Passive and catalytic antibodies and drug delivery*

Antibodies are one of the most promising components of the biotechnology repertoire for the purpose of drug delivery. On the one hand, they are proven agents for cell-selective delivery of highly toxic agents in a small but expanding number of cases. This technology calls for the covalent attachment of the cytotoxin to a tumor-specific antibody by a linkage that is reversible under appropriate conditions (antibody conjugate therapy, ACT— “passive delivery”). On the other hand, the linker cleavage can be accomplished by a protein catalyst attached to the tumor-specific antibody (“catalytic delivery”). Where the catalyst is an enzyme, this approach is known as antibody-directed enzyme prodrug therapy (ADEPT). Where the transformation is brought about by a catalytic antibody, it has been termed antibody-directed abzyme prodrug therapy (ADAPT). These approaches will be illustrated with emphasis on how their demand for new biotechnology is being realized by structure-based protein engineering.