title: Intracellular targeting using bispecific antibodies.
abstract: 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). Fig. 1. Intracellular delivery of effector molecules using bispecific antibodies. A bifunctional carrier is constructed by linking a monoclonal anti-effector antibody to a monoclonal cell-targeting antibody. A noncovalent complex forms when the effector is added and binds to its specific antibody-combining sites. The targeting antibody directs this preformed complex to a distinct receptor site on the cell membrane. Alternatively, cells can be pretreated with the bispecific antibody, allowing the empty combining sites of the cell-bound reagent to be filled by subsequently added effector molecules. Surface-localized complexes quickly enter cells via a receptor-mediated endocytosis pathway. Escape of the effector from the cell vesicle system and passage into the cytosol is achieved but occurs slowly (∼24 h).
authors.affiliation: Boston Biomedical Research Institute, Boston, MA.
authors.forename: V
authors.initials: V
authors.lastname: Raso