An Antibody-Avidin Fusion Protein Specific for the Transferrin Receptor Serves as a Delivery Vehicle for Effective Brain Targeting: Initial Applications in Anti-HIV Antisense Drug Delivery to the Brain

• Published in: The Journal of immunology (1950) 1999-10, Vol.163 (8), p.4421-4426
• Main Authors: Penichet, Manuel L, Kang, Young-Sook, Pardridge, William M, Morrison, Sherie L, Shin, Seung-Uon
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Animals; Anti-HIV Agents - metabolism; Antibody Specificity - genetics; Avidin - genetics; Avidin - metabolism; Biotin - blood; Biotin - pharmacokinetics; Brain - immunology; Brain - metabolism; Gene Targeting; Humans; Immunoglobulin Constant Regions - genetics; Immunoglobulin Constant Regions - metabolism; Immunoglobulin G - genetics; Immunoglobulin G - metabolism; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Heavy Chains - metabolism; Iodine Radioisotopes - pharmacokinetics; Male; Mice; Oligonucleotides, Antisense - metabolism; Peptide Nucleic Acids - pharmacokinetics; Rats; Rats, Sprague-Dawley; Receptors, Transferrin - genetics; Receptors, Transferrin - immunology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - metabolism; Tritium
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.163.8.4421

In the present study a novel Ab-avidin fusion protein has been constructed to deliver biotinylated compounds across the blood brain barrier. This fusion molecule consists of an Ab specific for the transferrin receptor genetically fused to avidin. The Ab-avidin fusion protein (anti-TfR IgG3-CH3-Av) expressed in murine myeloma cells was correctly assembled and secreted and showed both Ab- and avidin-related activities. In animal models, it showed much longer serum half-life than the chemical conjugate between OX-26 and avidin. Most importantly, this fusion protein demonstrated superior [3H]biotin uptake into brain parenchyma in comparison with the chemical conjugate. We also delivered a biotinylated 18-mer antisense peptide-nucleic acid specific for the rev gene of HIV-1 to the brain. Brain uptake of the HIV antisense drug was increased at least 15-fold when it was bound to the anti-TfR IgG3-CH3-Av, suggesting its potential use in neurologic AIDS. This novel Ab fusion protein should have general utility as a universal vehicle to effectively deliver biotinylated compounds across the blood-brain barrier for diagnosis and/or therapy of a broad range of CNS disorders such as infectious diseases, brain tumors as well as Parkinson's and Huntington's diseases.