PT  - JOURNAL ARTICLE
AU  - Ruben J. Boado
AU  - William M. Pardridge
TI  - Comparison of Blood-Brain Barrier Transport of Glial-Derived Neurotrophic Factor (GDNF) and an IgG-GDNF Fusion Protein in the Rhesus Monkey
AID  - 10.1124/dmd.109.028787
DP  - 2009 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 2299--2304
VI  - 37
IP  - 12
4099  - http://dmd.aspetjournals.org/content/37/12/2299.short
4100  - http://dmd.aspetjournals.org/content/37/12/2299.full
SO  - Drug Metab Dispos2009 Dec 01; 37
AB  - The brain drug development of glial-derived neurotrophic factor (GDNF) is prevented by the lack of transport of this protein across the blood-brain barrier (BBB). GDNF transport across the BBB can be made possible by re-engineering the neurotrophin as a fusion protein with a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR), which crosses the BBB on the endogenous insulin receptor. The present work was designed to compare the BBB transport in vivo of GDNF and the HIR MAb-GDNF fusion protein. Owing to species specificity of HIR MAb binding to the insulin receptor, the present studies were performed in the adult rhesus monkey. The brain uptake of human IgG1 was determined to assess the uptake of a brain plasma volume marker. The brain clearance of GDNF was no different from the clearance of the IgG1, which indicated GDNF does not cross the primate BBB in vivo. In contrast, BBB transport of the HIR MAb-GDNF fusion protein was shown with film and emulsion autoradiography, as well as the capillary depletion method. In parallel with the increased brain uptake, fusion of the GDNF to the HIR MAb resulted in a decrease in the uptake of GDNF by liver, spleen, and kidney. Administration of the HIR MAb-GDNF fusion protein had no effect on glycemic control. The brain uptake parameters show that a systemic dose of the HIR MAb-GDNF fusion protein of 0.2 mg/kg may generate a 10-fold increase in the cerebral concentration of GDNF in the human brain.Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics