Elimination of the immunogenicity of therapeutic antibodies.
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.
Gilliland
L K
LK
Sir William Dunn School of Pathology, University of Oxford, United Kingdom.
Walsh
L A
LA
Frewin
M R
MR
Wise
M P
MP
Tone
M
M
Hale
G
G
Kioussis
D
D
Waldmann
H
H
D000074323:Alemtuzumab; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D000941:Antigens / Q000378:metabolism; D001666:Binding Sites, Antibody / Q000235:genetics; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008212:Lymphocyte Depletion; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D015202:Protein Engineering / Q000379:methods*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000941:Antigens; D007135:Immunoglobulin Variable Region; D000074323:Alemtuzumab