Comparison of Blood-Brain Barrier Transport of Glial-Derived Neurotrophic Factor (GDNF) and an IgG-GDNF Fusion Protein in the Rhesus Monkey

Abstract

ABSTRACT: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.

Targeting Receptor-Mediated Transport for Delivery of Biologics Across the Blood-Brain Barrier

“…The HIRMAb-scFv was shown to cross the intact BBB as approximately 1% of the ID reached the rhesus monkey brain 2 hours after iv injection (71). Other HIRMAb-protein fusions include GDNF (72, 73), TNFR (74, 75), erythropoietin (76), and paraoxonase-1 (77, 78) all having similar pharmacokinetic parameters as the AGT-181 and HIRMab-scFv when administered to rhesus monkeys.…”

Nanobiotechnology-Based Strategies for Crossing The Blood–Brain Barrier

“…These include direct intracranial delivery of antibodies, disruption of the BBB and conjugation of antibodies to a 'molecular Trojan horse' using NPs [18]. A molecular Trojan horse is an endogenous peptide, or a mAb, used for receptor-mediated transport across the BBB via endogenous peptide future science group Nanobiotechnology-based strategies for crossing the blood-brain barrier Review receptors [19]. As an extension of this approach, substances, such as some enzymes that do not cross the BBB naturally, can be re-engineered and fused with mAbs to form chimeric mAbs that facilitate passage across the BBB [20].…”

Vascular Pathology as a Potential Therapeutic Target in SCI

“…For example, intravenous administration of recombinant GDNF conjugated to a monoclonal antibody raised against human insulin receptor (HIRMAb-GDNF) greatly enhances BBB penetrance and significantly reduces stroke infarct volume in rats [18]. A similar approach using a similarly engineered recombinant BDNF (HIRMAb-BDNF) results in significantly enhanced brain uptake in primates [17] and improves neuroprotection following experimental stroke in rat [180]. Lastly, intraparenchymal injection of an EPO-HIRAb fusion protein greatly reduces neurologic deficit following permanent middle cerebral artery occlusion in the rat [50].…”