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Peer-reviewedCC BY 4.0Cells

Anti-Drug Antibodies in Patients with Fabry Disease Treated with Agalsidase-Alpha or -Beta: A Retrospective Italian Multicenter Study

  • Andrea Matucci1
  • Michael Diomaiuti1
  • Amelia Morrone2,3
  • Pasquale Esposito4,5
  • Federico Pieruzzi6,7
  • Maurizio Pieroni8,9
  • Emanuele Vivarelli1,8
  • Elena Biagini10,11
  • Raffaello Ditaranto10,11
  • Maria Alessandra Schiavo10,11
  • Calogero Lino Cirami12
  • Leonardo Caroti12
17 more authors
  • Egrina Dervishi12
  • Ilaria Romani13
  • Cristina Sarti13,14
  • Mario Mangeri15
  • Barbara Trezzi6
  • Letizia Roggero6
  • Claudia Sgattoni16
  • Alessia Gennarini17
  • Giancarlo la Marca18,19
  • Giulia Forni18
  • Giacomo Mascia20
  • Marina Rinaldi2
  • Annamaria Del Franco9
  • Alessia Argirò9
  • Sandro Feriozzi21
  • Matteo Accinno8
  • Alessandra Vultaggio1,8
21 affiliations
  1. 1Immunoallergology Unit, Careggi University Hospital, 50134 Florence, Italy
  2. 2Laboratory of Molecular Genetics of Neurometabolic Diseases, Neuroscience and Human Genetics Department, Meyer Children’s Hospital IRCCS, 50134 Florence, Italy
  3. 3Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, 50139 Florence, Italy
  4. 4Unit of Nephrology, Dialysis and Transplantation, AOM-IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
  5. 5Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, 16132 Genova, Italy
  6. 6Nephrology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
  7. 7School of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy
  8. 8Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
  9. 9Cardiomyopathy Unit, Careggi University Hospital, 50134 Florence, Italy
  10. 10Cardiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant’Orsola, 40138 Bologna, Italy
  11. 11European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart (ERN GUARD-Heart), 40138 Bologna, Italy
  12. 12Nephrology, Dialysis and Transplantation Unit, Careggi University Hospital, 50134 Florence, Italy
  13. 13NEUROFARBA Department, University of Florence, 50019 Florence, Italy
  14. 14Stroke Unit, Careggi University Hospital, 50134 Florence, Italy
  15. 15Nephrology and Dialysis Department, Belcolle Hospital, 01100 Viterbo, Italy
  16. 16SOSD Genetica Medica e Coordinamento Malattie Rare, Azienda Ospedaliero-Universitaria delle Marche, 60126 Ancona, Italy
  17. 17Unit of Nephrology, Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, 24127 Bergamo, Italy
  18. 18Newborn Screening, Clinical Biochemistry and Clinical Pharmacy Lab Meyer Children’s Hospital IRCCS, 50139 Florence, Italy
  19. 19Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
  20. 20Divisione di Nefrologia e Dialisi Azienda Ospedaliera “G. Brotzu”, 09134 Cagliari, Italy
  21. 21Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
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Abstract

(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.

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Cite

BibTeXRIS
BibTeX
@article{matucci2026antidrug,
  title = {{Anti-Drug Antibodies in Patients with Fabry Disease Treated with Agalsidase-Alpha or -Beta: A Retrospective Italian Multicenter Study}},
  author = {Andrea Matucci and Michael Diomaiuti and Amelia Morrone and Pasquale Esposito and Federico Pieruzzi and Maurizio Pieroni and Emanuele Vivarelli and Elena Biagini and Raffaello Ditaranto and Maria Alessandra Schiavo and Calogero Lino Cirami and Leonardo Caroti and Egrina Dervishi and Ilaria Romani and Cristina Sarti and Mario Mangeri and Barbara Trezzi and Letizia Roggero and Claudia Sgattoni and Alessia Gennarini and Giancarlo la Marca and Giulia Forni and Giacomo Mascia and Marina Rinaldi and Annamaria Del Franco and Alessia Argirò and Sandro Feriozzi and Matteo Accinno and Alessandra Vultaggio},
  journal = {Cells},
  year = {2026},
  month = nov,
  doi = {10.3390/cells15212015},
  url = {https://www.mdpi.com/2073-4409/15/21/2015},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Anti-Drug Antibodies in Patients with Fabry Disease Treated with Agalsidase-Alpha or -Beta: A Retrospective Italian Multicenter Study
AU  - Andrea Matucci
AU  - Michael Diomaiuti
AU  - Amelia Morrone
AU  - Pasquale Esposito
AU  - Federico Pieruzzi
AU  - Maurizio Pieroni
AU  - Emanuele Vivarelli
AU  - Elena Biagini
AU  - Raffaello Ditaranto
AU  - Maria Alessandra Schiavo
AU  - Calogero Lino Cirami
AU  - Leonardo Caroti
AU  - Egrina Dervishi
AU  - Ilaria Romani
AU  - Cristina Sarti
AU  - Mario Mangeri
AU  - Barbara Trezzi
AU  - Letizia Roggero
AU  - Claudia Sgattoni
AU  - Alessia Gennarini
AU  - Giancarlo la Marca
AU  - Giulia Forni
AU  - Giacomo Mascia
AU  - Marina Rinaldi
AU  - Annamaria Del Franco
AU  - Alessia Argirò
AU  - Sandro Feriozzi
AU  - Matteo Accinno
AU  - Alessandra Vultaggio
PY  - 2026
DA  - 2026/11/05
JO  - Cells
DO  - 10.3390/cells15212015
UR  - https://www.mdpi.com/2073-4409/15/21/2015
AB  - (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.
SN  - 2073-4409
ER  -