THE X-RAY STRUCTURE OF AN ANTITUMOR ANTIBODY IN COMPLEX WITH ANTIGEN

The crystal structures of the murine BR96 Fab and its human chimera ha ve been determined in complex with the nonoate methyl ester derivative of Lewis Y (nLe(Y)) at 2.8 Angstrom and 2.5 Angstrom resolution, resp ectively. BR96 binds the carbohydrate in a large pocket which is forme d by residues of all CDR loops except L2. The binding of the carbohydr ate is mediated predominantly by aromatic residues in BR96. Analysis o f the structure suggests that BR96 is capable of recognizing a structu re larger than the Le(Y) tetrasaccharide, providing a possible explana tion for its high tumour selectivity. The structure provides a rationa le for mutagenesis experiments that have resulted in BR96 CDR loop mut ants with increased affinity for nLe(Y) and/or tumour cells.