1.9 A structure of the therapeutic antibody CAMPATH-1H fab in complex with a synthetic peptide antigen.
CAMPATH-1 antibodies have a long and successful history in the treatment of leukaemia, autoimmune disease and transplant rejection. The first antibody to undergo "humanisation", CAMPATH-1H, permits treatment with limited patient anti-globulin response. It recognises the CD52 antigen which is a small glycosylphosphatidylinositol(GPI)-anchored protein expressed on lymphocytes and mediates cell depletion. We present the 1.9 A structure of the CAMPATH-1H Fab complexed [corrected] with an analogue of the antigenic determinant of CD52. Analysis of the CAMPATH-1H binding site reveals that in contrast to most antibodies CDR L3 plays a dominant role in antigen binding. Furthermore CDR H3, which is essential for effective antigen recognition in most antibodies, participates in only two main-chain interactions in CAMPATH-1H. The CAMPATH-1H binding site is highly basic; ionic interaction with the enthanolamine phosphate of the CD52 GPI anchor has long been hypothesised to be important in antigen binding. The structure reveals a number of important specific ionic interactions, including Lys53H but not Lys52bH as had previously been suggested. Prolonged treatment with CAMPATH-1H can lead to patient anti-idiotype responses which may be exacerbated by the unusually high number of basic residues in the antibody. This suggests that a strategy where redundant basic residues are replaced with neutral counterparts may be effective in further reducing the immunogenicity of this versatile and widely used antibody.
James
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MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK.
Hale
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Waldmann
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Bloomer
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AC
Waldman
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D000074323:Alemtuzumab; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000737:chemistry*; D015703:Antigens, CD / Q000737:chemistry / Q000276:immunology; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000737:chemistry; D001666:Binding Sites, Antibody; D000074301:CD52 Antigen; D016466:CHO Cells; D003196:Computer Graphics; D006224:Cricetinae; D018360:Crystallography, X-Ray; D006023:Glycoproteins / Q000737:chemistry / Q000276:immunology; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry; D014162:Transfection
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000074301:CD52 Antigen; D006023:Glycoproteins; D007140:Immunoglobulin Fab Fragments; D011994:Recombinant Proteins; D000074323:Alemtuzumab