Pharmacokinetics and safety in rhesus monkeys of a monoclonal antibody-GDNF fusion protein for targeted blood-brain barrier delivery

Pharm Res. 2009 Oct;26(10):2227-36. doi: 10.1007/s11095-009-9939-6. Epub 2009 Jul 17.


Purpose: Glial-derived neurotrophic factor (GDNF) is a potential therapy for stroke, Parkinson's disease, or drug addiction. However, GDNF does not cross the blood-brain barrier (BBB). GDNF is re-engineered as a fusion protein with a chimeric monoclonal antibody (MAb) to the human insulin receptor (HIR), which acts as a molecular Trojan horse to deliver the GDNF across the BBB. The pharmacokinetics (PK), toxicology, and safety pharmacology of the HIRMAb-GDNF fusion protein were investigated in Rhesus monkeys.

Methods: The fusion protein was administered as an intravenous injection at doses up to 50 mg/kg over a 60 h period to 56 Rhesus monkeys. The plasma concentration of the HIRMAb-GDNF fusion protein was measured with a 2-site sandwich ELISA.

Results: No adverse events were observed in a 2-week terminal toxicology study, and no neuropathologic changes were observed. The PK analysis showed a linear relationship between plasma AUC and dose, a large systemic volume of distribution, as well as high clearance rates of 8-10 mL/kg/min.

Conclusions: A no-observable-adverse-effect level is established in the Rhesus monkey for the acute administration of the HIRMAb-GDNF fusion protein. The fusion protein targeting the insulin receptor has a PK profile similar to a classical small molecule.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / pharmacokinetics*
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Delivery Systems / methods*
  • Female
  • Glial Cell Line-Derived Neurotrophic Factor / administration & dosage
  • Glial Cell Line-Derived Neurotrophic Factor / adverse effects
  • Glial Cell Line-Derived Neurotrophic Factor / pharmacokinetics*
  • Macaca mulatta
  • Male
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / adverse effects
  • Recombinant Fusion Proteins / pharmacokinetics*


  • Antibodies, Monoclonal
  • Glial Cell Line-Derived Neurotrophic Factor
  • Recombinant Fusion Proteins