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Biomarker responses correlate with antibody status in mucopolysaccharidosis type I patients on long-term enzyme replacement therapy
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, investi...
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| Published in: | Molecular genetics and metabolism 2015-02, Vol.114 (2), p.129-137 |
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| creator | Langereis, Eveline J. van Vlies, Naomi Church, Heather J. Geskus, Ronald B. Hollak, Carla E.M. Jones, Simon A. Kulik, Wim van Lenthe, Henk Mercer, Jean Schreider, Lena Tylee, Karen L. Wagemans, Tom Wijburg, Frits A. Bigger, Brian W. |
| description | 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.
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.
Median follow-up was 2.3years. 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 |
| doi_str_mv | 10.1016/j.ymgme.2014.10.012 |
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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.
Median follow-up was 2.3years. 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).
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.
•Biomarker responses in ERT treated MPS I patients were evaluated.•IgG antibody titers and the effect on cellular uptake were determined.•Incomplete normalization of biomarkers suggests residual disease activity.•Uptake inhibiting antibodies are associated with a decreased biomarker response.•Conventional GAGs in urine by DMB overestimates biochemical correction.</description><identifier>ISSN: 1096-7192</identifier><identifier>EISSN: 1096-7206</identifier><identifier>DOI: 10.1016/j.ymgme.2014.10.012</identifier><identifier>PMID: 25467058</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adolescent ; Adult ; Antibody formation ; Biomarker ; Biomarkers - analysis ; Child ; Child, Preschool ; Dermatan Sulfate - analysis ; Disaccharides - analysis ; Disaccharides - blood ; Disaccharides - urine ; Enzyme Replacement Therapy ; Female ; Follow-Up Studies ; Glycosaminoglycans ; Heparin Cofactor II - analysis ; Heparitin Sulfate - analysis ; Heparitin Sulfate - blood ; Heparitin Sulfate - urine ; Humans ; Iduronidase - immunology ; Iduronidase - therapeutic use ; Immunoglobulin G - blood ; Infant ; Infant, Newborn ; Laronidase ; Male ; Mucopolysaccharidosis I - blood ; Mucopolysaccharidosis I - drug therapy ; Mucopolysaccharidosis I - immunology ; Mucopolysaccharidosis I - urine ; Mucopolysaccharidosis type I ; Recombinant Proteins - immunology ; Recombinant Proteins - therapeutic use ; Thrombin - analysis ; Young Adult</subject><ispartof>Molecular genetics and metabolism, 2015-02, Vol.114 (2), p.129-137</ispartof><rights>2014 Elsevier Inc.</rights><rights>Copyright © 2014 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c359t-8e030c933b23163fcad4f14fb692bca976e761c946740a81f9ae324cfbb16a863</citedby><cites>FETCH-LOGICAL-c359t-8e030c933b23163fcad4f14fb692bca976e761c946740a81f9ae324cfbb16a863</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25467058$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Langereis, Eveline J.</creatorcontrib><creatorcontrib>van Vlies, Naomi</creatorcontrib><creatorcontrib>Church, Heather J.</creatorcontrib><creatorcontrib>Geskus, Ronald B.</creatorcontrib><creatorcontrib>Hollak, Carla E.M.</creatorcontrib><creatorcontrib>Jones, Simon A.</creatorcontrib><creatorcontrib>Kulik, Wim</creatorcontrib><creatorcontrib>van Lenthe, Henk</creatorcontrib><creatorcontrib>Mercer, Jean</creatorcontrib><creatorcontrib>Schreider, Lena</creatorcontrib><creatorcontrib>Tylee, Karen L.</creatorcontrib><creatorcontrib>Wagemans, Tom</creatorcontrib><creatorcontrib>Wijburg, Frits A.</creatorcontrib><creatorcontrib>Bigger, Brian W.</creatorcontrib><title>Biomarker responses correlate with antibody status in mucopolysaccharidosis type I patients on long-term enzyme replacement therapy</title><title>Molecular genetics and metabolism</title><addtitle>Mol Genet Metab</addtitle><description>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.
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.
Median follow-up was 2.3years. 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).
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.
