{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:19:11Z","timestamp":1790007551521,"version":"4.0.1"},"reference-count":23,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2015,6,20]],"date-time":"2015-06-20T00:00:00Z","timestamp":1434758400000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R43-NS-088868"],"award-info":[{"award-number":["R43-NS-088868"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mutations in the lysosomal enzyme, N-sulfoglucosamine sulfohydrolase (SGSH), also called sulfamidase, cause accumulation of lysosomal inclusion bodies in the brain of children born with mucopolysaccharidosis type IIIA, also called Sanfilippo type A syndrome. Enzyme replacement therapy with recombinant SGSH does not treat the brain because the enzyme is a large molecule drug that does not cross the blood\u2013brain barrier (BBB). A BBB-penetrating form of SGSH was produced by re-engineering the enzyme as an IgG fusion protein, where the IgG domain is a monoclonal antibody (mAb) against the human insulin receptor (HIR). The HIRMAb domain of the HIRMAb\u2013SGSH fusion protein acts as a molecular Trojan horse to ferry the fused enzyme across the BBB. The HIRMAb\u2013SGSH was produced in stably transfected host cells and purified to homogeneity by protein A chromatography. The fusion protein reacted with antibodies against either human IgG or SGSH on Western blotting. High affinity binding to the HIR was retained following SGSH fusion to the HIRMAb, with an EC50 of 0.33 \u00b1 0.05 nM in an HIR binding ELISA. The SGSH enzyme activity of the HIRMAb\u2013SGSH fusion protein was 4712 \u00b1 388 units\/mg protein based on a two-step fluorometric enzyme assay. The HIRMAb\u2013SGSH was taken up by lysosomes in MPSIIIA fibroblasts, and treatment of these cells with the fusion protein caused an 83% reduction in sulfate incorporation into lysosomal glycosoaminoglycans. The HIRMAb\u2013SGSH fusion protein was radiolabeled with the [125I]-Bolton\u2013Hunter reagent and injected intravenously in the Rhesus monkey. The brain uptake of the fusion protein was high, \u223c1% injected dose\/brain. Calculations, based on this level of brain uptake, suggest normalization of brain SGSH enzyme activity is possible following administration of therapeutic doses of the fusion protein. These studies describe a novel IgG\u2013SGSH fusion protein that is a new noninvasive treatment of the brain in MPS type IIIA.<\/jats:p>","DOI":"10.1021\/mp500258p","type":"journal-article","created":{"date-parts":[[2014,6,20]],"date-time":"2014-06-20T08:58:03Z","timestamp":1403254683000},"page":"2928-2934","source":"Crossref","is-referenced-by-count":65,"title":["Insulin Receptor Antibody\u2013Sulfamidase Fusion\nProtein Penetrates the Primate Blood\u2013Brain Barrier and Reduces\nGlycosoaminoglycans in Sanfilippo Type A Cells"],"prefix":"10.1021","volume":"11","author":[{"given":"Ruben J.","family":"Boado","sequence":"first","affiliation":[{"name":"ArmaGen Technologies, Inc. , 26679 Agoura Road, Suite 100 , , ,","place":["Calabasas, California, United States, 91302"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff Zhiqiang","family":"Lu","sequence":"additional","affiliation":[{"name":"ArmaGen Technologies, Inc. , 26679 Agoura Road, Suite 100 , , ,","place":["Calabasas, California, United States, 91302"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric Ka-Wai","family":"Hui","sequence":"additional","affiliation":[{"name":"ArmaGen Technologies, Inc. , 26679 Agoura Road, Suite 100 , , ,","place":["Calabasas, California, United States, 91302"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M.","family":"Pardridge","sequence":"additional","affiliation":[{"name":"ArmaGen Technologies, Inc. , 26679 Agoura Road, Suite 100 , , ,","place":["Calabasas, California, United States, 91302"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,6,20]]},"reference":[{"key":"2026090204244455600_cit1","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1007\/s10545-008-0838-5","article-title":"Sanfilippo syndrome: a mini-review","volume":"31","author":"Valstar","year":"2008","journal-title":"J. Inherited Metab. Dis."