TY - JOUR T1 - Chronic Dosing of Mice with a Transferrin Receptor Monoclonal Antibody-Glial-Derived Neurotrophic Factor Fusion Protein JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1149 LP - 1154 DO - 10.1124/dmd.111.038349 VL - 39 IS - 7 AU - Qing-Hui Zhou AU - Ruben J. Boado AU - Eric Ka-Wai Hui AU - Jeff Zhiqiang Lu AU - William M. Pardridge Y1 - 2011/07/01 UR - http://dmd.aspetjournals.org/content/39/7/1149.abstract N2 - Glial-derived neurotrophic factor (GDNF) is a potential neurotrophic factor treatment of brain disorders, including Parkinson's disease. However, GDNF does not cross the blood-brain barrier (BBB). A brain-penetrating form of GDNF, which is a fusion protein of human GDNF and a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), has been engineered for the mouse and is designated the cTfRMAb-GDNF fusion protein. The present study examined the potential toxic side effects and immune response after treatment of mice with twice-weekly cTfRMAb-GDNF fusion protein at a dose of 2 mg/kg i.v. for 12 consecutive weeks. Chronic treatment with the fusion protein caused no change in body weight, no change in 23 serum chemistry measurements, and no histologic changes in brain and cerebellum, kidney, liver, spleen, heart, or pancreas. Chronic treatment caused a low-titer immune response against the fusion protein, which was directed against the variable region of the antibody part of the fusion protein, with no immune response directed against either the constant region of the antibody or against GDNF. A pharmacokinetics and brain uptake study was performed at the end of the 12 weeks of treatment. There was no change in clearance of the fusion protein mediated by the TfR in peripheral organs, and there was no change in BBB permeability to the fusion protein mediated by the TfR at the BBB. The study shows no toxic side effects from chronic cTfRMAb-GDNF systemic treatment and the absence of neutralizing antibodies in vivo. ER -