Anti-Drug Antibodies in Patients with Fabry Disease Treated with Agalsidase-Alpha or -Beta: A Retrospective Italian Multicenter Study
Andrea Matucci, Michael Diomaiuti, Amelia Morrone, Pasquale Esposito, Federico Pieruzzi, Maurizio Pieroni, Emanuele Vivarelli, Elena Biagini, Raffaello Ditaranto, Maria Alessandra Schiavo, Calogero Lino Cirami, Leonardo Caroti, Egrina Dervishi, Ilaria Romani, Cristina Sarti, Mario Mangeri, Barbara Trezzi, Letizia Roggero, Claudia Sgattoni, Alessia Gennarini, Giancarlo la Marca, Giulia Forni, Giacomo Mascia, Marina Rinaldi, Annamaria Del Franco, Alessia Argirò, Sandro Feriozzi, Matteo Accinno, Alessandra Vultaggio(1) Background: Anti-drug antibodies (ADAs) may develop during enzyme replacement therapy (ERT) for Fabry disease and potentially affect biochemical response. Evidence have been derived mainly from males, while comparisons between agalsidase-alpha and agalsidase-beta remain limited by differences in ADA assays. The aim of the study is to evaluate ADA prevalence and titers in patients with Fabry disease treated with agalsidase-alpha or agalsidase-beta and to investigate associations with sex, GLA genotype, residual α-galactosidase A activity, and lyso-Gb3 levels. (2) Methods: This multicenter observational study included 117 patients with Fabry disease receiving ERT (50 males, 67 females), treated with agalsidase-alpha (n = 52) or agalsidase-beta (n = 65). ADAs were measured using an in-house enzyme-linked immunosorbent assay, and lyso-Gb3 by liquid chromatography–tandem mass spectrometry. GLA variants were centrally classified as predicted null-type or predicted non-null-type on the basis of the variant class, and α-galactosidase A activity at diagnosis was normalized to the lower limit of the assay reference interval. Multivariable regression analysis identified factors associated with ADA positivity and lyso-Gb3 levels. (3) Results: ADAs were detected in 55/117 patients. Positivity was more frequent in males than females, with no statistically significant difference between agalsidase-alpha and agalsidase-beta. Predicted null-type variants were associated with higher ADA positivity and titers, particularly in males. In multivariable models, male sex and predicted null-type variants independently predicted ADA positivity, whereas higher normalized α-galactosidase A activity was associated with lower odds. ADA positivity was not independently associated with lyso-Gb3. (4) Conclusions: ADA detection was primarily associated with male sex and predicted null-type GLA variants; no statistically significant association with the agalsidase administered was found. The high prevalence of binding ADAs in females warrants confirmation using orthogonal and functional assays.