Elimination of the immunogenicity of therapeutic antibodies.

Journal article

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.

Authors: Gilliland, L; Walsh, L; Frewin, MR; Wise, M; Tone, M

• Publication status: Published
• Journal: Journal of Immunology
• Volume: 162
• Issue: 6
• Pages: 3663-3671
• Publication date: 1999-03-01
• EISSN: 1550-6606
• ISSN: 0022-1767
• Language: English
• Keywords: Protein Engineering; Antigens; Lymphocyte Depletion; Cricetinae; Binding Sites, Antibody; Injections, Intraperitoneal; Immunoglobulin Variable Region; Humans; Immune Tolerance; Antibodies, Monoclonal, Humanized; Mice, Transgenic; Antibodies, Anti-Idiotypic; Animals; Mutagenesis, Site-Directed; Antibodies, Monoclonal; Antibodies, Neoplasm; T-Lymphocytes; Cell Line; Mice