Intranasal delivery of ESBA105, a TNF-alpha-inhibitory scFv antibody fragment to the brain

• Published in: Journal of neuroimmunology Vol. 215; no. 1; pp. 65 - 72
• Main Authors: Furrer, Esther, Hulmann, Valérie, Urech, David M
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 30.10.2009
• Subjects: Administration, Intranasal; Allergy and Immunology; Animals; Antibody Affinity; Brain - drug effects; Brain - immunology; Brain - metabolism; CNS delivery; Drug Delivery Systems - methods; Humans; Immunoglobulin Fragments - administration & dosage; Immunoglobulin Fragments - metabolism; Intranasal; Local TNF inhibition; Male; Mice; Mice, Inbred BALB C; Neurodegenerative disease; Neurology; Pharmacokinetics; Single-chain antibody fragment; Tissue Distribution - immunology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism; Neurodegenerative disease; CNS delivery; Intranasal; Local TNF inhibition; Pharmacokinetics; Single-chain antibody fragment
• ISSN: 0165-5728; 1872-8421
• DOI: 10.1016/j.jneuroim.2009.08.005

Abstract Intranasal drug administration is an attractive route for targeted delivery of large molecular weight compounds to the central nervous system (CNS). The purpose of this study was to assess the feasibility of this non-invasive application method in mice, for delivery of ESBA105, a TNF-alpha inhibitory single-chain antibody fragment (scFv) with a molecular weight of 26.3 kDa, to the brain. Pharmacokinetic parameters were determined for different brain regions (olfactory bulb, cerebrum, cerebellum, brain stem) and for serum, following both, intranasal and intravenous administrations of 400 μg and 40 μg ESBA105, respectively. ESBA105 efficiently migrated from the nasal cavity to the brain and maximum ESBA105 concentrations ( Cmax ) in the brain were measured between 1.1 and 12.2 μg/mg of the total protein. Although a 10-fold higher dose was given intranasally, systemic exposure was about 33-fold lower for the intranasal route than following systemic application. Addition of a penetration enhancing peptide to the formulation enhanced the delivery of ESBA105 to the olfactory bulb and the cerebrum, without increasing systemic exposure.