Specific killing of lymphoma cells by cytotoxic T-cells mediated by a bispecific diabody.
Antibody fragments produced by bacterial fermentation lack natural effector functions. Bispecific antibody fragments, however, can be endowed with effector functions, for example cell-mediated killing, by binding to and retargeting of cytotoxic cells. Diabodies are a class of engineered antibody fragments with two antigen binding sites, consisting of two associated chains; each chain consists of heavy and light chain variable domains linked by a short polypeptide linker. In contrast to IgG, or other antibody fragments in which the two binding sites can take up a range of orientations and spacings, the diabody structure is more rigid and compact, with the two binding sites separated by 65 łA (less than half the distance in IgG). To establish whether diabodies could also be used in cell-mediated killing, we have explored the use of a bispecific diabody binding to an idiotypic marker on mouse B-cell lymphoma (BCL-1) and to mouse CD3. The bispecific diabody activated naive T-cells and also mediated the specific killing of the lymphoma cells by cytotoxic T-cells. The diabody was less active in T-cell activation but 10-fold more active (w/v) in killing than an analogous bispecific IgG.
Holliger
P
P
MRC Centre for Protein Engineering, Cambridge, UK.
Brissinck
J
J
Williams
R L
RL
Thielemans
K
K
Winter
G
G
D000818:Animals; D018033:Antibodies, Bispecific / Q000096:biosynthesis / Q000737:chemistry; D001483:Base Sequence; D017252:CD3 Complex / Q000276:immunology; D003001:Cloning, Molecular; D003196:Computer Graphics; D006224:Cricetinae; D003602:Cytotoxicity, Immunologic; D017931:DNA Primers; D004926:Escherichia coli; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000737:chemistry; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D015202:Protein Engineering; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D015183:Restriction Mapping; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D018033:Antibodies, Bispecific; D017252:CD3 Complex; D017931:DNA Primers; D007135:Immunoglobulin Variable Region; D011994:Recombinant Proteins