Intracellular Targeting Using Bispecific Antibodies

The technological development and application of bispecific antibodies for biological research have advanced steadily since the idea of creating hybrid reagents with dual specificity was first promulgated by Nisonoff and Rivers (1 ). It was realized that appropriately designed bispecific antibodies could provide a unique means for selectively delivering biologically active agents onto the surface of target cells so that they could ultimately be internalized (2 –7 ). Hybrid constructs developed in my laboratory used a specific antibody to reversibly bind the effector molecule within its combining site, whereas the second antibody or ligand component accurately targeted the complex to selected sites on the cell membrane Fig. 1 ). Those target receptor sites, along with the attached hybrid antibody complex, are subsequently taken inside the cell via receptor-mediated endocytosis. Cytotoxic drugs and toxins were chosen for delivery via the bispecific reagent because the entry of these potent molecules into target cells is signaled by an easily measured intracellular activity (2 –7 ).