Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease
Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50% of male patients with classical FD develop inhibiting anti-drug...
Main Authors: | , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2020-08-01
|
Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | https://www.mdpi.com/1422-0067/21/16/5784 |
id |
doaj-6bb61548db1441af83b377edf9e1fac9 |
---|---|
record_format |
Article |
spelling |
doaj-6bb61548db1441af83b377edf9e1fac92020-11-25T03:38:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-08-01215784578410.3390/ijms21165784Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry DiseaseSanne J. van der Veen0Wytze J. Vlietstra1Laura van Dussen2André B.P. van Kuilenburg3Marcel G. W. Dijkgraaf4Malte Lenders5Eva Brand6Christoph Wanner7Derralynn Hughes8Perry M. Elliott9Carla E. M. Hollak10Mirjam Langeveld11Department of Endocrinology and Metabolism, Amsterdam University Medical Centers (AUMC), University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Medical Informatics, Erasmus University, 3000 CA Rotterdam, The NetherlandsDepartment of Endocrinology and Metabolism, Amsterdam University Medical Centers (AUMC), University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsLaboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers (AUMC), University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Epidemiology and Data Science, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands. <email>m.g.dijkgraaf@amsterdamumc.nl</email>Department of Internal Medicine D, and Interdisciplinary Fabry Center (IFAZ), University Hospital Muenster, D-48149 Muenster, GermanyDepartment of Internal Medicine D, and Interdisciplinary Fabry Center (IFAZ), University Hospital Muenster, D-48149 Muenster, GermanyDepartment of Medicine, Division of Nephrology, University Hospital Würzburg, 97080 Würzburg, GermanyDepartment of Haematology, Royal Free London National Health Service Foundation Trust and University College London, London NW3 2QG, UKDepartment of Cardiology, St. Bartholomew’s Hospital and University College London, London EC1A 7BE, UKDepartment of Endocrinology and Metabolism, Amsterdam University Medical Centers (AUMC), University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Endocrinology and Metabolism, Amsterdam University Medical Centers (AUMC), University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsFabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene (<i>p</i> = 0.05), higher plasma lysoGb3 at baseline (<i>p</i> < 0.001) and agalsidase beta as first treatment (<i>p</i> = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk.https://www.mdpi.com/1422-0067/21/16/5784Fabry diseaseenzyme replacement therapyanti-drug antibodiesprediction model |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sanne J. van der Veen Wytze J. Vlietstra Laura van Dussen André B.P. van Kuilenburg Marcel G. W. Dijkgraaf Malte Lenders Eva Brand Christoph Wanner Derralynn Hughes Perry M. Elliott Carla E. M. Hollak Mirjam Langeveld |
spellingShingle |
Sanne J. van der Veen Wytze J. Vlietstra Laura van Dussen André B.P. van Kuilenburg Marcel G. W. Dijkgraaf Malte Lenders Eva Brand Christoph Wanner Derralynn Hughes Perry M. Elliott Carla E. M. Hollak Mirjam Langeveld Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease International Journal of Molecular Sciences Fabry disease enzyme replacement therapy anti-drug antibodies prediction model |
author_facet |
Sanne J. van der Veen Wytze J. Vlietstra Laura van Dussen André B.P. van Kuilenburg Marcel G. W. Dijkgraaf Malte Lenders Eva Brand Christoph Wanner Derralynn Hughes Perry M. Elliott Carla E. M. Hollak Mirjam Langeveld |
author_sort |
Sanne J. van der Veen |
title |
Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease |
title_short |
Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease |
title_full |
Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease |
title_fullStr |
Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease |
title_full_unstemmed |
Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease |
title_sort |
predicting the development of anti-drug antibodies against recombinant alpha-galactosidase a in male patients with classical fabry disease |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-08-01 |
description |
Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene (<i>p</i> = 0.05), higher plasma lysoGb3 at baseline (<i>p</i> < 0.001) and agalsidase beta as first treatment (<i>p</i> = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk. |
topic |
Fabry disease enzyme replacement therapy anti-drug antibodies prediction model |
url |
https://www.mdpi.com/1422-0067/21/16/5784 |
work_keys_str_mv |
AT sannejvanderveen predictingthedevelopmentofantidrugantibodiesagainstrecombinantalphagalactosidaseainmalepatientswithclassicalfabrydisease AT wytzejvlietstra predictingthedevelopmentofantidrugantibodiesagainstrecombinantalphagalactosidaseainmalepatientswithclassicalfabrydisease AT lauravandussen predictingthedevelopmentofantidrugantibodiesagainstrecombinantalphagalactosidaseainmalepatientswithclassicalfabrydisease AT andrebpvankuilenburg predictingthedevelopmentofantidrugantibodiesagainstrecombinantalphagalactosidaseainmalepatientswithclassicalfabrydisease AT marcelgwdijkgraaf predictingthedevelopmentofantidrugantibodiesagainstrecombinantalphagalactosidaseainmalepatientswithclassicalfabrydisease AT maltelenders predictingthedevelopmentofantidrugantibodiesagainstrecombinantalphagalactosidaseainmalepatientswithclassicalfabrydisease AT evabrand predictingthedevelopmentofantidrugantibodiesagainstrecombinantalphagalactosidaseainmalepatientswithclassicalfabrydisease AT christophwanner predictingthedevelopmentofantidrugantibodiesagainstrecombinantalphagalactosidaseainmalepatientswithclassicalfabrydisease AT derralynnhughes predictingthedevelopmentofantidrugantibodiesagainstrecombinantalphagalactosidaseainmalepatientswithclassicalfabrydisease AT perrymelliott predictingthedevelopmentofantidrugantibodiesagainstrecombinantalphagalactosidaseainmalepatientswithclassicalfabrydisease AT carlaemhollak predictingthedevelopmentofantidrugantibodiesagainstrecombinantalphagalactosidaseainmalepatientswithclassicalfabrydisease AT mirjamlangeveld predictingthedevelopmentofantidrugantibodiesagainstrecombinantalphagalactosidaseainmalepatientswithclassicalfabrydisease |
_version_ |
1724542199019864064 |