Lille, 59037, Lille, France., Benveniste O; Sorbonne Université, INSERM, UMR 974, Centre of Research in Myology, Association Institut de Myologie, Pitié-Salpêtrière University Hospital, 75013, Paris, France.; Internal Medicine and Clinical Immunology Department, Pitié-Salpêtrière University Hospital, DHU I2B, AP-HP, Paris, France.
Jazyk: angličtina
Zdroj: Orphanet journal of rare diseases [Orphanet J Rare Dis] 2018 Jul 31; Vol. 13 (1), pp. 127. Date of Electronic Publication: 2018 Jul 31.
DOI: 10.1186/s13023-018-0877-4
Abstrakt: Background: Fabry disease (OMIM #301500) is an X-linked disorder caused by alpha-galactosidase A deficiency with two major clinical phenotypes: classic and non-classic of different prognosis. From 2001, enzyme replacement therapies (ERT) have been available. We aimed to determine the epidemiology and the functional characteristics of anti-drug antibodies. Patients from the French multicenter cohort FFABRY (n = 103 patients, 53 males) were prospectively screened for total anti-agalsidase IgG and IgG subclasses with a home-made enzyme-linked immunosorbent assay (ELISA), enzyme-inhibition assessed with neutralization assays and lysoGb3 plasma levels, and compared for clinical outcomes.
Results: Among the patients exposed to agalsidase, 40% of men (n = 18/45) and 8% of women (n = 2/25) had antibodies with a complete cross-reactivity towards both ERTs. Antibodies developed preferentially in men with non-missense GLA mutations (relative risk 2.88, p = 0.006) and classic phenotype (58.6% (17/29) vs 6.7% (1/16), p = 0.0005). Specific anti-agalsidase IgG1 were the most frequently observed (16/18 men), but the highest concentrations were observed for IgG4 (median 1.89 μg/ml, interquartile range (IQR) [0.41-12.24]). In the men exposed to agalsidase, inhibition was correlated with the total IgG titer (r = 0.67, p < 0.0001), especially IgG4 (r = 0.75, p = 0.0005) and IgG2 (r = 0.72, p = 0.001). Inhibition was confirmed intracellularly in Fabry patient leucocytes cultured with IgG-positive versus negative serum (median: 42.0 vs 75.6%, p = 0.04), which was correlated with IgG2 (r = 0.67, p = 0.017, n = 12) and IgG4 levels (r = 0.59, p = 0.041, n = 12). Plasma LysoGb3 levels were correlated with total IgG (r = 0.66, p = 0.001), IgG2 (r = 0.72, p = 0.004), IgG4 (r = 0.58, p = 0.03) and IgG1 (r = 0.55, p = 0.04) titers. Within the classic group, no clinical difference was observed but lysoGb3 levels were higher in antibody-positive patients (median 33.2 ng/ml [IQR 20.6-55.6] vs 12.5 [10.1-24.0], p = 0.005).
Conclusion: Anti-agalsidase antibodies preferentially develop in the severe classic Fabry phenotype. They are frequently associated with enzyme inhibition and higher lysoGb3 levels. As such, they could be considered as a hallmark of severity associated with the classic phenotype. The distinction of the clinical phenotypes should now be mandatory in studies dealing with Fabry disease and its current and future therapies.
Databáze: MEDLINE
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