A therapeutic human anti-idiotypic antibody mimics CD55 in three distinct regions.
The human anti-idiotypic antibody 105AD7 was isolated from a colorectal cancer patient receiving the anti-tumor antibody 791T/36 for radioimmuno-scintigraphy of liver metastases. We have mapped the binding site of 791T/36 to the first two small consensus repeat (SCR) domains of the complement regulatory protein (CD55) that is overexpressed by a wide range of solid tumors. Cloning of both antigen and anti-idiotype has identified the molecular basis of their mimicry. Amino acid homology has been identified between three complementarity-determining regions of 105AD7 and three regions of CD55 within the first two SCR domains. 791T/36 and anti-anti-idiotypic (Ab3) polyclonal antibodies raised against 105AD7 showed specific binding to these peptides. The antibodies were also found to bind synergistically to combinations of these peptides, indicating cooperativity between the peptides in stabilizing antibody binding. This also implies that the contact face on both CD55 antigen and 105AD7 is generated by the cooperation of several peptides positioned on two domains in each protein. Thus a human monoclonal anti-idiotypic antibody generated by a cancer patient is able to show both amino acid and structural homology with the complement regulatory protein CD55. These findings help identify the mechanism by which a human anti-idiotypic antibody is able to mimic a tumor-associated antigen and stimulate anti-tumor B and T cell responses.
Spendlove
L
L
CRC Academic Unit of Clinical Oncology, University of Nottingham, City Hospital, GB. Ian.Spendlove@Nottingham.ac.uk
Li
L
L
Potter
V
V
Christiansen
D
D
Loveland
B E
BE
Durrant
L G
LG
D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000627:therapeutic use; D000595:Amino Acid Sequence; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000276:immunology*; D000937:Antigen-Antibody Reactions; D015703:Antigens, CD / Q000737:chemistry; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D001666:Binding Sites, Antibody; D018958:CD55 Antigens / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D016466:CHO Cells; D003001:Cloning, Molecular; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000628:therapy; D006224:Cricetinae; D005803:Genes, Immunoglobulin; D006801:Humans; D007106:Immune Sera / Q000276:immunology; D007111:Immunity, Cellular; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000556:secondary; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016719:Radioimmunodetection; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000276:immunology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D000276:Adjuvants, Immunologic; D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D000951:Antigens, Neoplasm; C497857:CD46 protein, human; D018958:CD55 Antigens; D007106:Immune Sera; D007135:Immunoglobulin Variable Region; C497859:Mcp protein, mouse; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins