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Elimination of the Immunogenicity of Therapeutic Antibodies¹

Lisa K. Gilliland^*, Louise A. Walsh, Mark R. Frewin^*, Matt P. Wise^*, Masahide Tone^*, Geoff Hale^*, Dimitris Kioussis and Herman Waldmann^2,*

^* Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom; Department of Pathology, University of Cambridge, Cambridge, United Kingdom; and Division of Molecular Immunology, National Institute for Medical Research, London, United Kingdom

The immunogenicity of therapeutic Abs limits their long-term use. The processes of complementarity-determining region grafting, resurfacing, and hyperchimerization diminish mAb immunogenicity by reducing the number of foreign residues. However, this does not prevent anti-idiotypic and anti-allotypic responses following repeated administration of cell-binding Abs. Classical studies have demonstrated that monomeric human IgG is profoundly tolerogenic in a number of species. If cell-binding Abs could be converted into monomeric non-cell-binding tolerogens, then it should be possible to pretolerize patients to the therapeutic cell-binding form. We demonstrate that non-cell-binding minimal mutants of the anti-CD52 Ab CAMPATH-1H lose immunogenicity and can tolerize to the "wild-type" Ab in CD52-expressing transgenic mice. This finding could have utility in the long-term administration of therapeutic proteins to humans.

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