Eveline J Langereis1, Naomi van Vlies2, Heather J Church3, Ronald B Geskus4, Carla E M Hollak5, Simon A Jones3, Wim Kulik6, Henk van Lenthe6, Jean Mercer3, Lena Schreider7, Karen L Tylee3, Tom Wagemans2, Frits A Wijburg8, Brian W Bigger7. 1. Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 2. Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Laboratory for Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 3. Genetic Medicine, Manchester Academic Health Science Centre, Central Manchester University Hospitals, NHS Foundation Trust, St Mary's Hospital, Manchester, UK. 4. Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 5. Department of Internal Medicine, Division of Endocrinology and Metabolism and Amsterdam Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 6. Laboratory for Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 7. Stem Cell & Neurotherapies, Centre for Genomic Medicine, University of Manchester, Manchester, UK. 8. Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: f.a.wijburg@amc.uva.nl.
Abstract
BACKGROUND: Antibody formation can interfere with effects of enzyme replacement therapy (ERT) in lysosomal storage diseases. Biomarkers are used as surrogate marker for disease burden in MPS I, but large systematic studies evaluating the response of biomarkers to ERT are lacking. We, for the first time, investigated the response of a large panel of biomarkers to long term ERT in MPS I patients and correlate these responses with antibody formation and antibody mediated cellular uptake inhibition. METHODS: A total of 428 blood and urine samples were collected during long-term ERT in 24 MPS I patients and an extensive set of biomarkers was analyzed, including heparan sulfate (HS) and dermatan sulfate (DS) derived disaccharides; total urinary GAGs (DMBu); urinary DS:CS ratio and serum heparin co-factor II thrombin levels (HCII-T). IgG antibody titers and the effect of antibodies on cellular uptake of the enzyme were determined for 23 patients. RESULTS: Median follow-up was 2.3 years. In blood, HS reached normal levels more frequently than DS (50% vs 12.5%, p=0.001), though normalization could take several years. DMBu normalized more rapidly than disaccharide levels in urine (p=0.02). Nineteen patients (83%) developed high antibody titers. Significant antibody-mediated inhibition of enzyme uptake was observed in 8 patients (35%), and this correlated strongly with a poorer biomarker response for HS and DS in blood and urine as well as for DMBu, DS:CS-ratio and HCII-T (all p<0.006). CONCLUSIONS: This study shows that, despite a response of all studied biomarkers to initiation of ERT, some biomarkers were less responsive than others, suggesting residual disease activity. In addition, the correlation of cellular uptake inhibitory antibodies with a decreased biomarker response demonstrates a functional role of these antibodies which may have important clinical consequences.
BACKGROUND: Antibody formation can interfere with effects of enzyme replacement therapy (ERT) in lysosomal storage diseases. Biomarkers are used as surrogate marker for disease burden in MPS I, but large systematic studies evaluating the response of biomarkers to ERT are lacking. We, for the first time, investigated the response of a large panel of biomarkers to long term ERT in MPS Ipatients and correlate these responses with antibody formation and antibody mediated cellular uptake inhibition. METHODS: A total of 428 blood and urine samples were collected during long-term ERT in 24 MPS Ipatients and an extensive set of biomarkers was analyzed, including heparan sulfate (HS) and dermatan sulfate (DS) derived disaccharides; total urinary GAGs (DMBu); urinary DS:CS ratio and serum heparin co-factor II thrombin levels (HCII-T). IgG antibody titers and the effect of antibodies on cellular uptake of the enzyme were determined for 23 patients. RESULTS: Median follow-up was 2.3 years. In blood, HS reached normal levels more frequently than DS (50% vs 12.5%, p=0.001), though normalization could take several years. DMBu normalized more rapidly than disaccharide levels in urine (p=0.02). Nineteen patients (83%) developed high antibody titers. Significant antibody-mediated inhibition of enzyme uptake was observed in 8 patients (35%), and this correlated strongly with a poorer biomarker response for HS and DS in blood and urine as well as for DMBu, DS:CS-ratio and HCII-T (all p<0.006). CONCLUSIONS: This study shows that, despite a response of all studied biomarkers to initiation of ERT, some biomarkers were less responsive than others, suggesting residual disease activity. In addition, the correlation of cellular uptake inhibitory antibodies with a decreased biomarker response demonstrates a functional role of these antibodies which may have important clinical consequences.
Authors: Christian Hinderer; Peter Bell; Jean-Pierre Louboutin; Yanqing Zhu; Hongwei Yu; Gloria Lin; Ruth Choa; Brittney L Gurda; Jessica Bagel; Patricia O'Donnell; Tracey Sikora; Therese Ruane; Ping Wang; Alice F Tarantal; Margret L Casal; Mark E Haskins; James M Wilson Journal: Mol Ther Date: 2015-05-29 Impact factor: 11.454
Authors: Abhijit Ricky Pal; Eveline J Langereis; Muhammad A Saif; Jean Mercer; Heather J Church; Karen L Tylee; Robert F Wynn; Frits A Wijburg; Simon A Jones; Iain A Bruce; Brian W Bigger Journal: Orphanet J Rare Dis Date: 2015-04-10 Impact factor: 4.123
Authors: Eveline J Langereis; Tom Wagemans; Wim Kulik; Dirk J Lefeber; Henk van Lenthe; Esmee Oussoren; Ans T van der Ploeg; George J Ruijter; Ron A Wevers; Frits A Wijburg; Naomi van Vlies Journal: PLoS One Date: 2015-09-25 Impact factor: 3.240
Authors: Arian Pano; Ann J Barbier; Bonnie Bielefeld; David A H Whiteman; David A Amato Journal: Orphanet J Rare Dis Date: 2015-04-24 Impact factor: 4.123
Authors: Orazio Gabrielli; Lorne A Clarke; Anna Ficcadenti; Lucia Santoro; Lucia Zampini; Nicola Volpi; Giovanni V Coppa Journal: BMC Med Genet Date: 2016-03-10 Impact factor: 2.103
Authors: Elina Makino; Helen Klodnitsky; John Leonard; James Lillie; Troy C Lund; John Marshall; Jennifer Nietupski; Paul J Orchard; Weston P Miller; Clifford Phaneuf; Drew Tietz; Mariet L Varban; Marissa Donovan; Alexey Belenki Journal: Sci Rep Date: 2018-02-27 Impact factor: 4.379
Authors: Christiane S Hampe; Julie B Eisengart; Troy C Lund; Paul J Orchard; Monika Swietlicka; Jacob Wesley; R Scott McIvor Journal: Cells Date: 2020-08-05 Impact factor: 6.600
Authors: 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 Journal: Int J Mol Sci Date: 2020-08-12 Impact factor: 5.923