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

Pardridge WM, Boado RJ - Pharm. Res. (2009)

Bottom Line: However, GDNF does not cross the blood-brain barrier (BBB).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.

View Article: PubMed Central - PubMed

Affiliation: ArmaGen Technologies, Inc., 914 Colorado Ave., Santa Monica, California 90401, USA. wpardridge@armagen.com

ABSTRACT

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.

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Related in: MedlinePlus

Plasma glucose in 4 treatment groups of Rhesus monkeys at the pre-test, and various times after the bolus IV injection of 0–10 mg/kg of the HIRMAb-GDNF fusion protein. Data are mean ± S.D. (n = 6–10 animals per group). There are no significant changes in plasma glucose among the treatment groups.
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Fig1: Plasma glucose in 4 treatment groups of Rhesus monkeys at the pre-test, and various times after the bolus IV injection of 0–10 mg/kg of the HIRMAb-GDNF fusion protein. Data are mean ± S.D. (n = 6–10 animals per group). There are no significant changes in plasma glucose among the treatment groups.

Mentions: The 32 Rhesus monkeys in the multiple-dose, 2-week terminal toxicity study were administered 0, 0.4, 2.0, or 10.0 mg/kg of the HIRMAb-GDNF fusion protein every 12 h for 5 consecutive doses, or 0, 2, 10, or 50 mg/kg of the fusion protein. Administration of the study drug was associated with no deaths, no clinical findings, no change in food intake, no change in body or organ weights, and no change in 40 clinical pathology blood or urine tests (Methods). There was no change in glycemic control in any of the four treatment groups (Fig. 1). There were no macroscopic or microscopic changes in peripheral organs, and no macroscopic or microscopic changes in the brain (cerebrum, cerebellum, spinal cord), based on hematoxylin & eosin staining, GFAP immunocytochemistry, or fluoro Jade B fluorescence microscopy. An additional 24 Rhesus monkeys were evaluated in a single-dose safety pharmacology study, which showed no changes in continuous ECG telemetry, pulmonary function tests, arterial blood gases, or neurobehavioral functional observational battery. No increases in cardiac troponin I in plasma were detected.Fig. 1


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

Pardridge WM, Boado RJ - Pharm. Res. (2009)

Plasma glucose in 4 treatment groups of Rhesus monkeys at the pre-test, and various times after the bolus IV injection of 0–10 mg/kg of the HIRMAb-GDNF fusion protein. Data are mean ± S.D. (n = 6–10 animals per group). There are no significant changes in plasma glucose among the treatment groups.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2737114&req=5

Fig1: Plasma glucose in 4 treatment groups of Rhesus monkeys at the pre-test, and various times after the bolus IV injection of 0–10 mg/kg of the HIRMAb-GDNF fusion protein. Data are mean ± S.D. (n = 6–10 animals per group). There are no significant changes in plasma glucose among the treatment groups.
Mentions: The 32 Rhesus monkeys in the multiple-dose, 2-week terminal toxicity study were administered 0, 0.4, 2.0, or 10.0 mg/kg of the HIRMAb-GDNF fusion protein every 12 h for 5 consecutive doses, or 0, 2, 10, or 50 mg/kg of the fusion protein. Administration of the study drug was associated with no deaths, no clinical findings, no change in food intake, no change in body or organ weights, and no change in 40 clinical pathology blood or urine tests (Methods). There was no change in glycemic control in any of the four treatment groups (Fig. 1). There were no macroscopic or microscopic changes in peripheral organs, and no macroscopic or microscopic changes in the brain (cerebrum, cerebellum, spinal cord), based on hematoxylin & eosin staining, GFAP immunocytochemistry, or fluoro Jade B fluorescence microscopy. An additional 24 Rhesus monkeys were evaluated in a single-dose safety pharmacology study, which showed no changes in continuous ECG telemetry, pulmonary function tests, arterial blood gases, or neurobehavioral functional observational battery. No increases in cardiac troponin I in plasma were detected.Fig. 1

Bottom Line: However, GDNF does not cross the blood-brain barrier (BBB).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.

View Article: PubMed Central - PubMed

Affiliation: ArmaGen Technologies, Inc., 914 Colorado Ave., Santa Monica, California 90401, USA. wpardridge@armagen.com

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus