Sex-based antibody subclass maturation drives direct enzymatic inhibition in fabry disease patients receiving enzyme replacement therapy
Baldwin, Tomas Kurdi, Hibba Doykov, Ivan Robertson, Francesca Rosmini, Stefania Nordin, Sabrina Augusto, Joao Kozor, Rebecca Baruteau, Julien Davison, James
Baldwin, Tomas
Kurdi, Hibba
Doykov, Ivan
Robertson, Francesca
Rosmini, Stefania
Nordin, Sabrina
Augusto, Joao
Kozor, Rebecca
Baruteau, Julien
Davison, James
Abstract
Background: Enzyme replacement therapy (ERT) for Fabry disease can elicit anti-drug antibodies (ADAs) that may diminish efficacy and limit clinical benefit.
Objectives: To develop and apply a multiplexed proteomic assay for quantitative, subclass-specific ADA and complement profiling in Fabry disease to inform personalized ERT selection.
Methods: We created a targeted LC-MS/MS platform to quantify ADA binding across IgG1-4, IgM, and IgA1, and complement proteins C1Qc-C9, in serum from Fabry patients (n = 39) and healthy controls. Neutralizing capacity was measured via enzymatic inhibition assay. Subclass-specific cross-reactivity was assessed for agalsidase alfa, agalsidase beta, and pegunigalsidase alfa.
Results: IgG4 binding was significantly higher in Fabry males (p = 0.007), with no sex-based differences for other Ig classes. Complement binding (C1Qc, C3) was elevated in ∼25% of patients, with IgG1, IgG2, IgM, and IgA1 correlating with C1Qc (r > 0.6). Seven patients (three female) exhibited >50% ERT inhibition; IgG4 binding correlated with enzymatic inhibition (p < 0.0025) and elevated lyso-Gb3 in males (p < 0.02). We assessed cross-reactivity of IgG4 in a patient who had received only agalsidase alfa, finding a 49% reduction in IgG4 binding to Pegunigalsidase alfa compared to Agalsidase alfa (p = 0.003) and 45% to Peguingalsidase alfa compared to agalsidase beta (p = 0.035). IgG4 comprised >50% of immune complexes for agalsidase alfa/beta but only 25% for pegunigalsidase alfa, indicating a potentially distinct immunogenic profile.
Conclusion: Quantitative subclass-specific ADA and complement profiling reveals sex-specific IgG4 patterns, neutralizing capacity, and ERT-specific immunogenic differences, supporting its utility for personalized therapy in Fabry disease.
Capsule summary: A novel multiplex LC-MS/MS assay quantifies ADA subclasses and complement in Fabry disease, uncovering distinct IgG4 patterns and ERT-specific profiles that enhance understanding of treatment immunogenicity.
MIDER Authors
Affiliations
University College London; King’s College London; University of Glasgow; NHS Greater Glasgow and Clyde; Royal North Shore Hospital; University of Sydney; Great Ormond Street Hospital for Children NHS Foundation Trust; Royal Free London NHS Foundation Trust; University Hospitals Birmingham NHS Foundation Trust; Barts Health NHS Trust
Date
2026-04-09
Type
Article
Collections
Citation
Baldwin T, Kurdi H, Doykov I, Robertson F, Rosmini S, Nordin S, Augusto J, Kozor R, Baruteau J, Davison J, Moreno-Martinez D, Ramaswami U, Vijapurapu R, Geberhiwot T, Steeds R, Moon J, Hughes D, Mills K, Heywood WE. Sex-based antibody subclass maturation drives direct enzymatic inhibition in fabry disease patients receiving enzyme replacement therapy. Front Mol Biosci. 2026 Apr 9;13:1702751. doi: 10.3389/fmolb.2026.1702751.