| Title: |
Deep characterization of the anti-drug antibodies developed in Fabry disease patients, a prospective analysis from the French multicenter cohort FFABRY |
| Authors: |
Mauhin, Wladimir; Lidove, Olivier; Amelin, Damien; Lamari, Foudil; Caillaud, Catherine; Mingozzi, Federico; Dzangue-Tchoupou, Gaelle; Arouche-Delaperche, Louiza; Douillard, Claire; Dussol, Bertrand; Leguy-Seguin, Vanessa; D''halluin, Pauline; Noel, Esther; Zenone, Thierry; Matignon, Marie; Maillot, Francois; Ly, Kim-Heang; Besson, Gerard; Willems, Marjolaine; Labombarda, Fabien; Masseau, Agathe; Lavigne, Christian; Froissart, Roseline; Lacombe, Didier; Ziza, Jean-Marc; Hachulla, Eric; Benveniste, Olivier |
| Contributors: |
Inserm; Université de Lille; CHU Lille; Lille Inflammation Research International Center (LIRIC) - U995; Centre de recherche en Myologie – U974 SU-INSERM; Université Pierre et Marie Curie - Paris 6 UPMC; Institut Necker Enfants-Malades INEM - UM 111 (UMR 8253 / U1151); Aix Marseille Université AMU; Université Francois Rabelais Tours; Université Paris-Est Créteil Val-de-Marne - Paris 12 UPEC UP12; Université de Tours UT; Université de Bordeaux UB; Lille Inflammation Research International Center - U 995 LIRIC |
| Publication Year: |
2024 |
| Collection: |
LillOA (Lille Open Archive - Université de Lille) |
| Subject Terms: |
Fabry disease; Anti-drug antibodies; Agalsidase; Lysosomal storage disease; Enzyme replacement therapy; IgG4 |
| Description: |
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: ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/octet-stream |
| Language: |
English |
| Relation: |
Orphanet Journal of Rare Diseases; Orphanet J. Rare Dis.; http://hdl.handle.net/20.500.12210/5058 |
| Availability: |
https://hdl.handle.net/20.500.12210/5058 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.1217072D |
| Database: |
BASE |