•Biomarker responses in ERT treated MPS I patients were evaluated.•IgG antibody titers and the effect on cellular uptake were determined.•Incomplete normalization of biomarkers suggests residual disease activity.•Uptake inhibiting antibodies are associated with a decreased biomarker response.•Conventional GAGs in urine by DMB overestimates biochemical correction.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Antibody formation</subject><subject>Biomarker</subject><subject>Biomarkers - analysis</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Dermatan Sulfate - analysis</subject><subject>Disaccharides - analysis</subject><subject>Disaccharides - blood</subject><subject>Disaccharides - urine</subject><subject>Enzyme Replacement Therapy</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Glycosaminoglycans</subject><subject>Heparin Cofactor II - analysis</subject><subject>Heparitin Sulfate - analysis</subject><subject>Heparitin Sulfate - blood</subject><subject>Heparitin Sulfate - urine</subject><subject>Humans</subject><subject>Iduronidase - immunology</subject><subject>Iduronidase - therapeutic use</subject><subject>Immunoglobulin G - blood</subject><subject>Infant</subject><subject>Infant, Newborn</subject><subject>Laronidase</subject><subject>Male</subject><subject>Mucopolysaccharidosis I - blood</subject><subject>Mucopolysaccharidosis I - drug therapy</subject><subject>Mucopolysaccharidosis I - immunology</subject><subject>Mucopolysaccharidosis I - urine</subject><subject>Mucopolysaccharidosis type I</subject><subject>Recombinant Proteins - immunology</subject><subject>Recombinant Proteins - therapeutic use</subject><subject>Thrombin - analysis</subject><subject>Young Adult</subject><issn>1096-7192</issn><issn>1096-7206</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNp9kE1v1DAQhi1ERT_gFyAhH7lk8UfijQ8coIJSqVIvcLYcZ9L1EsfB4xSFa_94vWzLkdOMRs_Mq3kIecvZhjOuPuw3a7gLsBGM12WyYVy8IGecaVVtBVMvn3uuxSk5R9wzxnmj61fkVDS12rKmPSMPn30MNv2ERBPgHCcEpC6mBKPNQH_7vKN2yr6L_Uox27wg9RMNi4tzHFe0zu1s8n1EjzSvM9BrOtvsYcpI40THON1VGVKgMP1ZA5SUebQOQgFo3kGy8_qanAx2RHjzVC_Ij69fvl9-q25ur64vP91UTjY6Vy0wyZyWshOSKzk429cDr4dOadE5q7cKtoo7XV6rmW35oC1IUbuh67iyrZIX5P3x7pzirwUwm-DRwTjaCeKChqtG1Fwz1RZUHlGXImKCwczJF0-r4cwc7Ju9-WvfHOwfhsV-2Xr3FLB0Afp_O8-6C_DxCEB5895DMuiKKge9T-Cy6aP_b8AjFeKazw</recordid><startdate>201502</startdate><enddate>201502</enddate><creator>Langereis, Eveline J.</creator><creator>van Vlies, Naomi</creator><creator>Church, Heather J.</creator><creator>Geskus, Ronald B.</creator><creator>Hollak, Carla E.M.</creator><creator>Jones, Simon A.</creator><creator>Kulik, Wim</creator><creator>van Lenthe, Henk</creator><creator>Mercer, Jean</creator><creator>Schreider, Lena</creator><creator>Tylee, Karen L.</creator><creator>Wagemans, Tom</creator><creator>Wijburg, Frits A.</creator><creator>Bigger, Brian W.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201502</creationdate><title>Biomarker responses correlate with antibody status in mucopolysaccharidosis type I patients on long-term enzyme replacement therapy</title><author>Langereis, Eveline J. ; van Vlies, Naomi ; Church, Heather J. ; Geskus, Ronald B. ; Hollak, Carla E.M. ; Jones, Simon A. ; Kulik, Wim ; van Lenthe, Henk ; Mercer, Jean ; Schreider, Lena ; Tylee, Karen L. ; Wagemans, Tom ; Wijburg, Frits A. ; Bigger, Brian W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c359t-8e030c933b23163fcad4f14fb692bca976e761c946740a81f9ae324cfbb16a863</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Antibody formation</topic><topic>Biomarker</topic><topic>Biomarkers - analysis</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Dermatan Sulfate - analysis</topic><topic>Disaccharides - analysis</topic><topic>Disaccharides - blood</topic><topic>Disaccharides - urine</topic><topic>Enzyme Replacement Therapy</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Glycosaminoglycans</topic><topic>Heparin Cofactor II - analysis</topic><topic>Heparitin Sulfate - analysis</topic><topic>Heparitin Sulfate - blood</topic><topic>Heparitin