},{"key":"2026090204244455600_cit2","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1002\/ana.22092","article-title":"Mucopolysaccharidosis type IIIA:\nclinical spectrum and genotype\u2013phenotype correlations","volume":"68","author":"Valstar","year":"2010","journal-title":"Ann. Neurol."},{"key":"2026090204244455600_cit3","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/ng1295-465","article-title":"Cloning\nof the sulphamidase gene and identification of mutations in Sanfilippo\nA syndrome","volume":"11","author":"Scott","year":"1995","journal-title":"Nature Genet."},{"key":"2026090204244455600_cit4","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1038\/mt.2008.84","article-title":"Mannose\n6-phosphate\nreceptor-mediated transport of sulfamidase across the blood\u2013brain\nbarrier in the newborn mouse","volume":"16","author":"Urayama","year":"2008","journal-title":"Mol. Ther."},{"key":"2026090204244455600_cit5","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1111\/j.1365-2990.2010.01158.x","article-title":"Intracisternal enzyme\nreplacement therapy in lysosomal storage diseases:\nroutes of absorption into brain","volume":"37","author":"Jolly","year":"2011","journal-title":"Neuropathol.\nAppl. Neurobiol."},{"key":"2026090204244455600_cit6","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1038\/jcbfm.2012.126","article-title":"Drug transport\nacross the blood\u2013brain barrier","volume":"32","author":"Pardridge","year":"2012","journal-title":"J. Cereb.\nBlood Flow Metabol."},{"key":"2026090204244455600_cit7","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/B978-0-12-396962-0.00011-2","article-title":"Reengineering biopharmaceuticals for targeted delivery\nacross the blood\u2013brain barrier","volume":"503","author":"Pardridge","year":"2012","journal-title":"Methods\nEnzymol."},{"key":"2026090204244455600_cit8","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1002\/bit.21120","article-title":"Humanization\nof anti-human insulin receptor antibody for drug targeting across\nthe human blood\u2013brain barrier","volume":"96","author":"Boado","year":"2007","journal-title":"Biotechnol.\nBioeng."},{"key":"2026090204244455600_cit9","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1002\/bit.24795","article-title":"Pharmacokinetics\nand brain uptake in the Rhesus monkey of a fusion protein of arylsulfatase\nA and a monoclonal antibody against the human insulin receptor","volume":"110","author":"Boado","year":"2013","journal-title":"Biotechnol. Bioeng."},{"key":"2026090204244455600_cit10","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.ymgme.2004.07.001","article-title":"Expression and functional characterization of human\nmutant sulfamidase in insect cells","volume":"83","author":"Montfort","year":"2004","journal-title":"Mol. Genet.\nMetab."},{"key":"2026090204244455600_cit11","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1007\/BF01799255","article-title":"A fluorimetric\nenzyme assay for the diagnosis of Sanfilippo disease type A (MPS IIIA)","volume":"19","author":"Karpova","year":"1996","journal-title":"J. Inherited Metab. Dis."},{"key":"2026090204244455600_cit12","doi-asserted-by":"crossref","first-page":"6955","DOI":"10.1074\/jbc.M110.192062","article-title":"Secondary storage\nof dermatan sulfate in Sanfilippo disease","volume":"286","author":"LaManna","year":"2011","journal-title":"J.\nBiol. Chem."},{"key":"2026090204244455600_cit13","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1111\/j.1471-4159.1990.tb04886.x","article-title":"Capillary\ndepletion method for quantifying\nblood\u2013brain barrier transcytosis of circulating peptides and\nplasma proteins","volume":"54","author":"Triguero","year":"1990","journal-title":"J. Neurochem."