The x-ray structure of an anti-tumour antibody in complex with antigen.
The crystal structures of the murine BR96 Fab and its human chimera have been determined in complex with the nonoate methyl ester derivative of Lewis Y (nLey) at 2.8 A and 2.5 A resolution, respectively. BR96 binds the carbohydrate in a large pocket which is formed by residues of all CDR loops except L2. The binding of the carbohydrate is mediated predominantly by aromatic residues in BR96. Analysis of the structure suggests that BR96 is capable of recognizing a structure larger than the Le(y) tetrasaccharide, providing a possible explanation for its high tumour selectivity. The structure provides a rationale for mutagenesis experiments that have resulted in BR96 CDR loop mutants with increased affinity for nLey and/or tumour cells.
Jeffrey
P D
PD
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Bajorath
J
J
Chang
C Y
CY
Yelton
D
D
Hellström
I
I
Hellström
K E
KE
Sheriff
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D000912:Antibodies, Neoplasm / Q000737:chemistry* / Q000276:immunology / Q000627:therapeutic use; D001666:Binding Sites, Antibody / Q000502:physiology; D002240:Carbohydrate Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D007983:Lewis Blood Group Antigens / Q000737:chemistry* / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009154:Mutation; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000276:immunology
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D007140:Immunoglobulin Fab Fragments; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D011993:Recombinant Fusion Proteins