Sulfate - urine</topic><topic>Humans</topic><topic>Iduronidase - immunology</topic><topic>Iduronidase - therapeutic use</topic><topic>Immunoglobulin G - blood</topic><topic>Infant</topic><topic>Infant, Newborn</topic><topic>Laronidase</topic><topic>Male</topic><topic>Mucopolysaccharidosis I - blood</topic><topic>Mucopolysaccharidosis I - drug therapy</topic><topic>Mucopolysaccharidosis I - immunology</topic><topic>Mucopolysaccharidosis I - urine</topic><topic>Mucopolysaccharidosis type I</topic><topic>Recombinant Proteins - immunology</topic><topic>Recombinant Proteins - therapeutic use</topic><topic>Thrombin - analysis</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Langereis, Eveline J.</creatorcontrib><creatorcontrib>van Vlies, Naomi</creatorcontrib><creatorcontrib>Church, Heather J.</creatorcontrib><creatorcontrib>Geskus, Ronald B.</creatorcontrib><creatorcontrib>Hollak, Carla E.M.</creatorcontrib><creatorcontrib>Jones, Simon A.</creatorcontrib><creatorcontrib>Kulik, Wim</creatorcontrib><creatorcontrib>van Lenthe, Henk</creatorcontrib><creatorcontrib>Mercer, Jean</creatorcontrib><creatorcontrib>Schreider, Lena</creatorcontrib><creatorcontrib>Tylee, Karen L.</creatorcontrib><creatorcontrib>Wagemans, Tom</creatorcontrib><creatorcontrib>Wijburg, Frits A.</creatorcontrib><creatorcontrib>Bigger, Brian W.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular genetics and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Langereis, Eveline J.</au><au>van Vlies, Naomi</au><au>Church, Heather J.</au><au>Geskus, Ronald B.</au><au>Hollak, Carla E.M.</au><au>Jones, Simon A.</au><au>Kulik, Wim</au><au>van Lenthe, Henk</au><au>Mercer, Jean</au><au>Schreider, Lena</au><au>Tylee, Karen L.</au><au>Wagemans, Tom</au><au>Wijburg, Frits A.</au><au>Bigger, Brian W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Biomarker responses correlate with antibody status in mucopolysaccharidosis type I patients on long-term enzyme replacement therapy</atitle><jtitle>Molecular genetics and metabolism</jtitle><addtitle>Mol Genet Metab</addtitle><date>2015-02</date><risdate>2015</risdate><volume>114</volume><issue>2</issue><spage>129</spage><epage>137</epage><pages>129-137</pages><issn>1096-7192</issn><eissn>1096-7206</eissn><abstract>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.
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.
Median follow-up was 2.3years. 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).
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.
•Biomarker responses in ERT treated MPS I patients were evaluated.•IgG antibody titers and the effect on cellular uptake were determined.•Incomplete normalization of biomarkers suggests residual disease activity.•Uptake inhibiting antibodies are associated with a decreased biomarker response.•Conventional GAGs in urine by DMB overestimates biochemical correction.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25467058</pmid><doi>10.1016/j.ymgme.2014.10.012</doi><tpages>9</tpages></addata></record> |
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| subjects | Adolescent Adult Antibody formation Biomarker Biomarkers - analysis Child Child, Preschool Dermatan Sulfate - analysis Disaccharides - analysis Disaccharides - blood Disaccharides - urine Enzyme Replacement Therapy Female Follow-Up Studies Glycosaminoglycans Heparin Cofactor II - analysis Heparitin Sulfate - analysis Heparitin Sulfate - blood Heparitin Sulfate - urine Humans Iduronidase - immunology Iduronidase - therapeutic use Immunoglobulin G - blood Infant Infant, Newborn Laronidase Male Mucopolysaccharidosis I - blood Mucopolysaccharidosis I - drug therapy Mucopolysaccharidosis I - immunology Mucopolysaccharidosis I - urine Mucopolysaccharidosis type I Recombinant Proteins - immunology Recombinant Proteins - therapeutic use Thrombin - analysis Young Adult |
| title | Biomarker responses correlate with antibody status in mucopolysaccharidosis type I patients on long-term enzyme replacement therapy |
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