},{"key":"2026090204244455600_cit14","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1023\/A:1016244500596","article-title":"Human insulin receptor\nmonoclonal antibody undergoes high affinity binding to human brain\ncapillaries in vitro and rapid transcytosis through the blood\u2013brain\nbarrier in vivo in the primate","volume":"12","author":"Pardridge","year":"1995","journal-title":"Pharm. Res."},{"key":"2026090204244455600_cit15","doi-asserted-by":"crossref","first-page":"205","DOI":"10.3109\/10611860903353362","article-title":"Genetic\nengineering of IgG\u2013glucuronidase fusion\nproteins","volume":"18","author":"Boado","year":"2010","journal-title":"J. Drug Targeting"},{"key":"2026090204244455600_cit16","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1042\/BJ20061783","article-title":"SUMF1 enhances sulfatase\nactivities in vivo in five sulfatase deficiencies","volume":"403","author":"Fraldi","year":"2007","journal-title":"Biochem. J."},{"key":"2026090204244455600_cit17","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.expneurol.2011.04.004","article-title":"Impact of high-dose, chemically modified sulfamidase\non pathology in a murine model of MPS IIIA","volume":"230","author":"Rozaklis","year":"2011","journal-title":"Exp. Neurol."},{"key":"2026090204244455600_cit18","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1042\/bj3020601","article-title":"The effect of elevated plasma phenylalanine\nlevels on protein synthesis rates in adult rat brain","volume":"302","author":"Dunlop","year":"1994","journal-title":"Biochem. J."},{"key":"2026090204244455600_cit19","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.ymgme.2007.02.009","article-title":"Murine model (Galnstm(C76S)slu) of MPS IVA with missense mutation at the active site cysteine\nconserved among sulfatase proteins","volume":"91","author":"Tomatsu","year":"2007","journal-title":"Mol. Genet.\nMetab."},{"key":"2026090204244455600_cit20","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1172\/JCI119708","article-title":"Drug targeting\nof a peptide radiopharmaceutical\nthrough the primate blood\u2013brain barrier in vivo with a monoclonal\nantibody to the human insulin receptor","volume":"100","author":"Wu","year":"1997","journal-title":"J. Clin.\nInvest."},{"key":"2026090204244455600_cit21","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1002\/bit.23118","article-title":"Expression\nin CHO cells and pharmacokinetics and brain uptake in the Rhesus monkey\nof an IgG\u2013iduronate-2-sulfatase fusion protein","volume":"108","author":"Lu","year":"2011","journal-title":"Biotechnol. Bioeng."},{"key":"2026090204244455600_cit22","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1021\/bc400319d","article-title":"Blood\u2013brain\nbarrier molecular Trojan horse enables brain imaging of radioiodinated\nrecombinant protein in the Rhesus monkey","volume":"24","author":"Boado","year":"2013","journal-title":"Bioconjugate\nChem."},{"key":"2026090204244455600_cit23","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1124\/dmd.109.028787","article-title":"Comparison\nof blood\u2013brain barrier transport\nof GDNF and an IgG\u2013GDNF fusion protein in the Rhesus monkey","volume":"37","author":"Boado","year":"2009","journal-title":"Drug Metab. Dispos."}],"container-title":["Molecular Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/mp500258p","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article-pdf\/11\/8\/2928\/14376230\/mp500258p.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article-pdf\/11\/8\/2928\/14376230\/mp500258p.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T08:24:52Z","timestamp":1788337492000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article\/11\/8\/2928\/1379853\/Insulin-Receptor-Antibody-Sulfamidase-Fusion"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,20]]},"references-count":23,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2014,6,20]]},"published-print":{"date-parts":[[2014,8,4]]}},"URL":"https:\/\/doi.org\/10.1021\/mp500258p","relation":{},"ISSN":["1543-8384","1543-8392"],"issn-type":[{"value":"1543-8384","type":"print"},{"value":"1543-8392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,6,20]]}}}