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Protein Engineering, Vol. 12, No. 9, 787-796, September 1999
© 1999 Oxford University Press

Genetically engineered brain drug delivery vectors: cloning, expression and in vivo application of an anti-transferrin receptor single chain antibody–streptavidin fusion gene and protein

Jian Yi Li, Keijiro Sugimura1, Ruben J.Boado, Hwa Jeong Lee, Crystal Zhang, Stefan Duebel2 and William M.Pardridge3

Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90095, USA and 2 Institute for Molecular Genetics, University of Heidelberg, Heidelberg, Germany

A single chain Fv antibody–streptavidin fusion protein was expressed and purified from bacterial inclusion bodies following cloning of the genes encoding the variable region of the heavy chain and light chain of the murine OX26 monoclonal antibody to the rat transferrin receptor. The latter undergoes receptor mediated transcytosis through the brain capillary endothelial wall in vivo, which makes up the blood–brain barrier (BBB); therefore, the OX26 monoclonal antibody and its single chain Fv analog may act as brain drug delivery vectors in vivo. Attachment of biotinylated drugs to the antibody vector is facilitated by production of the streptavidin fusion protein. The bi-functionality of the OX26 single chain Fv antibody–streptavidin fusion protein was retained, as the product both bound biotin and the rat transferrin receptor in vitro and in vivo, based on pharmacokinetic and brain uptake analyses in anesthetized rats. The attachment of biotin–polyethyleneglycol–fluorescein to the OX26 single chain Fv antibody–streptavidin fusion protein resulted in illumination of isolated rat brain capillaries in confocal fluorescent microscopy. In conclusion, these studies demonstrate that genetically engineered single chain Fv antibody–streptavidin fusion proteins may be used for non-invasive neurotherapeutic delivery to the brain using endogenous BBB transport systems such as the transferrin receptor.

Keywords: blood–brain barrier/drug delivery/single chain antibody/streptavidin

1 Present address: Suntory Institute for Biomedical Research, Osaka, Japan

3 To whom correspondence should be addressed


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