{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T13:42:34Z","timestamp":1791034954089,"version":"4.1.0"},"reference-count":26,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2007,12,13]],"date-time":"2007-12-13T00:00:00Z","timestamp":1197504000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biotech &amp;amp; Bioengineering"],"published-print":{"date-parts":[[2008,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Glial\u2010derived neurotrophic factor (GDNF) is a neurotrophin that could be developed as a neurotherapeutic for Parkinson's disease, stroke, and motor neuron disease. However, GDNF does not cross the blood\u2013brain barrier (BBB). Human GDNF was re\u2010engineered by fusion of the mature GDNF protein to the carboxyl terminus of the chimeric monoclonal antibody (MAb) to the human insulin receptor (HIR). The HIRMAb\u2010GDNF fusion protein is bi\u2010functional, and both binds the HIR, to trigger receptor\u2010mediated transport across the BBB, and binds the GDNF receptor (GFR)\u2010\u03b11, to activate GDNF neuroprotection pathways behind the BBB. COS cells were dual transfected with the heavy chain (HC) and light chain fusion protein expression plasmids, and the HC of the fusion protein was immunoreactive with antibodies to both human IgG and GDNF. The HIRMAb\u2010GDNF fusion protein bound with high affinity to the extracellular domain of both the HIR, ED<jats:sub>50<\/jats:sub>\u2009=\u20090.87\u2009\u00b1\u20090.13 nM, and the GFR\u03b11, ED<jats:sub>50<\/jats:sub>\u2009= 1.68\u2009\u00b1\u20090.17 nM. The HIRMAb\u2010GDNF fusion protein activated luciferase gene expression in human neural SK\u2010N\u2010MC cells dual transfected with the c\u2010ret kinase and a luciferase reporter gene under the influence of the rat tyrosine hydroxylase promoter, and the ED<jats:sub>50<\/jats:sub>, 1.68\u2009\u00b1\u20090.45 nM, was identical to the ED<jats:sub>50<\/jats:sub> in the GFR\u03b11 binding assay. The fusion protein was active in vivo in a rat middle cerebral artery occlusion model, where the stroke volume was reduced 77% (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001). In conclusion, these studies describe the re\u2010engineering of GDNF, to make this neurotrophin transportable across the human BBB. Biotechnol. Bioeng. 2008;100: 387\u2013396. \u00a9 2007 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/bit.21764","type":"journal-article","created":{"date-parts":[[2007,12,13]],"date-time":"2007-12-13T18:46:32Z","timestamp":1197571592000},"page":"387-396","source":"Crossref","is-referenced-by-count":86,"title":["GDNF fusion protein for targeted\u2010drug delivery across the human blood\u2013brain barrier"],"prefix":"10.1002","volume":"100","author":[{"given":"Ruben J.","family":"Boado","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuntao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M.","family":"Pardridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2007,12,13]]},"reference":[{"key":"e_1_2_1_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.21120"},{"key":"e_1_2_1_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.21369"},{"key":"e_1_2_1_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/bc060349x"},{"key":"e_1_2_1_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.21602"},{"key":"e_1_2_1_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2004.08.012"},{"key":"e_1_2_1_7_1","doi-asserted-by":"crossref","first-page":"27505","DOI":"10.1074\/jbc.M000306200","article-title":"Binding of GDNF and neurturin to human GDNF family receptor alpha 1 and 2. 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