Intracellular antibody-caspase-mediated cell killing: An approach for application in cancer therapy

Antibodies have been expressed inside cells in an attempt to ablate the fun ction of oncogene products. To make intracellular antibodies more generally applicable and effective in cancer therapy, we have: devised a method in w hich programmed cell death or apoptosis can be triggered by specific antibo dy-antigen interaction, When intracellular antibodies are linked to caspase 3, the "executioner" in the apoptosis pathway, and bind to the target anti gen, the caspase 3 moieties are self-activated and thereby induce cell kill ing. We have used this strategy in a model system with two pairs:of intrace llular antibodies and antigens. In vivo coexpression of an antibody-caspase 3 fusion with its antigenic target induced apoptosis that was specific for antibody, antigen, and active caspase 3. Moreover, the antibody-caspase 3 fusion protein was not toxic to cells in the absence of antigen. Therefore, intracellular antibody-mediated apoptosis should be useful as a specific t herapeutic approach for the treatment of cancers, a situation where target cell killing is required.