{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T06:08:27Z","timestamp":1793858907754,"version":"4.6.1"},"reference-count":23,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T00:00:00Z","timestamp":1573689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Fabry disease (FD) is a lysosomal storage disease, treatable by enzyme replacement therapy (ERT) that substitutes deficient \u03b1\u2010galactosidase A (AGAL). The formation of neutralising anti\u2010drug antibodies (ADA) inhibiting AGAL activity during infusion is associated with disease progression in affected male patients. In this study we analysed if ADAs also inhibit endothelial enzyme uptake as well as intracellular enzyme activity. Therefore, fluorescence\u2010labelled AGAL in combination with ADA\u2010positive sera from FD patients (n = 8) was used to analyse enzyme uptake in endothelial and FD\u2010specific cells. Furthermore, immune adsorption and a comprehensive ADA epitope mapping were performed. Pre\u2010incubation of AGAL with ADAs significantly inhibited intracellular enzyme activity, which was rescued by immune adsorption (both\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u2009.01). ADAs from some patients also inhibited enzyme uptake. ADA epitope mapping identified an epitope at position 121 to 140 aa potentially responsible for uptake inhibition for these patients. Further analyses revealed the presence of stable AGAL\/ADA\u2010immune complexes at pH 4.5 and decreased intracellular enzyme activity in endothelial cells (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u2009.001). Finally, the pre\u2010incubation of AGAL with ADAs resulted in a reduced depletion of intracellular globotriaosylceramide in patient\u2010derived AGAL\u2010deficient cells, demonstrating a direct negative impact of ADAs on intracellular clearance. Neutralising ADAs may not only inhibit infused AGAL activity, but according to their epitopes can also inhibit endothelial AGAL uptake. Indeed, internalised AGAL\/ADA\u2010complexes may not dissociate, underlining the importance of novel therapeutic approaches for ADA reduction and prevention to increase therapy efficiency in affected patients.\n                  <\/jats:p>","DOI":"10.1002\/jimd.12176","type":"journal-article","created":{"date-parts":[[2019,10,6]],"date-time":"2019-10-06T03:53:41Z","timestamp":1570334021000},"page":"334-347","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Neutralising anti\u2010drug antibodies in Fabry disease can inhibit endothelial enzyme uptake and activity"],"prefix":"10.1002","volume":"43","author":[{"given":"Franciska","family":"Stappers","sequence":"first","affiliation":[{"name":"Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology University Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Scharnetzki","sequence":"additional","affiliation":[{"name":"Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology University Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease University Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Manikowski","sequence":"additional","affiliation":[{"name":"Institute of Physiological Chemistry and Pathobiochemistry and Cells\u2010in\u2010Motion Cluster of Excellence (EXC1003\u2010CiM) University of Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan\u2010Martin","family":"Brand","sequence":"additional","affiliation":[{"name":"Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease University Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay","family":"Grobe","sequence":"additional","affiliation":[{"name":"Institute of Physiological Chemistry and Pathobiochemistry and Cells\u2010in\u2010Motion Cluster of Excellence (EXC1003\u2010CiM) University of Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8409-2886","authenticated-orcid":false,"given":"Malte","family":"Lenders","sequence":"additional","affiliation":[{"name":"Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology University Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Brand","sequence":"additional","affiliation":[{"name":"Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology University Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,11,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61589-5"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200107053450102"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.285.21.2743"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2018030329"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2014121226"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.12.1001"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00924.x"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0047805"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2018.11.008"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2008.03.003"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2017-104863"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2018070740"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0877-4"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2008.10.004"},{"key":"e_1_2_8_16_1","first-page":"157","article-title":"Fabry's disease: enzymatic diagnosis of hemizygotes and heterozygotes. Alpha\u2010galactosidase activities in plasma, serum, urine, and leukocytes","volume":"81","author":"Desnick RJ","year":"1973","journal-title":"J Lab Clin Med"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0009-8981(81)90384-3"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.80.12.3734"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2019-106005"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.49.6.556"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2013030290"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2003-0988-L"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)60731-0"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.02.003"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12176","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jimd.12176","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12176","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T23:20:41Z","timestamp":1693351241000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jimd.12176"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,14]]},"references-count":23,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,3]]}},"alternative-id":["10.1002\/jimd.12176"],"URL":"https:\/\/doi.org\/10.1002\/jimd.12176","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,14]]},"assertion":[{"value":"2019-06-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-11-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}