THE IMMUNOGENICITY OF THE 7E3 MURINE MONOCLONAL FAB ANTIBODY FRAGMENTVARIABLE REGION IS DRAMATICALLY REDUCED IN HUMANS BY SUBSTITUTION OF HUMAN FOR MURINE CONSTANT REGIONS

A murine monoclonal antibody (7E3) directed against the platelet glyco protein IIb/IIIa was engineered to reduce immunogenicity by substituti ng human for murine constant regions. The chimeric antibody is functio nally identical to the murine antibody in vitro. Results from clinical trials with 7E3 Fab antibody fragments, however, show that the 7E3 va riable region, which elicits the vast majority of the immune response to murine 7E3 Fab, is rendered dramatically less immunogenic (incidenc e reduced from 17% to 1%) when the identical variable region is linked to human rather than murine constant regions. Neither murine nor huma n constant regions were highly immunogenic themselves. We conclude tha t the constant regions of the Fab fragments are critical in modulating the immune response elicited by the linked 7E3 variable region. Becau se naturally occurring antihuman Fab fragment antibodies are prevalent both in the normal human population and in the patient population stu died here, murine 7E3 Fab and chimeric 7E3 Fab may be fundamentally di fferent in their interactions with the human immune system. This diffe rence may be related to the dramatic difference in immunogenicity obse rved between murine 7E3 Fab and chimeric 7E3 Fab.