Abstract
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.
Footnotes
This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R01-NS065917].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.038349.
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ABBREVIATIONS:
- GDNF
- glial-derived neurotrophic factor
- BBB
- blood-brain barrier
- MAb
- monoclonal antibody
- TfR
- transferrin receptor
- MTH
- molecular Trojan horse
- HIR
- human insulin receptor
- HIRMAb
- engineered MAb against the HIR
- cTfRMAb
- chimeric MAb against the mouse TfR
- GFR
- GDNF receptor
- ID
- injected dose
- NAb
- TfR-neutralizing antibody
- ELISA
- enzyme-linked immunosorbent assay
- CHO
- Chinese hamster ovary
- AUC
- area under the concentration curve
- PS
- permeability-surface area
- PBS
- phosphate-buffered saline
- PBSB
- phosphate-buffered saline containing 1% bovine serum albumin.
- Received January 24, 2011.
- Accepted April 18, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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